National Institute on Drug Abuse
RESEARCH
MONOGRAPH SERIES
Problems of Drug
Dependence 1997:
Proceedings of the
59th Annual Scientific
Meeting
The College on Problems
of Drug Dependence, Inc.
178
U.S. Department of Health and Human Services • National Institutes of Health
BOARD OF DIRECTORS
Scott E. Lukas, Ph.D.
Billy R. Martin, Ph.D.
A. Thomas McLellan, Ph.D.
Roy W. Pickens, Ph.D.
Frank Porreca, Ph.D.
Beny J. Primm, M.D.
Peter Reuter, Ph.D.
Sidney H. Schnoll, M.D., Ph.D.
Charles R. Schuster, Ph.D.
James E. Smith, Ph.D.
Maxine L. Stitzer, Ph.D.
Alice M. Young, Ph.D.
Steven G. Holtzman, Ph.D., President
Linda A. Dykstra, Ph.D., President-elect
Robert L. Balster, Past-president
George E. Bigelow, Ph.D., Treasurer
Richard Bonnie, L.L.B.
Linda B. Cottler, Ph.D., M.P.H.
Harriet de Wit, Ph.D.
Avram Goldstein, M.D.
Dorothy Hatsukami, Ph.D.
John Hughes, M.D.
M. Ross Johnson, Ph.D.
Michael J. Kuhar, Ph.D.
EXECUTIVE OFFICER
Martin W. Adler, Ph.D.
SCIENTIFIC PROGRAM COMMITTEE
Thomas R. Kosten, Chair
Martin W. Adler
James Anthony
Maureen Bronson
Kathryn A. Cunningham
Ellen B. Geller
M. Ross Johnson
Reese T. Jones
Mary J. Kreek
Sidney H. Schnoll
Charles R. Schuster
Maxine L. Stitzer
George R. Uhl
i
TABLE OF CONTENTS
PLENARY SESSION
In Memoriam: Sydney Archer, Ph.D. - January 23, 1926 - August 22, 1997
J. M. Bidlack
1
The National Institute on Drug Abuse:
A. I. Leshner
3
Introduction of the Nathan B. Eddy Memorial Award Recipient
W. L. Dewey
9
Nathan B. Eddy Award Lecture
M. W. Adler
11
SYMPOSIUM IV
Opioids and Neuropeptides in Immune Function and Host Defenses Against Retroviruses
T. Eisenstein and J. Madden, Chairpersons
23
SYMPOSIUM V
The Effects of Prenatal Cocaine Exposure on CNS Development
S. Mackler, Choir
27
SYMPOSIUM VI
Drugs of Abuse, Impulsivity and Risk Taking
H. de Wit and Gene Heyman, Chairpersons
30
SYMPOSIUM VII
Recent Progress in Transporter Research
M. Kuhar and J. Justice, Chairpersons
33
SYMPOSIUM VIII
Drug Dependence and the Genome
T. Kosten, Chair
36
SYMPOSIUM IX
Current HIV and Drug Abuse Prevention Research Findings and Future Directions
S. Coyle and R. Needle, Chairpersons
39
SYMPOSIUM X
Approaches to the Molecular Genetics of Drug Abuse
George Uhl, Chair
40
SYMPOSIUM XI
Ethical Laboratory Research with Humans: The Devil is in the Details
M. Fischman and C.-E. Johanson, Chairpersons
41
SYMPOSIUM XIII
Novel Applications of Human Drug Discrimination of Understanding Effects
C. Rush and J. Kamien, Chairpersons
45
ii
SYMPOSIUM XIV
PTSD and Substance Abuse: Nosology, Epidemiology, Genetics and Neurobiology
N. Breslau and R. Price, Chairpersons
48
SYMPOSIUM XV
HIV in the Brain
B. Hoffer, Choir
52
SYMPOSIUM XVI
Combined Cocaine and Opioid Abuse: From Neurobiology to the Clinic
S. S. Negus and 1. Rowlett, Chairpersons
55
WORKSHOPS
Making Audiences AMAZED, Not GLAZED: Techniques for Improving Presentations
R. Eisenberg and F. George, Chairpersons
58
Food, Sex and Drug Incentives: Implications of a Common Substrate for Development of
Anti-Craving Medications
59
F. Vocci, A. R. Childress, Chairpersons
Fighting Back - Community Interventions to Reduce Drug Abuse
R. S. Schottenfeld and C. Winick, Chairpersons
61
ORAL COMMUNICATIONS I
Nicotine: Laboratory and Clinical Studies
64
ORAL COMMUNICATIONS II
Marijuana:
Clinical Studies
68
ORAL COMMUNICATIONS III
Benzodiazepines
72
ORAL COMMUNICATIONS IV
Medicinal Chemistry: Cocaine and Opioids
76
ORAL COMMUNICATIONS V
Neurobiology of Stimulants
81
ORAL COMMUNICATIONS VI
Analgesia
85
ORAL COMMUNICATIONS VII
Treatment for Opioid Dependence
89
ORAL COMMUNICATIONS VIII
Cannahinoids: Chemistry, Receptors and Behavior
93
ORAL COMMUNICATIONS IX
Treatment for Stimulant Addictions
96
iii
ORAL COMMUNICATIONS X
HIV/AIDS: Risk Behaviors
101
ORAL COMMUNICATIONS XI
Effects of Stimulants in Human Subjects
104
ORAL COMMUNICATIONS XII
Opioids: Behavioral Studies
107
ORAL COMMUNICATIONS XIII
Effects on the Immune System
112
ORAL COMMUNICATIONS XIV
Alcohol
118
ORAL COMMUNICATIONS XV
Perinatal Substance Abuse
122
ORAL COMMUNICATIONS XVI
Opioid Receptors and Signal Transduction
126
ORAL COMMUNICATIONS XVII
Psychiatric Comorbidity in Drug Abusers
129
ORAL COMMUNICATIONS XVIII
Drug Use in Pregnancy
133
POSTER SESSION I
Treatment of Cocaine Dependence
Imaging
Nicotine
Opioids: Chemistry, Molecular Biology, Physiology and Behavior
Benzodiazepines and Barbiturates
HIV/AIDS: Risk Prevention
137
POSTER SESSION II
HIV/AIDS: Risk Reduction, Testing, Treatment, CNS Effects
Drug Effects on Immune Function and Health
Cardiovascular Effects of Cocaine
Cocaine: Behavior
Pharmacokinetics: Drug Testing
Analgesia
PCP, NMDA and Sigma Receptors; Inhalants
Marijuana, Cannabinoids
187
iv
241
POSTER SESSIONS III
Alcohol
Family Risk Factors
Adolescents
Comorbidity of Substance Abuse and Psychiatric Disorders
Drugs and Crime
Employment
Research Design and Analysis
Dopamine and Serotonin
Caffeine
POSTER SESSIONS IV
288
Amphetamines
Cocaine: Motor Effects
Treatment for Opiate Dependence
Polydrug Abuse
Drug Abuse in Women
Substance Abuse in Pregnancy
L A T E ABSTRACTS
344
ANNUAL REPORTS
BIOLOGICAL EVALUATION OF COMPOUNDS FOR THEIR PHYSICAL
DEPENDENCE POTENTIAL AND ABUSE LIABILITY. XXI. DRUG EVALUATION
COMMITTEE OF THE COLLEGE ON PROBLEMS OF DRUG DEPENDENCE (1997)
A. E. Jacobson, Biological Coordinator, Drug Evaluation Committee, CPDD
346
DEPENDENCE STUDIES OF NEW COMPOUNDS IN THE RHESUS MONKEY, RAT
AND MOUSE (1997)
M. D. Aceto, E. R. Bowman, L. S. Harris, and E. L. May
363
EVALUATION OF NEW COMPOUNDS FOR OPIOID ACTIVITY (1997)
J. H. Woods, F. Medzihradsky, C. B. Smith, R. R. Butelman, and G. Winger
408
PROGRESS REPORT FROM THE TESTING PROGRAM FOR STIMULANT
AND DEPRESSANT DRUGS (1996)
C. P. France, L. R. Gerak, J. K. Rowlett, W. L. Woolverlon, G. Winger,
and J. H. Woods
429
STANDARD BINDING AND FUNCTIONAL ASSAYS RELATED TO MEDICATIONS
DEVELOPMENT DIVISION TESTING FOR POTENTIAL COCAINE AND OPIATE
NARCOTIC TREATMENT MEDICATIONS
L. Toll, I. P. Berzetei-Gurske, W. E. Polgar, S. R. Brandt, I. D. Adapa,
L. Rodriguez, R. W. Schwartz, D. Haggart, A. O’Brien, A. White,
J. M. Kennedy, K. Craymer, L. Farrington, and J. S. Auh
440
AUTHOR INDEX
467
SUBJECT INDEX
483
v
IN MEMORIAM
SYDNEY ARCHER
January 23, 1917 - August 22, 1997
Dr. Sydney Archer, a Research Professor and former Dean of Science at Rensselaer Polylechnic Institute, died from
a stroke on August 22, 1996 in Albany, New York. Syd, as he was known to his numerous colleagues and friends,
was a Charter Fellow and former member of the Board of Directors of the Committee (now College) on Problems of
Drug Dependence. He was an active participant in CPDD meetings for more man four decades.
Syd was born in Brooklyn on January 23, 1917. He received his B.S. in Chemistry from the University of
Wisconsin in 1937. After completing his Ph.D. in Organic Chemistry at Pennsylvania State University in 1940,
he was a postdoctoral fellow at Northwestern University and the University of Chicago. In 1943, Syd started his
career at Sterling-Winthrop Research Institute as a Research Chemist. He became Director of the Chemistry
Division in 1964, and from 1968 to 1973. Syd was Vice President and Associate Director of Research at SterlingWinthrop. Syd synthesized hundreds of opioids during his tenure at Sterling-Winthrop, including pentazocine and
1
cyclazocine. He was the first to demonstrate that the substitution of a N-cyclopropylmethyl group for the N-methyl
group in the benzomorphan series resulted in compounds displaying antagonist properties. Syd was instrumental in
introducing partial agonists into the opioid field, compounds with both agonist and antagonist properties. In 1968,
he was the recipient of the Medicinal Chemistry Award from the American Chemical Society.
While at working at Sterling-Winthrop, Syd was also an Adjunct Professor at Rensselaer Polytechnic Institute,
teaching medicinal chemistry in the evenings. His lectures on medicinal chemistry were also well known by his
many colleagues, particularly. those that saved on NIDA Study Sections with him. Syd’s enthusiasm for
chemistry and its applications was boundless and contagious.
Upon retiring from Sterling-Winthrop in 1973. Syd launched a second career, as a Research Professor of Medicinal
Chemistry at Rensselaer Polytechnic lnstitute in Troy, New York. He was Dean of the School of Science from
1980 to 1985. Syd played a central role in the creation of the New York State Capital District Center for Drug
Abuse Research and Treatment. Holding more man 100 patents. Syd was named Inventor of the Year by the Eastern
New York Patent Law Association in 1978. For the past two decades, most of his research in the drug abuse field
focused on novel approaches for designing new drugs to treat heroin, cocaine, and alcohol abuse. Also, Syd
synthesized a number of fluorescent opioids. He made key contributions in identifying opioid receptors on immune
cells, and on microglia, the brain’s macrophages, that can become infected with HIV-1. Syd was continuing to
synthesize new compounds up to the time of his death.
Syd will be remembered for his inspiration, boundless enthusiasm, and optimistic outlook. He always focused on
the future and had an endless supply of new ideas and energy. Also, Syd will be remembered for knowing the best
restaurants in the world and for his strong appreciation of classical music. Syd was an extremely supportive
colleague, and I was privileged to collaborate with him for a number of years. Syd is survived by his wife.
Therese, and his three children, David, Eve, and Daniel.
Prepared by: J. M. Bidlack
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY
2
DRUG ABUSE AND ADDICTION: RESEARCH PROGRESS AND FUTURE PROSPECTS
A. I. Leshner
National Institute on Drug Abuse, National Institutes of Health, Rockville, MD
I am extremely happy to be here again this year--to have the opportunity to meet face-to-face with so many of the
talented scientists who are moving the drug abuse and addiction research field forward and to hear about the great
science that you have been doing over the past year. I want to offer my congratulations to the College on Problems
of Drug Dependence (CPDD) as a whole and to Marty Adler for superb leadership efforts in bringing together this
impressive showcase of the state of the science of drug abuse and addiction.
Since I took on the directorship of the National Institute on Drug Abuse (NIDA), three CPDD meetings ago, I have
tried to come up with a different theme each year to bring to the annual meeting. The first year I came, my theme
was ‘I’ve got a secret’. This year I’ve brought a different theme -- ‘the science is going great and people know it.’
What I would like to do this morning is to bring you up to date on some of NIDA’s activities in a variety of areas
and to share with you my perspective on the state of our science and my assessment of the progress we have made
together in bringing public perception and scientific reality about drug abuse and addiction closer to being on the
same track.
First of all I want to talk about some of the things that have been happening in NIDA, as well as some of the things
that have been happening in the field, or, generally, because I think they have enormous relevance to everything that
we are doing. And I want to make sure that everyone is aware of the policy and process issues that may affect your
lives as grantees of the National Institutes of HeaIth (NIH). Let me just take a few minutes to talk about those
issues.
REVIEW ISSUES
As many of you know, there has been a lot of activity surrounding the topic of grant review during the past year,
both at NIDA and within the NIH Division of Research Grants (DRG) as a whole. For example, as part of
reinvention activities and the ongoing effort to maintain high standards for peer review at the NIH, a subcommittee
of the NlH Committee on Improving Peer Review was formed and tasked with examining the process by which
scientific review groups rate grant applications and making recommendations to improve that process. What has
resulted after two years of deliberations has been a change in the criteria for the rating of grant applications to NIH.
Basically, there is an attempt to move away from a focus on the fine details of a proposal and to look at a broader set
of issues, such as the overall impact that the research proposed will have on the field and the approach the
investigator intends to take. Another criterion relates to innovation and creativity and the issue of whether or not
novel approaches will be used in conducting the research. And, of course, the qualifications of the investigator also
weigh heavily in the review process. Obviously, not all criteria will be applied equally to every proposal. But since
all criteria will be looked at by the study section for each proposal, I encourage all of you to become familiar with
them. You can get a description of these new criteria either on the NIDA homepage, the NIH homepage, or the
CPDD homepage. In addition, this information is being sent out with every grant application. Use of the new
criteria began in May and wilI be effective for the September round of Council.
The second item that I want to mention relates to the process that has been going on this year of integrating the
review of neuroscience research grants into the rest of the NIH system. As most of you know, the integration of
NIDA, NIMH and NIAAA into the NIH grant review system has necessitated reexamination of the overall NIH
review in certain areas of scientific investigation, A major objective is to integrate the review of grant applications
from these institutes into the DRG peer review structure. These integration efforts will help to ensure quality peer
review that identifies the most meritorious science for each institute to consider for funding. Basic and clinical
neuroscience research has been the initial focus, with behavioral science to be considered next. What is happening in
the neuroscience area essentially, is that all of the proposals from the seven NIH institutes that fund neuroscience
3
research are being reshuffled into the newly created study sections. At this point, the neuroscience activities are
conceptually complete. I encourage you to look at the desctiptor of those activities on the NIH and the NIDA
homepages.
POLICY ITEMS
There have also been a number of policy areas of importance to the field that we have devoted a significant amount
of time addressing this year. One example here relates to the administration of drugs to human subjects. The
National Advisory Council on Drug Abuse, recognizing the importance of designing, reviewing, and conducting
such research within the fundamental ethical principles governing all biomedical and behavioral research with human
subjects has been working over the past year to develop a set of recommended guidelines. The Council’s guidelines
are not intended to supplant the functions of either the IRB or OPRR but, instead are advisory to applicants, IRBs,
IRGs and others. They are not codified and do not constitute Federal regulation. Rather, the guidelines ate intended
to encourage a sensitive, ethical approach which is also consistent with the best current practices and experience in
the field of drug abuse research They are meant to inform the IRB who obtalns local authority for looking at the
studies about the conditions under which, under normal circumstances, drugs of abuse might be administered to
human subjects. The Council recommends consideration of a number of general issues including risk/benefit,
informed consent, subject selection, and confidentiality as well as a number of specific issues including informed
consent medical and psychological screening and services, administration of drugs to individuals who have never
used drugs, involvement of individuals currently addicted to drugs, drug doses and routes of administration, prior and
current drug treatment status, pregnancy, age of research participants. study personnel training and experience, HIV
risk reduction counseling and testing, safety of research participants outside of the research site, referral to treatment,
incomplete discIosure, and payment for participation in research.
NIDA BUDGET
In terms of our budget, prospects for next year look optimistic. The President’s FY 98 funding request for NIH is
$13.078 billion, including $521.9 million for NIDA--a $32.8 million increase over FY 97. This represents a 6.7%
overall increase for NIDA. against an NIH increase of 2.6%. The purpose of NIDA’s increase is two-fold. About
half of these funds are to be directed to anti-addiction medication development The other half is to be dedicated to
advances in prevention and treatment research. These categories cover essentially everything that NIDA is involved
hi. As I have said before, we are no longer in that era that occurred during the late 1980’s--where an increase of 14%
would be considered meager. In these times of cutbacks and tight budgetary constraints even a 2.6% increase for the
National Institutes of Health is a major statement by the President of his enthusiasm for the work that NM does.
And both Dr. Varmus and Secretary Shalala have been touting the work NIDA supports as something that they
believe in. So I am hopeful that we will be able to hold on to this increase, and, as NIH’s budget may rise in the
process, we will keep our special status as well. This is the direct result of a lot of work by many different people.
And although it may take some time, I think it is clear to all of you that, ultimateIy, the advocacy efforts of your
society really do pay off.
I am hopeful that fiscal year 1998 will turn out well as some rather unusuaI budgetary events ocurred in fiscal year
1997. In total we have received about $11 million added to our budget over the course of the past year. From
General McCafrey, Director of the Office of National Drug Control Policy (ONDCP), we received $4.8 million for
anti-cocaine medication development and another $4.2 million as part of the Resident’s methamphetamine initiative.
Since the total of that initiative is $10 million. the fact that $4.2 million of it came to NIDA. is a statement that
the administration understands that science is a meaningful way to get a handle on the drug problem in this country.
I think that those on the board with whom we met yesterday and the Deputy Director of the ONDCP, would agree
that we are experiencing a very special set of circumstances at this particular point in history, where the
administration actually understands the power of science. I would also add that Dr. Harold Varmus, the Director of
NIH, has also, at his discretion, added $2 million to our funding for anti-cocaine medication development.
4
STATE OF THE SCIENCE
In many ways, science in the area of drug abuse and addiction has had a phenomenal year! And what I would actually
like to do for a few moments is tout the enormous progress the field has been making--thanks largely to your efforts
-and to share with you what I see as a very positive future ahead. In my view, the science that all of you have been
doing and reporting has made this a spectacular year! It is unbelievable to me. having been the NIDA Director now
for three and a half years, how rapidly and how continuously we seem to be acceIerating the rate of advances in this
field. I am very proud and pleased to say we probably know more about drug abuse and addiction than we know
about any other thing that affects the brain directly or indirectly. And although all of us in this room by now are
used to this great rate of advances, I have been having a wonderful time bragging to a variety of different sectors who
are not, as yet, so well informed about our current level of understanding about drug abuse and addiction and the
phenomenal progress that is being made. Even though much of this information is news to these audiences, it is
becoming increasingly evident that we are finally beginning to make some headway in closing the gap between
scientific reality and public perception about drug abuse and addiction.
SHAPING NIDA’S RESEARCH AGENDA
It has been a wonderful year in terms of recognition of the power of science, and you are the vehicle for its practice
The question is how will the money we receive to support drug abuse research best be spent? NIDA continues to
use a variety of mechanisms to further shape our research agenda and to set our course for the future needs of the
field. In addition to the many areas of emphasis already included in our research portfolio. NIDA is also moving
ahead on our three new initiatives for FY 1997-1998 -- the Treatment Initiative, the Methamphetamine Initriative and
the Child and Adolescent Initiative.
Treatment Initiative
Having shown that addiction is a treatable disease. NIDA-supported research has made extensive progress in
developing treatments, both pharmacologic and behavioral, But there is still a great deal more we need to do in this
area. Thus, NIDA is mounting a major treatment initiative which will take therapies (both behavioral and
pharmacologic) that are shown to he effective in small scale studies and evaluate them in large, multi-phased, multisite trials. An equally important part of this initiative will be to close the gap between what we know through
scientific research about the treatment of drug addiction and the public’s perception of drug addiction treatment. This
we hope to accomplish by broadening the dissemination of our research findings.
As part of its Treatment Initiative. NIDA will conduct and disseminate research to improve the efficacy, outcomes,
effectiveness, and accessibility of existing treatments. We will implement the next step of our Behavioral Therapies
Development Program by applying a mum-phased controlled evaluation process to the theory-based behavioral
therapies that were developed in Phase I. Once the therapies are tested in the larger clinical trials, they will be
replicated in real life treatment settings. In addition, NIDA will conduct research to integrate new treatment
medications into existing treatments as well as develop new. comprehensive treatment approaches which involve not
only pharmacotherapies, but behavioral and psychosocial strategies as well. And we will build upon our current
transIational research on treatment in the managed care arena.
The development of effective medications for the treatment of addiction remains a lop priority for NIDA, especially
the development of an anti-cocaine medication and will comprise an important part of our Treatment Initiative. In
the area of medications development NIDA will conduct and support research to identify new and novel molecular
targets to he tested for anticocaine medication development. To find an anti-cocaine medication, NIDA will screen
and test a large number of the available compounds that exist in the compound libraries of pharmaceutical
companies. NIDA’s Medications Development Program will also establish a network of sites capable of delivering
high quality clinical data for multi-phase trials to a variety of targeted populations. And to fully reap health benefits
from the knowledge gained through fundamental clinical trial treatment investigations, NIDA will continue its
efforts to transfer its knowledge and technology to the private sector, where firms like biotechnology and
pharmaceutical companies can produce products that treat or prevent addiction.
5
Methamphetamine Research Initiative
NIDA’s Community Epidemiology Work Croup (CEWG) and other monitoring mechanisms have indicated that
there have heen significant increases in methamphetamine use in specific areas of the country. In fact, half of you in
this room--those of you who have come from the West Coast, undoubtedly understand why methamphetamine use is
such a big issue. Those on the East Coast may not be as aware of it, but in San Diego, methamphetamine has just
passed crack and cocaine as the drug of choice. at least for people who are entering the criminal justice system.
Thus, NIDA has, over the past year, become involved in a variety of activities to help ensure that methamphetamine
use does not become a national epidemic. Knowing that research provides the foundation needed for long-term
solutions to the methamphetamine abuse problem, NIDA is launching a Methamphetamine Research Initiative to
complement existing national efforts. As part of this initiative, NIDA will conduct research that will elucidate the
neurobiological mechanisms of methampbetamine’s actions in the brain and identify molecular targets for possible
medication development. NIDA supported research will also focus on understanding the consequences and long-term
damage of methamphetamine use to the brain, especially the dopamine system, as well as the drug’s effects on other
organ systems. And NIDA will support research to develop methamphetamine prevention programs that are
specifically geared toward the unique charactecristics of the methamphetamine user, as well as treatment approaches
that are specifically tailored for poly-drug addiction to mehamphetamine and other substances.
Child and Adolescent Initiative
The problem of drug abuse among youth is another topic that has received unprecedented attention in recent years.
This is a critical area where translational research is desperately needed. As data from the 1996 Monitoring the
Future Study and other research-based monitoring tools show drug use among youth continues at unacceptable
levels. For this reason. we have launched a Child and Adolescent Initiative the goal of which is to use the basic
science of development to identify the determinants of drug taking behaviors among children and adolescents and
apply these findings to the development of new and improved prevention and treatment approaches. As part of this
initiative, NIDA will support research that identities the pathways leading to drug addiction in children and
adolescents. This research will focus on the risk and protective factors in increasing or decreasing the probability
that a child will become susceptible to addiction. NIDA-supported research will also develop and test prevention
programs that are age appropriate and based on the findings from the study of attitude formation and change. In
addition, NIDA will build its research portfolio to focus on the basic behavioral processes involved in decisionmaking at various stages of child and adolescent development. And NIDA will conduct cognitive research to measure
the impact that peer pressure has on a child’s susceptibility to drug-taking behaviors. The research will also attempt
to determine the interplay between peer pressure and risk and protective factors.
INFORMATION
DISSEMINATION
As I stated earlier, we have been making extraordinary advances in the science of drug abuse and addiction. The
science the field has been producing--much of which will be reported over the course of this meeting--is, in fact,
something in which we can and should take a great deal of pride. But as I mentioned at last year’s meeting, it is
vital that we go beyond doing the science and get the word out about our findings. During the past year we at NIDA
have been engaged in numerous efforts to disseminate the findings of much of your research by sponsoring satellite
symposia at the annual meetings of many professional groups. For example. in August NIDA co-sponsored the
Conference On Drug Abuse (CODA) with the American Psychological Association, Science Directorate, as a
satellite conference to APA’s annual convention. The goal of CODA was to highlight the best in drug abuse and
addiction research and included numerous drug abuse symposia, paper and poster sessions. NIDA also sponsored a
number of satellite symposia held in conjunction with the Society for Neuroscience annual meeting. And as I hope
all of you are well aware, we at NIDA have worked with CPDD on the dedicated HIV/AIDS track that is running
through this meeting covering a multitude of areas relating to AIDS and drug abuse--two epidemics that during the
last decade and a half have become increasingly interlocked.
6
ADVANCES IN CHANGING PUBLIC PERCEPTION
Although the science is going well, advancing the science is only part of what we need to accomplish. The ultimate
worth of our efforts lies in the extent to which our research is useful to those it is intended to help and that the
findings we generate are actually implemented in practice. In addition to generating superb science, NIDA, as well as
many other factions of the drug abuse and addiction field, have continued to work very hard over the past year to
increase public awareness about the nature of drug abuse and addiction and to advance our goal of bridging what I
have calling the “great disconnect” between public perception and scientific reality.
For example. NIDA has organized several more “Town Meetings” entitled “Understanding Drug Abuse and
Addiction: Myths Vs. Reality” in which NIDA researchers discussed ways that state policy makers, organizations.
schools and communities can utilize the latest scientific research to assess state and local drug problems and develop
programs to meet these needs, Thus far, we have held these meetings in Miami and Tampa, Florida; Anchorage
Alaska; Columbus, Ohio; St. Louis, Missouri; Dallas, Texas and Chicago Illinois. In the coming year, we plan to
continue these meetings in several more locations across the country.
We have also been working hard to continue building a constituency for NIDA. As part of this effort, in November
we hosted our Third Annual Constituent Conference where we presented NIDA’s ‘Report Card highlighting specific
actions taken by the Institute in response to constituent group recommendations and discussed strategies to prepare
the field for implementing promising prevention and treatment approaches as they become available.
The first year we held this meeting representatives from 20 groups came: the second year 30 groups were represented;
and this year the number of organizations that participated grew to 40. What we are seeing is the beginning of a
coalescence around the science of drug abuse and addiction, and hopefully. they will be joining with groups like
CPDD in being our support system and also our information diffusion system. We have been going to their
meetings and writing columns for their newsletters. These groups represent the science, the practice, and the
advocacy in lay communities. These meetings have been valuable vehicles for obtaining advice about all kinds of
information we need, and, then, we tell the participants what we have done about their ideas and suggestions. Some
of you have been to these meetings, and they are very interesting. From my perspective, they are very useful
because they certainly keep one grounded in what the issues are and their concern to people who have to the the
problems on the front line
NIDA also sponsored a National Conference on Prevention Research last fall which provided a forum for presenting
the most successful prevention strategies and programs developed through research to prevent and reduce drug abuse
among youth. Much of the research presented and discussed at this conference was then compiled by NIDA into the
first research-based guide ever developed for preventing young people from using drugs. The guide, entitled,
“Preventing Drug Abuse Among Children and Adolescents: A Research-Bared Guide” contains state of the art
science-based principles on the content, structure, and delivery of effective drug abuse prevention interventions as
well as examples of successful prevention interventions. Here again is an attempt to take the science and make it
useful. The principIes contained in this guide, derived from ten years of prevention research, are intended to serve as
advice, literally. to communities developing their own prevention programs or evaluating them. In recent years,
there has been an attempt to move drug prevention away from the question of whether a particular method works to
much more important questions, including why does it work and what are the elements that are critical to a particular
situation? Thus far we have distributed 100,000 copies and have been astounded at how hungry the field is for this
kind of information.
We have also engaged in efforts to better inform health care professionals with the facts about drug abuse and
addiction by co-sponsoring a day-long symposium with the journal Hospital Practice (a publication of McGraw-Hill
Companies, Inc.) entitled “New Understandings of Drug Addiction”. The purpose of this meeting was to bring
primary care physicians current information on the biology of drug addiction and its implications for treatment.
Proceedings from the symposium were published in a Hospital Practice Special Report which is going out to over
120,000 primary care physicians. This report contains very good descriptors for a primer of what we have learned
about drug abuse and addiction, neuroscience, behavioral science, clinical issues, and a few service issues are included
in it as well.
7
As I am sure many of you know, the May 5, 1997 issue of TIME magazine. featured an extensive piece on the.
biological basis of addiction, highlighting the work of many of NIDA’s grantees. This piece was not only well done
but, in my view, is symbolic of a very slow but hopefully increasing understanding that there is more to drug abuse
and addiction than just failure to quell a moral weakness. I think the science that you all do is what is fueling this
very slow but gradual process, and I think the evidence points to this rising tide of understanding about what is
happening.
Another event we participated in, that I personally was very pleased about, was the NIH Office of Science Education
sponsored Mini-Med School held on Capitol Hill. in May. This activity was intended to provide Congressional staff
with information about the basics of medicine and medical research in order to help them make more. informed policy
decisions. The lecture I gave on drug abuse and addiction was broadcast on C-SPAN enabling us to reach an
enormous viewing audience.
We have had some other kinds of public events, and, again, I know some of you have been involved in those
activities. Next March, Bill Moyers is going to do a five-part special on addiction and recovery for public television
that NIDA has played a part in and I know be has interviewed a number of you as well. The producers of the special
have asked us to co-produce a number of their handouts that will go out to teachers and to their general viewing
audience as part of this effort. We also just gave out our first series of PRISM Awards in Hollywood to television
personalities, shows, and movies that do an accurate job of depicting drug abuse and addiction.
There is no doubt that, relative to many other areas, the science of drug abuse and addiction is doing well in many
respects. In addition to the enormous scientific progress that all of you have been making individually, overall,
people are beginning to recognize that our collective efforts are paying off. Not only are individual scientists
gaining recognition in the lines of work that they want to do, but I think we are also beginning to see a very gradual
change in understanding the way in which science can be brought to bear on the issue of drug abuse and addiction.
The fact that we have been singled out by members of the administration, the Congress, and many other groups as
sources for accurate, up-to-date Information to help get a handle on these issues is an important testimony to science.
Furthermore, it is testimony to the hunger and the need for the kind of work that all of us are doing. There also
seems to be a gradual change in public opinion about the nature of drug abuse and addiction and public understanding
of the facts is the only chance we as a country have to get a handle on the problem. Although things ate going well
we cannot rest on our laurels too long. In order to continue and even accelerate the progress we are making in
ensuring that science will replace ideology as the foundation for drug abuse and addicton prevention,treatment and
policy strategies it is essential that we keep the momentum going!--both in advancing the science and in getting the
word out about the findings our science is generating.
8
INTRODUCTION OF THE NATHAN B. EDDY MEMORIAL AWARD RECIPIENT
W. L. Dewey
Research and Graduate Studies, Medical College of Virginia, Virginia Commonwealth
University, Richmond, VA
Ladies and Gentlemen,
It is indeed a pleasure and an honor for me to present Dr. Martin Adler the Nathan B. Eddy award winner for 1997.
Marty was nominated for this award for many reasons: his many scientific contributions, his leadership role in our
discipline, his excellence as a teacher and role mode, his endless and tireless work for the field and for his
phenomenal continuance of the work of Dr. Eddy to oversee the activity of CPDD.
Dr. Adler is a world leader in the area of understanding the effects of opioids and opiates on thermoregulation. The
effects of opiates on thermoregulation like the effects of these drugs on some other systems are species specific,
dose dependent and often affected by many other biological variables. Dr. Alder has elucidated how and why each of
these variables affect opiate pharmacology.
Just as the opiates can cause an increase in body temperatute under certain conditions and a decrease at other
conditions they also cause seizures at some and have antiseizure activity under other conditions. Dr. Adler has done a
great deal to expand our knowledge in this area as well. In addition, he has been instrumental in our understanding of
the complex effects of opiates on the eye.
It is obvious that Dr. Adler has chosen some of the more complex systems to study effects of the opiates. He has
done more than anyone else to elucidate the mechanisms by which these interesting drugs alter these biological
systems. He has identified the endogenous ligands and the specific opiate receptor types involved in each of these
interesting pharmacological phenomena. His studies included both acute and chronic administration of the opioids.
Information generaled by his laboratory following chronic administration has been important in our attempt to
understand the mechanisms of the development of tolerance and physical dependence to opiates.
In recent years be has expanded the breadth of his interests to include interesting investigations into the effects of the
opiates on the immune system. He had the wisdom to choose excellent collaborators who have sound knowledge of
this system. Dr. Adler contributes much to this group as one of the worlds leaders in the pharmacology of opiates.
Even though I believe the contributions of the work described above are enormous, they do not tell the whole story
of the contributions of this man to science. He is a stimulating lecturer who makes difficult concepts understandable
to his audience. Dr. Adler has educated an impressive number of graduate students and postdoctoral fellows who have
gone on to be contributing independent investigators in their own right. He has contributed to the field of
pharmacology and more significantly to drug abuse research in other ways. He has been an excellent field editor of
the most prestigious journal in the field of pharmacology as well as a tireless reviewer of papers for many other
journals. Dr. Adler has served the more broad field of pharmacology by contributing expertly to his department and
to his professional society.
But it is in the specific field of substance abuse that Marty’s service contributions are beyond comparison. He has
contributed extensively to the National Institute on Drug Abuse. He has served on study sections and review groups
for an extended period of time. He has chaired NIDA study sections at least twice in his career. He has served on
the editorial board of the NIDA monograph series and on the search committee for the Director of the Institute, His
contributions as executive secretary of the College on Problems of Drug Dependence can not be overstated. When he
took on this responsibility it was a time of major transition in the organization. He set-up the offices in
Philadelphia simultaneously with the most impressive growth in participation of scientists and scope of activity of
the organization. He has kept this organization together as officers come and go and as the committee of twenty
some people become a membership organization of hundreds. The glue that kept it all together has been Marty
9
Adler. The fact that he is one of the worlds leading researchers in his area has allowed him to be an executive officer
who contributes far beyond what normally is expected. This certainly is reminiscent of the important contributions
of Dr. Eddy to this field.
Dr. Marty Adler has contributed to biomedical research in every conceivable way. In each, he has contributed with
distinction and has been an example for all of the rest of us. It is a pleasure to have worked with Marty Adler in so
many ways and it is a privilege to be in the same field with such an outstanding scientist. It is now my pleasure to
ask Marty to come forward and accept this award and present the 1997 Nathan B. Eddy Award Lecturer.
Respectfully submitted.
10
NATHAN B. EDDY AWARD LECTURE
M. W. Adler
Department of Pharmacology, Temple University, Philadelphia, PA
This is an overwhelming moment! I beard someone say recently that it was particularly great to receive an award
for something you’ve had fun doing all your life. I want to thank CPDD, the Awards Committee, and Dr. Billy
Martin, who chaired it. Special thanks go to my nominators - Drs. William Dewey who spearheaded the effort
Robert Balster. Mary Jeanne Kreek, Joseph Brady, Thomas Crowley, and Louis Harris. I also want to thank Dr.
Steven Holtzman, especially for the phone call informing me that I was to be the recipient of the 1997 Eddy
Memorial Award. It was probably the most pleasant shock I have ever had. Let me also thank Ellen Geller, with
whom I work every day but who never let me know that I had been nominated. It was an Oscar-deserving
performance. A lot of what I have accomplished over the years at Temple can he credited to her. But I wouldn’t
even he here if it wasn’t for my wife Toby who arranged for me to get into graduate school while I was in Korea.
She and an ex-professor of mine, Dr. James Ingalls, contacted Dr. Michael Clay at Columbia and I was accepted
with a teaching assistantship----all without my knowledge. Toby told me about it on one of my monthly phone
calls that I was able to get through from Korea. All I had to do was accept. It took me a month to get over the
surprise, but on the next call. I had her accept for me.
I only met Dr. Eddy a couple of times since I didn’t attend a CPDD meeting until the early ’70s. This award was
named to honor him, and a look at the scientists who have won the award is like looking at the Who’s Who of the
drug abuse research field.
Each of the people on this list is undoubtedly deserving of the honor, but it’s almost a shame that we have only
one such award each year because our field includes so many distinguished and deserving scientists.
I thought long and bard about what I should talk about in this lecture and I asked several friends and colleagues for
their suggestions. As one would expect when asking a group of scientists for an opinion not necessarily based on
any facts, there was little overall consensus as to the best approach. The closest I could come to finding some
common threads in the suggestions was that the talk should he personal. it should include some science (but not
too much since the purpose was not to intentionally put the audience to sleep), and, if possible, there should he a
take-home message.
11
The key to the longevity and stability of the pyramid is the broad base. I’m going to start with the take-home
message: at many institutions, we are training our students too narrowly and without a broad base, a situation
which will impede many of them to or 20 years after they complete their training. What I’m going to try to do in
this talk is to Integrate that message into a somewhat cursory look at some of my research over the years to
illustrate why one needs to have a rather broad base.
My graduate training began at Columbia University, where I received the Master’s degree and did a thesis on stress.
Most of the coursework consisted of the first year of medical school courses, supplemented with some special
courses and laboratories in experimental physiology and in biochemistry. For reasons that I won’t go into, I felt
that Columbia was not the place where I wanted to do my doctorate, so I went to see Dr. Alfred Gilman at Einstein.
The nervous system was the research emphasis at Einstein because of an NIH interdisciplinary training program.
While taking most of the second year medical school courses - microbiology, pathology, and pharmacology - I
started my research with Dr. Murray Jarvik. Fortunately or unfortunately, Dr. Gilman accepted nothing less than
outstanding performance and his students were expected to be in the upper 10% of the medical school class. That
would have been difficult anywhere. but at Einstein it was trial by torture. In addition to the coursework, graduate
12
students were expected to take part in the Microbiology Journal Club. We were also offered the opportunity to
assist in setting up organs and tissues for the daily Pathology conference. That was great since we were paid a
small stipend, enough so that we could have bought a Big Mac every couple of days if McDonald’s had been in
existence at that time. Believe it or not, there really was life before McDonald’s. In Pharmacology, graduate
students set up all demonstrations and all laboratories. Before we graduated, we also took all or parts of several
other courses including Physical Diagnosis, Radioisotopes, Statistics, Experimental Neurology, and Experimental
Psychiatry. In other words, we took a lot of coursework. But we also did a lot of research and 12-hour days and a
minimum of 6 days a week were the norm.
In terms of research, Dr. Jarvik was interested in learning and memory and was using monkeys in his work. He
used a visual discrimination and delayed response test and was interested in the effects of centrally acting drugs.
Circuitry was never my strong point, but we had to learn to build our own circuits for the specific tests we were
using. We decided that we should try to automate some of the apparatus, so we (mostly Dr. Jarvik) got some old
Western Telegraph units and designed and built an apparatus that let us do the counting of the responses
automatically and tell us if the responses were correct, incorrect, premature, random, etc. It turns out that we had
built one of the early, although very crude, versions of a computer readout device.
Things were working quite well until I met Josephine. I’ll bet that most of you never knew that I had a Josephine
in my life. Josephine was one of the rhesus monkeys we used in our studies and she decided to show me that she
was smarter than I was. Murray and I would set up the test apparatus and have the one who did not set it up try to
solve the problem. One day, 1 gave up after 2 hours. Murray then put Josephine into the chamber and within 5
minutes, she bad solved the problem. One of the drugs I was testing was amphetamine. Unfortunately, Josephine
died, although the dose was not particularly high. Well, Josephine’s intelligence and her death made me decide that
I wanted to find out why she had died. I was particularly intrigued by the fact that she had had a prefrontal
lobectomy a year earlier. The only clue in the literature was a small series of studies carried out in the late 1940s
and early 1950s reporting that amphetamine could cause convulsions in monkeys with cortical damage. Josephine
showed an initial excitation followed by depression and death, but no seizures.
I decided that I would study the effects of several centrally acting drugs after cortical ablations in rats. I devised an
apparatus for doing that and for making electrolytic lesions in the caudate nucleus. Cortical ablations were in 2
areas, the frontal cortex (including area 10) and the posterior cortex (including area 17). Luckily, I had taken a
course in histology and was able to work with a technician to determine the extent of the brain damage, and I had
taken pathology so I was able to determine glial infiltration, etc. To make a long story very short, bilateral
ablations of the frontal or posterior cortex resulted in an increased responsiveness to amphetamine, and there was
no change after caudate lesions. Further. it took several weeks for the increased sensitivity to become manifest after
the cortical ablations. These results led to me paper of which 1 think I am most proud (Adler, M.W., Changes in
sensitivity to amphetamine in rats with chronic brain lesions, J. Pharmacol. 134 :214:221, 1961.)
13
Submission of this paper also led to a protracted struggle to get the work published, because the editor of JPET
initially refused to accept the term “denervation supersensitivity” as a possible explanation. To the best of my
knowledge, this was the first paper to use that term for the brain. Until that time, Cannon and Rosenblueth’s 1949
definition of “denervation supersensitivity” was applied only to the peripheral nervous system. The support of Dr.
Gilman and my 2 mentors (Drs. Murray Jarvik and Seth Sharpless) finally led me to tell the editor that I would
withdraw the paper rather than use some new term that he wanted me to devise. He relented.
With the end of my doctoral work in sight, I had to decide whether to go for a postdoctoral position or take a
faculty position somewhere. I was the first to receive a Ph.D. in any discipline from the Albert Einstein College
of Medicine. The year was 1960. Since we had one and eight-ninths children and some debt when I received the
degree, I decided to go for a faculty position. Times were certainly different. With the statement from Dr. Gilman
that “my students do not look for a job, jobs look for my students” ringing in my ears, I waited. In less than 2
weeks, the phones started ringing and the mail started coming in. I guess that I had at least a dozen offers in a
month, ranging from faculty positions in physiology, biochemistry, and pharmacology in outstanding medical
schools to a couple from industry. I was flattered and overwhelmed. I quickly decided to go into academia A
friend (Dr. David Brodie from Merck) had Dr. Roger Sevy, the chair of Pharmacology at Temple University School
of Medicine, contact me. I went to see him and immediately decided that was the place for me. The final offer that
I accepted was for the huge salary of $7200/year. which still allowed me to begin to pay off my debts. Happily,
that went up quite rapidly. The choice of Temple was undoubtedly one of the best choices I’ve ever made and I’ve
never been sorry that I made that choice. Because I’ve now been at Temple for over 36 years, it’s a good thing that
I feel that way.
As soon as I arrived at Temple, I applied for an NIH grant and got one for 3 years. It had to do with brain lesions
and seizures and we used flurothyl (hexaflurodiethyl ether) as our principal agent to induce seizures. We found that
there was a marked increase in the duration of the seizures and a decease in the threshold after frontal and posterior
cortical ablations. In other words, the denervation supersensitivity that we had seen with amphetamine extended to
convulsant agents as well. We also carried out numerous studies with flurothyl itself in normal tats since it had so
many advantages over pentylenetetrazol, the standard chemical convulsant, and it led to several studies in
collaboration with Dr. Everett Maynert and his group at the Johns Hopkins School of Medicine. Repeated seizures
produced a marked decrease in the seizure threshold. Interestingly enough, however, we found no changes in wholebrain levels of serotonin, norepinephrine, or dopamine. We also continued to study the effects of lesions in various
areas of the brain of rats, especially the limbic system and lateral geniculate nucleus, and their relationship to
seizures and sensory input, and we studied the relationship of the time course of brain damage to the ability of
anticonvulsants to antagonize seizures.
I guess that the next phase of my research life began when I lost my grant in 1967. While trying to decide what to
put in my next application, I went to a FASEB meeting. I was on a bus going somewhere at the meeting and I sat
next to someone that I had met only casually. We started talking about research and funding and I told him my
situation. He suggested that I start studying morphine. I told him that I wasn’t interested in morphine but was
interested in seizure mechanisms and lesions and he said, “Perfect ---morphine causes seizures.” I was glad that I
followed the advice of that scientist since I’ve been a druggie ever since. That person was Dr. Joseph Cochin.
14
It turned out that Joe was chairing the study section, although I didn’t know it at the time and he didn’t tell me.
Subsequently, our group and the group at Boston University became friends. not only because of Joe but because of
Dr. Conan Kornetsky whom I had met through Murray Jarvik. The story I just told you about Dr. Cochin was an
example of his abiding interest in helping young scientists. When Joe died in 1986. Conan Kornetsky, with my
strong support, proposed to CPDD that an award be given yearly, in Joe’s honor, to a young scientist. Dr. Lisa
Gold. winner of this year’s Cochin Award is a perfect example of the type of bright young scientist that Joe always
went out of his way to help.
For the next 3 or 4 years, I continued to study seizures, brain lesions, and morphine, but began more and more to
look al the withdrawal syndrome and possible sites of morphine dependence in the brain. In 1971, I received a
telephone call telling me that a new institute, the National Institute on Drug Abuse, was being formed. First, my
grant from NIMH on brain lesions and morphine was switched to a new NIDA number (DA00049). Second, I was
informed that NIDA was given a sizable amount of start-up funds and I was invited to submit a new grant
application for some of those funds. Talk about being in the right place at the right time! I spoke to several of my
colleagues at Temple and we decided to apply. Although this was prior to the actual discovery of the opioid
receptors. their existence had been postulated by Drs. William Martin, Akira Takemori, Phillip Portoghese, and
Avram Goldstein (all Eddy Award winners). Our group also believed that opioid receptors must be the explanation
for the actions of opioid drugs and we titled the grant “Narcotic Receptors in Addicted and Non-Addicted States.”
Our work was to be based on graded dose-response data to determine drug-receptor affinity. My fellow Temple
faculty members on that application were Drs. Ronald Tallarida (Professor of Pharmacology), Concetta Harakal
(currently Professor Emeritus), Marcus Reidenberg (currently Professor of Pharmacology and Medicine at Cornell).
Philip Gildenberg (currently a neurosurgeon in Texas), and Mr. Michael Loughnane (currently using his
considerable skills in bioengineering in his own company). We’ve continued with that grant and it is now starting
its 24th year. Long live NIDA! Of the original group, Ron Tallarida and I are still part of it. In 1974, Ellen
Geller joined us and in 1976, Alan Cowan. Both are still active and important parts of our group.
After we submitted the grant application, we received a site visit, the norm at the time. One of my site visitors
was Dr. William R. Martin. 1 didn’t know Bill personally at the time, but his wise counsel at the site visit and in
subsequent years did much to help me in this field. Bill was an extraordinary scientist and an extraordinary human
being. He was a true gentleman in every sense of the word and I feel honored to join him as an Eddy Award
winner.
Being awarded that grant changed my research completely. I got out of the brain lesion field and into one of
opiates, antagonists, and effects on a variety of systems. In particular, we began to work on 4 systems or
15
endpoints: analgesia, the pupil, body temperature, and seizures. The only area in which I had any real background
at that time was seizures and one of our first papers on this grant demonstrated that there was a lowered seizure
threshold during the withdrawal syndrome.
Shortly after starting the grant, 1 went on a 6-month research leave to the Mario Negri Institute for Pharmacologic
Research in Milan. Professor Silvio Garattini was and still is the Director of that prestigious institution. I waked
with Professor Luigi Valzelli on behavioral effects of opioids and with Dr. Rosario Samanin on analgesia and the
role of the raphe nuclei. Several papers resulted from that work. A study with raphe lesions in rats was
particularly important to my thinking since we were able to determine that it was the location of the lesion rather
than the drop in serotonin that was responsible for the decreased effect of morphine on antinociception. Thus, it
was the “hard-wiring” that was the determinant of the change.
Our group at Temple continued to study morphine and naloxone on antinociception and that led to another paper of
which I’m particularly proud (Tallarida, R.J., Harakal, C., Maslow, J., Geller, E.B. and Adler, M.W., The
relationship between pharmacokinetics and pharmacodynamic action as applied to in vivo pA: application to the
analgesic effect of morphine. J. Pharmacol. Exp. Ther. 206 :38-45, 1978.) In this paper, using the rat tailcompression method for assessing antinociception,we (mostly Ron Tallarida) developed a time-dependent method
for determining pA2 values in vivo. The pA2 method that we developed has proven to be useful in determining
pA2 for a variety of agonist-antagonist combinations.
Our studies with morphine and seizures produced quite a surprise. All of the literature and texts at that tune said
that morphine caused seizures. We found the opposite. After doing multiple replications of our findings and after
arguing with the reviewers (later, Bill Martin told me that he was one of them), the paper showing that morphine
had anticonvulsant effects in the rat and that the effect was independent of the effect on respiration was finally
published in 1976. Much of this work was carried out by Chen-Ho (Geraline) Lin, who was a post-doc in my lab
at the time. Our findings of the anticonvulsant properties of morphine led us to a large series of studies and finally
culminated in a paper in Science in 1979 that classitied 20 opioids into 4 classes based on their effects on seizure
thresholds, stereospecificity, dose-response relationships, naloxone sensitivity, and tolerance and cross-tolerance.
We concluded in the paper that multiple opioid receptors were involved. Of course, by this time the opioid receptor
had been shown to exist and the endogenous ligands for those receptors identified. Three of the five scientists that
contributed the most to those findings - Drs. Avram Goldstein, Eric Simon, and Hans Kosterlitz - are former
winners of the Eddy Award.
Dr. Frank Tortella who was a postdoctoral fellow in my laboratory at the time, extended our findings on seizures
by showing that the route of administration of the opioid was a critical variable in whether the final effect was
excitatory or inhibitory. He also demonstrated anticonvulsant actions of opioid peptides.
Along with our studies on analgesia and seizures, we began a series of investigations on the effects of opioids on
the pupil. As all of you know, morphine causes miosis in humans and that is one of the cardinal signs of opioid
overdosage. In most species, such as mice, rats, cats, horses, and primates, however, morphine causes mydriasis.
In rats, we found that there was a dose-related mydriasis and a dose-related fluctuation in the size of the pupil.
These effects were both antagonized by naloxone. Although the effects of opioids on the pupil are dramatic, we
later concluded that the endogenous opioid system is not a prime component of pupillary stability or diameter.
However, we were also able to demonstrate that, contrary to what everyone believed at the time, some tolerance
does develop to the pupillary effects of morphine.
Along with our studies of opioids on analgesia, brain excitability, and pupillary size, we also studied the effects of
opioids on body temperature and thermoregulation. One of our earliest studies in this field was part of a thesis
project by one of my students, Frank Baldino. After identifying warm-sensitive and cold-sensitive neurons in the
rat preoptic anterior hypothalamus, he was able to show that iontophoretically applied morphine excited warmsensitive neurons and inhibited cold-sensitive cells. A collaborator in these studies was Dr. Alexander Beckman at
the University of Pennsylvania.
16
In studying the effects of a large group of opioids on body temperature, we found that they could be put into 5
groups and we postulated in 1980 that all of the effects could be explained by a 2-receptor model. In a JPET paper
in 1983, we expanded on that idea and we presented a diagram of how the 2-receptor system might work, using
morphine as our example.
(From Geller, E.B., Hawk, C., Keinath, S.H., Tallarida, R.J. and Adler, M.W., JPET, 225:391-398, 1983.)
In our conclusions to that paper, we stated that “until highly selective and, perhaps. truly specific opiate receptor
agonists and antagonists are available, it may be useful to think of thermoregulatory actions of opioids in rats after
s.c administration as being mediated by two receptors,” Time has proven us correct. We now know that
hyperthermic responses in the rat (and most likely most or all species) are mediated via the µ opioid receptor and
hypothermic responses via the receptors. Furthermore, the hyperthermic effects are mediated almost solely in the
brain while the hypothermic responses are a combination of central and peripheral effects. Interestingly, the
receptor does not seem to be involved in temperature regulation at normal ambient temperatures. In the past two
years, all of our ideas with the µ and receptors and their role in thermoregulation have been confirmed with the
use of antisense oligodeoxynucleotides. Similarly, we have used antisense oligos to confirm much of our analgesia
work.
In the course of our studies on thermoregulation, we decided to see what would happen if we combined a opioid
agonist with a neuroleptic such as CPZ which causes a moderate degree of hypothermia. To say that we were
surprised by the findings would be an understatement.
(From Adler, M.W. and Geller, E.B, Eur. J. Pharmacol. 140:233-237, 1987.)
17
That graph was published in 1987 and Ellen Geller and I were granted a patent based on these results.
Unfortunately, there is still no clinically useful agonist on the market. When there is, a combination such as
this could prove extremely useful in such diverse applications as cardiac surgery, treatment of the near-drowning
syndrome, protection of the brain and spinal cord after stroke, and as an adjunct in cancer chemotherapy.
That the endogenous opioid system is the key system in thermoregulation is of great importance since
thermoregulation allows not only for survival but is necessary for the functioning of virtually all enzymatic
processes in the body. Although we knew the importance of the opioid system, we didn’t how how it worked.
Two postdoctoral fellows in my laboratory, Drs. Thomas Lynch and Cynthia Handler, along with several others in
the group, supplied the key. We were able to build our own whole-body, gradient-layer calorimeters to measure
oxygen consumption, heat exchange, and body temperature in freely moving rats. One of our first papers using the
calorimeters was published in 1992.
ln that and a subsequent group of papers, we were able to demonstrate that the µ and opioid systems produce their
opposite effects by means of oxygen consumption and heat-loss/heat-gain mechanisms and thus regulate body
temperature. I’ll get back to this in a little while.
A little less than ten years ago, we slowly began to move into two entirely new fields. The first was the
interaction of various neuropeptides with the opioid system in terms of seizures, analgesia. and thermoreguladon. I
had begun to question the idea that all of the effects of the opioids could be explained on the basis of the site of
action of the drugs, the neuronal connections involved, and the neurotransmitter systems. It seemed to me that it
was just too simple an explanation for such a wonderfully tuned system as the brain with all its checks and
balances. redundant pathways, and feedback loops. I started to think about what I had been taught many years ago
when I took courses in anatomy, neuroanatomy, and physiology. We were taught that in some systems there were
two levels of control, one for the large effects and one to tine tune those effects. Why shouldn’t there also be
several levels of control for the chemical transmission of information and the activation of neurons? When the
neuropeptides came on the scene, there was the additional level of control that I felt was needed. Our first report
was presented in 1988 at a FASEB meeting and was followed by a full publication in 1990. One of my graduate
students, Paul Tiseo, measured the release of substance P (SP) and somatostatin in the spinal cord of rats after
noxious cold or heat. We had perfected the use of the cold-water tail-flick method in rats in 1985 to determine
antinociceptive actions of agonists. Heat caused an increase in somatostatin, while cold produced an increase in
SP. Because our group had previously shown that cold-induced pain was blocked by the agonists dynorphin A117 and U50,488H, then release of SP should be blocked when the agonist was administered to a rat and the rat was
exposed to cold-induced nociception. And it was!
(From Tiseo, P.J., Adler, M.W. and Liu-Chen, L.-Y.J. Pharmacol. Exp. Ther. 252:539-545, 1990.)
18
This dose-related effect of dynorphin could be blocked by naloxone and the same picture could be seen with
U50,488H. When Dr. Li Xin joined our group as a postdoctoral fellow in 1992, he introduced the technique of in
vivo microdialysis in freely moving rats to our group. Using that technique, we were able to replicate in the PAG
what we had found in the spinal cord. Actually, 1992 was a very good year, since I received a MERIT Award from
NIDA that year. That has given me the freedom to explore new avenues and I think we’ve been quite successful.
We have since gone on to study several neuropeptides, including SP, CCK, neurotensin, TRH, and somatostatin in
terms of opioid-induced analgesia, thermoregulation, and anticonvulsant activity. We believe that the actions of the
opioids on the nervous system are the result of the interaction of the endogenous opioid peptide system of ligands
and receptors with various neuropeptides and neurotransmitters. Our hypothesis is as follows:
“When a perturbation occurs in the thermoregulatory (i.e., POAH) or the nociceptive (i.e., PAG)
systems of the brain, a cascade of chemical events takes pIace that involves a number of
neuropeptides and cytokines acting via the endogenous opioid system to produce an action. That
action subsequently involves systems receiving afferents from the PAG and the POAH and the
final effects are then executed through the more traditional neurotransmitter systems. The specific
neuropeptides or cytokines involved are dependent on the particular effect being produced and the
particular brain nuclei involved.”
I believe that the specific cascade differs for different events and different areas of the brain. Indeed, we have begun
to accumulate data to support that hypothesis and I would like to show you two cartoons based on data we've found
in our laboratory.
The second of the two fields that we began to move into about ten years ago was that of drugs of abuse and the
immune system. Awareness of the AIDS epidemic was rising and it was rapidly noted that a large proportion of
the reported cases were associated with two types of risk behaviors: homosexual contacts and drug abuse. For
several decades, most texts in pharmacology and medicine contained statements to the effect that drug users had a
much higher incidence of several diseases. This was attributed to the dual causes of living in unsanitary conditions
and poor nutrition. The more I thought about this, the more I began to wonder if the drugs themselves might not
have an effect on the immune system. I began a study of the effects of cocaine on the immune system of male and
female mice with Dr. Francis Havas of our Department of Microbiology and Immunology. In 1987, we published
our findings that neither low nor high doses of cocaine altered antibody production, resistance to infection with
Streptococcus pneumoniae, or resistance to tumors in BALB/c mice
At about this time, NIDA invited a few of us to get together to discuss the possibility of studying drugs and the
immune system. I don’t remember all who were there, but they included Drs. Herman Friedman from the
University of South Florida, Arthur Falek and Bob Donahoe from Emory University, and Joseph Wybran. Joe was
a physician from Belgium who had shown and published a remarkable paper (Wybran, J., Appelboom, T., Famaey,
J.-P. and Govaerts, A., Suggestive evidence for receptors for morphine and methionine-enkephalin on normaI
human blood T lymphocytes, J. Immunol. 123:1068-1070, 1979.) In it, he concludes that “these observations
suggest that normal human blood T lymphocytes bear surface receptor-like structures for morphine. Such findings
may provide a link between the central nervous system and the immune system.” I’m sorry to say that just a few
short years later, this brilliant scientist and humanitarian was assassinated in the parking lot behind his hospital.
An award honoring his memory is given yearly by the Brain/Immune group that meets as a satellite meeting to the
CPDD.
NIDA’s interest in the field stemmed from the association between drugs of abuse and AIDS. Congress became
interested in supporting research in this area and NIDA agreed to be the lead institute. Dr. Marvin Snyder of NIDA,
a former CPDD Morrison Award winner, was instrumental in this effort. The progress that has been made by
NIDA grantees in understanding the interrelationships between drugs of abuse and immunoregulation in just a few
years is nothing short of phenomenal.
19
My studies with Dr. Havas made me realize that I knew very little about immunology. The little that I did know
came from the course in Microbiology that I had taken when I was a graduate student, and knowledge about
immunology at that time was extremely rudimentary. I approached Dr. Toby Eisenstein, a member of the
Department of Microbiology/lmmunology at Temple, who is a microbiologist and immunologist and expert in the
field of host/parasite resistance and began to proselytize her about studying opioids and the immune system. My
brainwashing worked. The first fruits of our collaboration were presented at a meeting of the New York Academy
of Sciences in 1990. That study with the in vivo administration of morphine showed that the secondary immune
response to tetanus toxoid was markedly suppressed. Ellen Geller and I decided to sit in on a graduate course in
immunology at Temple and, although we certainly did not become immunologists, at least we learned some of the
terminology.
At about the same time that we were beginning to find some in vivo effects of morphine. Dr. Eisenstein and I felt
that we should begin to look at the mechanisms involved while continuing to explore what happens in the whole
animal and in ex vivo measurements. We enticed two mote scientists from Temple to join our small group, Dr.
Thomas Rogers, a molecular immunologist specializing in studies with T cells and Dr. Lee-Yuan Liu-Chen, a
molecular and biochemical pharmacologist. Based on our pilot results, the four of us submitted a grant application
to NIDA on October 1, 1989. Following a site visit, the grant was approved and funded. The hypothesis was
simple:
“Opioids alter selective components of the immune system, resulting in the compromising of
immune competence, and the various types and subtypes of opioid receptors play a differential
role in these effects.”
Next came some fascinating results that we published in 1991 in PNAS under the sponsorship of Dr. Hans
Kosterlitz. Dr. Dennis Taub, a graduate student at the time who is currently doing research at the National Institute
on Aging, played a lead role in those studies. Using selective opioid agonists and antagonists in vitro, we reported
that µ and opioid receptors are involved in regulation of lymphoid cell production of antibodies. The effects were
blocked by the selective antagonists.
Our work in this field has expanded dramatically. Among our findings, we reported that the strain of mouse used
can markedly affect the response of the immune system to opioids. We also found that morphine-induced
macrophage suppression can be restored by the cytokiies IL-1, IL-6, and IFN- but not some other cytokines, and
that opioids inhibit cytokine production by macrophages. The primary effects of opioid immunosuppression seem
to be on the macrophage and the T cell. We have also recently reported on two cDNA sequences in the R1.1
thymoma cell line. Two kappa-opioid sequences have been identified, one that is like the one in the nervous system
and one that is a truncated form. Whether that represents an active site is not known at this time, but Drs. Rogers
and Liu-Chen are working on it. Finally, a paper that has just appeared in the J. of Infectious Diseases
demonstrates that morphine can produce sepsis in mice. The mechanisms and the full consequences of that finding
will be explored in depth by Dr. Eisenstein.
Well, although I have a full plate of research and I feel quite satiated and satisfied, I’ve always felt that one should
leave room for dessert. When that dessert is something that you hadn’t anticipated would be so wonderful. the
enjoyment is all the greater. I think that I’ve found the dessert. My two lines of research, opioids and endogenous
neuropeptide systems, and opioids and immunocompetence are blending into an exciting new field--the interactions
of cytokines and neuropeptides.
We have found and reported that the fever praduced in rats by IL-1ß and TNF- can be blocked by CTAP. the
selective µ receptor antagonist. Furthermore, the fever can be explained by the release of ß-endorphin. Thus, the
role of the endogenous opioid system in thermoregulation now seems to encompass cytokine-induced fever. I
showed you some of these ideas in the cartoon about the thermoregulatory system. Just as when a peripheral
peptide found in the brain was then called a neuropeptide, so too might we be witnessing a new era in brain research
with the findings that glib are brain macrophages, that they produce cytokines in the brain, they interact with
endogenous opioid systems, and that cytokine receptors may exist on neurons.
20
Well, I think that I’ve gone on far too long. Maybe I should have done what a friend recently did. She had prepared
a 45-minute presentation but was informed at the last minute that she had only 20 minutes allocated. She said,
“don’t worry, since I’m from New York, I won’t cut anything out. I’ll just talk faster.” I think I should have
listened to her. But I would like to reiterate the message I started with: at many institutions, we are c training our
students too narrowly and without a broad base, a situation which will impede many of them 10 or 20 years after
they complete their training.
I want to thank Temple University for providing me with a home and for not bothering me too much, I also thank
all my students and colleagues at Temple over the years and some of them are shown on the next slide.
I thank the many people at NIDA who have provided the money these many years with which to feed my research
habit. I particularly want to thank Dr. Alan Leshner, the Director of NIDA, for all of his efforts in persuading
Congress and the public that those of us doing drug abuse research are doing (as Dr. Joseph Brady says) “good
deeds” and are helping to illuminate the mechanisms involved in drug abuse.
Last, but certainly not least, I want to thank my family, especially my wife Toby, for all the backing and support
they have given me over all these years. I’m pleased that my daughter Eve, my son Charles and his wife Laura and
their children, Ilyssa and Jennifer, are also in the audience now.
21
It feels wonderful to have my name added to the illustrious scientists who have received the Nathan B. Eddy
Memorial Award. I am truly honored and I accept the award with a great sense of humility.
Thank you all!
22
SYMPOSIUM IV
OPIOIDS AND NEUROPEPTIDES IN IMMUNE FUNCTION AND HOST DEFENSE
AGAINST RETROVIRUSES
T. K. Eisenstein1 and J. Madden2
1
Department of Microbiology and Immunology, Temple University School of Medicine,
Philadelphia, PA; and 2 Department of Human Genetics, Georgia Mental Health Institute,
Atlanta, GA
Opioids and neuropeptides are well established to be immunomodulalory. In the case of the alkaloid opioids, the
experimental evidence shows immunosuppression. Naturally occurring opioid peptides and other neuropeptides can
be immunosuppressive or immunopotentiating. Important questions which remain to be addrersed are the
mechanisms of the immunosuppression and the significance of the decrease in host immune responses for resistance
to infection. Other questions of importance are, can we find opioids that can be used for analgesia that do not depress
immune function, and can immunopotentiating opioids be used therapeutically to enhance immune responses and
resistance to infection? This symposium addresses these questions, with particular attention to immunomodulation
of HIV expression by opioids and other neuropeptides.
OPIOID-INDUCED
OXIDE
IMMUNOMODULATION:
EVIDENCE FOR THE ROLE OF NITRIC
D. T. Lysle, T. How, and D. K. Nakayama
Departments of Psychology and Surgery, University of North Carolina, Chapel Hill, NC
In recent years, the role of nitric oxide in Immune processes has become apparent as demonstrated by studies
showing that it is involved in the control of bacterial and parasitic growth, the development of autoimmune disease,
and the regulation of cells within the immune system. Despite extensive knowledge of the biochemistry of nitric
oxide, little is known about the in vivo regulation of inducible nitric oxide synthase (iNOS), the enzyme responsible
for nitric oxide production by cells of the immune system. The present study tested the hypothesis that
Lipopolysaccharide (LPS) induced expression of iNOS by splenocytes is modulated by opioid receptors in the central
nervous system. To determine parameters of iNOS expression, rats received injections of LPS, and using RT-PCR
and western blotting, it was found that the maximal iNOS mRNA and protein expression occurs at 100 µg/kg, with
peak expression at 8 hours.
To evaluate the effect of opioids on iNOS expression, N-methylmorphine, the quaternary form of morphine, was
administered ICV to rats, at doses of 0, .04, .4. or 40 µg in combination with a systemic Injection of LPS (100
µg/kg). The results show that iNOS mRNA and protein expression are increased in a dose-dependent manner by the
central administration of N-methylmorphine. Serum nitrite levels were also significantly increased, providing further
evidence that activation of central opioid receptors enhances iNOS expression. In contrast, the ICV administration of
the opioid antagonist N-methylnaltrexone to rats at doses of 0, .01, .1, 1.0, or 10 µg produced a dose-dependent
reduction in iNOS mRNA and protein expression. These results suggest that endogenous opioids may play a role in
the regulation of iNOS expression. This research extends our knowledge of the in vivo regulation of nitric oxide
production, and may have important implications for the treatment of septic shock.
23
OPIOIDS WITH DIFFERENTIAL IMMUNOMODULATORY EFFECTS IN VIVO AND IN
VITRO
R. J. Weber
Section of Medical Sciences, Department of Biomedical and Therapeutic Sciences, University
of Illinois College of Medicine at Peoria, Peoria, IL
Central nervous system mediated, morphine-induced immunosuppression has teen hypothesized to be due to
activation of the hypothalamic-pituitary-adrenal (HPA) axis or the sympathetic nervous system or both (Weber and
Pert; Science 245:188-190, 1989). Morphine microinjection into the PAG resulted in suppression of splenic NK cell
activity, splenic and thymic T-lymphocyte proliferation, and inhibition of splenic macropbage phagocytosis and
nitric oxide and TNF production. Peritoneal macrophage phagocytosis was also inbibited. Plasma ACTH and
corticosterone concentrations was determined before and after injection of morphine in jugular catheterized Fischer
344N male rats. A temporal increase in ACTH was observed which peaked at 40 minutes (9-fold) following PAG
morphine injection and was accompanied by a subsequent 2-fold sustained increase in corticosterone. The
glucocorticoid antagonist, RU486, was ineffective in blocking either the suppression of NK cell activity or T cell
proliferation. Consequently, we examined the role of the sympathetic nervous system on the observed
immunosuppression. Catecholamine levels were measured kinetically and continuously in splenic microdialysates
from freely moving Fischer 344N rats, both before and after bilateral administration of morphine or saline into the
PAG. Our results indicate that morphine induces a substantial increase in norepinephrine (NE), serotonin (5-HT), and
metabolite levels. The elevated levels of NE, and 5-HT reach a maximum between 15 to 30 minutes after injection
of morphine, and then gradually decline. Both NE and 5-HT levels return to a basal level approximately 150 minutes
after morphine injection. We have also compared the immunosuppressive effects of morphine with buprenorphine, a
potent analgesic and partial agonist at the opioid receptor, that does not induce immunosuppression. Preliminary data
indicates that buprenorphine fails to alter the levels of bioamines and does not decrease lymphocyte proliferation or
NK cell activity. In conclusion morphine injection into the PAG leads to an increase in catecholamine levels within
the spleen, and is correlated with changes in splenic lymphocyte function. ACTH and corticosterone increases
following PAG morphine are correlated with changes in immune function, but are apparently not associated. These
findings, along with the failure of buprenorphine to alter splenic catecholamines, suggest that the sympathetic
nervous system, but not the HPA axis, plays a major role in immunosuppression observed following PAG
morphine.
We have also identified a potent non-peptidic delta opioid receptor-selective analgesic which does not suppress
immune function. PAG or ICV administration of SNC80 did not suppress splenic NK activity. No functional
changes were seen with thymic or splenic T-cell proliferation in response to interleukin-2 (IL-2), R73 (antibody to
CD3/TCR). or IL-2 + R73. Cell surface staining followed by flow cytometric analysis showed no change in the
following cell populations: CD3+. CD4+, CD8+, or NKP.R1+. Similarly, no difference was found in cell surface
antigen density from any tissue compartment studied. These results suggest that ligands with this opioid receptor
subtype selectivity could be useful in the treatment of pain in certain clinical situations where suppression of
immune function is undesirable. Examples include burn victims, AIDS patients, and cancer patients being treated for
intractable pain and opting for adoptive immunotherapy.
Although the central nervous system mediated indirect effect of opioids has been shown to suppress immune
function the direct effect of certain novel opioid derivatives on cells of the immune system, has been shown to
induce immunopotentiation in vivo (Sanchez S.R., Rice K.C., et al., NIDA Res Monogr, 1996). Studies with
naltrindole (NTI), selective for the 2 opioid receptor, and benzylidenenaltrexone (BNTX, selective for the 1 opioid
receptor, have been shown to act as antagonists in cIassical neuronal opioid receptor systems. We have identified a
class of novel NTI-derived non-peptidic opioid receptor ligands with direct immunopotentiating effects on mitogen
stimulated lymphocytes. In vitro, the NTI analogues SoRI 9331 and 9340 consistently produced a dose dependent
(10-7 to 10-6 M) potentiation of lymphocyte proliferation following mitogen stimulation. BNTX related compounds,
SoRI 9334 and 9336, produced no significant effect on T-cell proliferation. Future studies will address
structure/activity relationships of these and other compounds and investigate the cellular mechanisms of
24
immunopotentiation. This series of novel non-peptidic opioid ligands could serve as immunotherapeutic agents with
potential use in the treatment of infectious diseases including AIDS and cancer, and as adjuvants for poorly
immunogenic vaccines.
In conclusion, our studies provide examples of opioids which suppress, enhance or have no effect on the immune
system, depending on the anatomical site of administration (central vs peripheral), receptor selectivity of the opioid
agonist (mu, delta, kappa). Further understanding of the neuroanatomical site of action, peripheral pathways
connecting the brain and the immune system, and structure and function of opioid receptors on immune cells should
eventually lead to realizing the immunotherapeutic potential of opioids.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA/AI 08988
EFFECT OF MORPHINE ON REACTIVITY TO HIV PEPTIDES
S. A. Schwartz and M. Nair
Division of Allergy, Immunology,
University of New York at Buffalo
and Rheumatology,
Department
of Medicine,
State
Previous work by our laboralory has shown that various HIV structural and regulatory peptides manifest
immunomodulatory activities. We demonstrated that a recombinant, HIV fusion protein, env-gag, consisting of
domains from gp41 and p24 could induce: 1) proliferation of CD3+ and CD3- lymphocytes from normal donors, 2)
novo polyclonal B cell activation, and 3) suppression of pokeweed stimulated immunoglobulin synthesis. Further,
env-gag selectively suppressed natural killer (NK) cell activities of mononuclear cells from HIV infected patients in
comparison to normal controls. Since we earlier reported that NK cell activities were suppressed in a cohort of
intravenous drug users, we undertook a series of experiments to determine if various recreational drugs may serve as
cofactors in susceptibility and progression of HIV infections. Initial studies with ethanol demonstrated that it could
selectively suppress env-gag induced proliferation and NK activities of lymphocytes from HIV infected patients.
Suppression of NK activities could be reversed in vitro with interferon alpha ± interleukin 2, suggesting that these
cytokines could be useful in the treatment of AIDS patients. Other experiments within our laboratory demonstrated
that env-gag, together with an excitatory amino acid agonist, could induce encephalopathy in a rodent model. Now
we report that morphine can also potentate some of these biological activities of HIV peptides. We have shown that
morphine can suppress env-gag induced lymphocyte proliferation. Also, we observed that morphine can induce
spontaneous apoptosis of lymphocytes from healthy donors. Thus we conclude that some of the immunomodulatory
effects of morphine may be due to induction of apoptosis of immunocompetent cells. It has recently been recognized
that receptors for certain chemoattractive cytokines or chemokines may also serve as entry co-receptors for HIV.
Further, the natural ligands of these receptors, the chemokines, can compete with HIV for binding, and thus have a
protective effect on the host. Preliminary data from our laboratory demonstrate that morphine can enhance expression
of chemokine receptors and suppress production of the chemokines. Both of these activities are associated with
increased susceptibility to infection with HIV and progression of disease. In summary, our data support our
hypothesis that morphine is a co-factor in susceptibility to AIDS.
ACKNOWLEDGMENTS: Supported in part by Grant #R01MH47225 from the National Institute of Mental
Health and the. Theodore T. Jacobs, M.D. Endowment for Immunology of the Buffalo General Foundation.
25
SUBSTANCE P UPREGULATES HIV EXPRESSION IN HUMAN MACROPHAGES
S. D. Douglas, W.-Z. Ho, and J.-P. Lai
Division of Immunologic and Infectious Diseases, Children’s Hospital of Philadelphia,
University of Pennsylvania Medical School, Philadelphia, PA
Substance P (SP) is an undecapeptide which regular a number of important immunologic and infIammatory
functions, and is a neurotransmitter in the conduction of nociceptive stimuli. Substance P stimulates human
peripheral blood monocytes to produce inflammamry cytokines, including IL-l, IL-6, IL-10, IL-12, and TNF
upregulates HIV expression in T cells and monocytes in vitro. We have recently demonstrated that substance
TNF
Penhances TNF and IL-10 production by monocyte macrophages isolated from both adult human peripheral blood
and placental cord blood. We have further demonstrated that substance P modulates HIV replication in human
peripheral blood monocytederived macrophages. Recently, using nested RT-PCR analysis, we have identified the
presence of mRNA for the neurokinin 1 receptor (the receptor for substance P), and for the beta and gamma
transcripts of the substance P gene in human peripheral blood isolated monocytes and macrophages. These transcripts
were confirmed by DNA sequencing. The addition of HIV BAL to monocyte/macrophages upregulates the expression
of SP protein and mRNA in monocytederived macrophages. Thus, SP may be an important determinant in HIV
infection. and may affect HIV-AIDS disease. in the CNS.
ACKNOWLEDGMENTS:
Supported by NIMH R01-MH-49981.
SYNERGISM OF MET-ENKEPHALIN AND AZT IN RETARDING A MURINE RETROVIRUS
INFECTION
S. Specter
University of South Florida College of Medicine, Tampa, FL
Combination of antiviral chemotherapy using azidothymidine (AZT) and methionine enkephalin (Met-ENK), as an
immunostimulatory compound, has previously been shown by us to decrease morbidity and mortality due to murine
retrovirus infection, Friend leukemia virus (FLV), in BALB/c mice. In vitro Met-ENK (50-100 µg/ml) and AZT (1
µg/ml) were used in a combined protocol for treatment of established FLV infection. In a model using FLV, AZT
was able to reduce viral titers in susceptible Mus dunni cells while Met-ENK was not, thus, confirming that the
neuropeptide does not have direct anti-viral activity. However, Met-ENK treated spleen cells added to AZT reduced
FLV replication in culture. These studies further demonstrated that Met-ENK effects were mediated via opioid
receptors on lymphocytes, as activity could be inhibited by the opioid receptor antagonist naloxone. Additionally,
results indicate thast, at least in part, Met-ENK effects were due to the induction of interferon gamma (IFN ), which
inhibited FLV replication. Furthermore, the antiviral activity induced by Met-ENK was neutralized by anti-IFNantibody, but not irrelevant antiserum. Thus, cytokines, most specifically IFN- are important in the ability to
inhibit retrovirus infection in vitro. The dam suggest that this combination may provide benefit in human retrovirus
infections.
ACKNOWLEDGMENTS:
Supported by PHS grants DA 10161 and DA 07245.
26
SYMPOSIUM V
THE EFFECTS OF PRENATAL COCAINE EXPOSURE ON CNS DEVELOPMENT
S. Mackler, R. H. Finnell, C. V. Vorhees, and H. Hurt
Medical Research Service, Philadelphia, PA
The dramatic increase in the availability of cocaine in the United States over the last two decades has been associated
with a large number of women who have used cocaine while they were pregnant. Early anecdotal reports indicated
that infants exposed to cocaine while in utero exhibited manifestations of abnormal central nervous system (CNS)
development. Predictions followed of an epidemic of these ‘crack babies’ who would overwhelm existing social
support systems. This symposium reviewed both animal and human studies that, in response to this use of cocaine
by women during their reproductive years, have examined the effects of cocaine on the developing mammalian
CNS.
Is cocaine a teratogen ? (RH Finnell, Texas A&M University, College Station TX) A teratogen is any type of
environmental agent that compromises the normal development of the embryo or fetus. In general, birth defects are
rare events, and only 2-3% of these defects are thought to result from exposure to a teratogen. However. these
outcomes should be preventable, emphasizing the importance of identifying teratogens. Six principles have been
established in the identification of a teratogen (Wilson, 1977). 1. The susceptibility of the organism depends on
the genotype of the conceptus and the manner of interactions with the environment. This principle can be supported
by both variations in susceptibility and phenotype. Cocaine can result in multiple birth defects in animal models
(e.g. Finnell et al., 1990; Webster and Brown-Woodman, 1990), including CNS, cardiovascular, and genitourinary
malformations. 2. The susceptibility to a teratogen changes with the developmental stage of exposure. The most
sensitive time of susceptibility for major structural defects is thought to be during the period of organogenesis.
immediately after implantation and in the first third of a pregnancy. Studies examining different periods of exposure
to cocaine demonstrate conflicting results (Fantel and MacPhail, 1982), but there is sufficient evidence to support
this principle of teratology. 3. Agents must act in specific ways to initiate abnormal development. Postulated
mechanisms for cocaine’s effects on the embryo/fetus include uterine artery vasoconstriction, hypoxia, and the
generation of reactive oxygen species. Studies of embryo explants support these mechanisms (Fantel et al., 1992).
4. The final manifestations of abnormal development include death, malformation, growth retardation, or a
functional disorder. Several studies have demonstrated that cocaine administered to a pregnant animal can lead to
these outcomes. 5. Access to the adverse environmental agent and its influences depend on the nature of the
compound. Cocaine does cross the mammalian placenta and fetal CNS cocaine levels can be higher than those in
the maternal CNS. 6. Does a dose-response relationship exist between the teratogen and abnormal outcomes?
Although not as well established, there does appear to be an increase in malformations with higher doses of cocaine
(e.g. El-Bizri et al., 1991). Prenatal cocaine exposure does not result in a characteristic postnatal syndrome, as has
been established with ethanol and the fetal alcohol syndrome. The existing animal studies do strongly suggest,
however, that cocaine is a teratogen.
The effects of cocaine in molecules that regulate CNS development. (SA Mackler, University of Pennsylvania and
Philadelphia VAMC, Philadelphia PA) Studies of maternal cocaine treatment and CNS development must address
several experimental factors. Comparisons among many published studies are made difticult by these complex
issues, which include the amount and timing of cocaine administration to the pregnant animal, where and what
types of changes should be examined for in the CNS. and whether or not effects in the postnatal period result from
abnormal fostering by the drug-treated mother. Exposure of the embryo or fetus to cocaine may affect molecules
that both: 1) contribute to the phenotype of a differentiated neuron; and 2) are necessary for normal development
throughout the CNS (these two categories are not mutually exclusive). Examples of specific molecules found in
differentiated neurons include those present in dopammergic and related CNS pathways, where the effects of cocaine
are critical in the mature adult. In the forebrain and midbrain of the neonatal rat, levels of mRNAs (deBartolomeis
et al., 1994) and biogenic amines (El-Bizri et al., 1991) along with monoaminergic receptor sensitivities
(Henderson et al., 1991) and binding to dopamine uptake sites (Stadlin et al., 1994) were largely unaffected by
21
maternal cocaine treatment. Some proteins in these dopaminergic pathways exhibited transient alterations in
function which did not persist into adult ages.
Molecules that regulate CNS development have also been examined. Examination of the midgestation mouse, after
maternal cocaine treatment during initial neural tube development, revealed few changes in mRNA levels encoding
multiple proteins involved in CNS and vascular development (Mackler et al., 1996). These data suggest that, even
if cocaine leads to uterine vasoconstriction and hypoxia, these are specific and limited changes in gene expression.
mRNAs for subunits of the GABAA receptor were increased at gestational day 10.5 (Mackler et al., 1996), and
GABA can exert a trophic influence early in CNS development. A detailed study of sonic hedgehog (shh) mRNA
expression has recently been conducted (Mackler and Koebbe, unpublished data). shh plays a critical role in the
induction of neuronal phenotypes along the ventral CNS, including dopaminergic cells in the midbrain. Cocaine
treatment for 3 days preceding the appearance of shh mRNA did not alter its spatial and temporal pattern of
expression. In addition, the appearance of shh in the eye and limb buds also did not change after maternal cocaine.
treatment. Fetuses and neonates without obvious structural defects after maternal cocaine treatment do not appear,
in the majority of experiments, to exhibit permanent biochemical and physiological alterations.
A comparison of the developmental effects of cocaine and methaphetamine. (CV Vorhees, University of
Cincinnati, Cincinnati OH) Animal studies describing offspring behavior after exposure to cocaine have been
reviewed (Spear 1995, Vorhees 1996); the present discussion is restricted to the effects of the stimulants cocaine.
m&hetamine (MA), or 3.4-methylenedioxymethamphetamine (MDMA) on spatial learning. Critical factors in
these experiments include the dose, dose rate, and stage of development at exposure, along with controls for litter
effects, drug-induced diet reductions, and maternal rearing. In addition, for assessments of spatial learning using
Morris mazes. the ratio of the search area to target size is important: tbe higher this ratio, the greater the spatial
demands and more valid the results. In one study, an impairment was observed on the first trial of learning in
cocaine-exposed offspring (s.c. 10 mg/kg on E3-17; tune of conception=E0), but no specifications for the task were
provided (Smith et al., 1989). Another study found no impairment in cocaine-exposed offspring (p.o. 60 mg/kg on
E13-20; Riley and Foss, 1991). but the spatial configuration ratio was 67:1, near the lower limit for assessing
spatial learning. Reduced learning also occurred in the first 8 trials of acquisition (s.c. cocaine 40 mg/kg on E7-21)
using surrogate dams (Heyser et al., 1995). Analyses of swim path types in this study revealed no other differences,
suggesting that the cocaine deficit was not a true spatial deficit. Others have investigated the effects of prenatal
cocaine on working memory. Radial arm maze deficits occurred in cocaine offspring (s.c. 30 mg/kg on E7-19;
Levin and Seidler, 1993). Abnormal Morris maze working memory without radial arm memory deficits has also
been seen (s.c. cocaine 15 mg/kg b.i.d. on E7-19; spatial configuration ratio 256:1; Cutler et al., 19%). These data
on prenatal exposure suggest that cocaine may have some effect on working memory, but either a modest or no
effect on spatial learning/refetence memory. In contrast reuptake inhibitor-releaser stimulants (MA and MDMA)
have pronounced effects on spatial learning/reference memory. For prenatal MA (s.c. 15 or 20 mg/kg b.i.d. on E712 or 13-18; Acuff-Smith et al., 1995). reference memory was affected without acquisition deficits. By contrast,
neonatal exposure to MA (b.i.d. doses of s.c. 15-30 mg/kg MA) resulted in large spatial learning deficits in the
Morris maze (spatial ratio 317:1) after postnatal days (P)11-20 treatment, but not after P1-10 treatment (Vorhees et
al., 1994; 1997). This effect has been found in three different strains of rats and ranges from a 20-50% deficit in
performance depending on the dose and strain. Similar spatial acquisition deficits occurred in rats after P11-20
treatment with MDMA (b.i.d. 20 mg/kg), along with deficits in sequential learning in a multiple-T swimming
maze (b.i.d. 5,10 and 20 mg/kg). Overall, the data suggest that there are striking differences between cocaine and
other stimulants in their effects on spatial learning and memory. These effects are dependent on the stage of brain
development at which exposure occurs.
Does prenatal cocaine use adversely affect human infants? (H. Hurt, Albert Einstein Medical Center, Philadelphia
PA). The long-term outcomes of children exposed to cocaine while in utero are not clear. These outcomes are
extremely difficult to measure, and many confounding variables that are present in groups of women who used
cocaine. during their pregnancies have complicated most studies. These variables include poor prenatal care, the use
of other drugs, the presence of sexually-transmitted diseases and other ilhtesses, and chaotic lifestyles. The children
of cocaine-using mothers may be raised in unenriching home environments and have minimal interactions with their
caregivers. Many previous studies, which have been limited by these multiple confounders, also have had inherent
28
problems in their design, including the absence of proper control groups, small numbers of subjects, examiners that
have not been blinded 10 the childrens’ exposure status. the use of nonstandard instruments, and inadequate
adjustments for confounding variables. Cocaine does adversely affect human pregnancy, including fetal loss,
abruptio placentae, preterm labor, preterm delivery, and meconium-stained amniotic fluid. What about immediate
effects on these babies when they are born? Most investigators have concentrated on studies of central nervous
system function. There are findings from many studies that demonstrate neurobehavioral abnormalities in the
immediate postnatal period (e.g. Eisen et al., 1991). It is in the long-term period, up to ages when these children
will enter school. that results are now being described. Differences in recognition memory and information
processing between cocaine-exposed and control infants at 13 months have been reported (Jacobson et al., 19%), and
infant motor performance is abnormal at four and seven months. These changes in infant motor performance are no
longer detectable at 15 months of age (Fetters and Tronick, 19%). Deficits in cognitive function, using the Bayley
Scales of Infant Development, the Stanford-Binet, and the McCarthy Scales of Childrens’ Abilities in children 2 to 3
years of age, have not been identified (Griffith et al., 1994). Less age-appropriate play and representational play
have been reported in toddlers exposed to multiple drugs, but no differences in play were observed after comparing
videotapes of 83 cocaine-exposed to 93 control children. In the latter study the examiners were blinded 10 the drug
exposure status of each child. The Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) was
performed in an inner-city cohort of 71 cocaine-exposed and 78 control children. No differences in IQ were noted al
the age of four years. This cohort was subdivided into three groups by reports of the frequency of maternal cocaine
use: no exposure; light exposure (<3 times per week); and heavy exposure (>3 times per week). No differences in
IQ scores were observed and the results from this study do not support a dose-response relationship between cocaine
exposure during pregnancy and long-term cognitive function. All of these studied children lived in an inner-city
environment in families with a low socioeconomic status (Hurt et al., 1996). and these factors may have contributed
to the low IQ scores observed in all three groups. Another study of older children after cocaine exposure while in
utero (Richardson et al., 1996) did find a decreased ability to sustain attention at six years of age when compared to a
non-cocaine-exposed group. In summary, the data so far do not conclusively demonstrate a long-term detrimental
effect that is solely attributable to cocaine exposure in utero. Concern for adverse outcomes on cognitive
performance, based on animal studies and anecdotal reports, should remain high and careful observation of these
children will need to occur during the early school years. It is critical to define if identifiable problems are present
so that appropriate interventions can be designed. Children may be able to recover from subtle structural or
chemical alterations that occur in response to cocaine exposure during development; however, the environment in
which they are raised may not allow them to achieve age-appropriate levels of cognitive function.
REFERENCES. References are not all listed because of space limitations. A full list of citations is available from
Scott A. Mackler ((215) 8236034; email smackler@mail.med.upenn.edu).
El-Bizri, H.; Guest, I.; Varma, D.R. Effects of cocaine on rat embryo development in vivo and in cultures. Ped
Research 29:187-190, 1991.
Fantel, A.G.; Barber, C.V.; Mackler, B. Ischemia/reperfusion:a new hypothesis for the developmentaI toxicity of
cocaine. Teratology 46:285-292, 1992.
Griffith, D.R.; Azuma, S.D.; Chasnoff, I.J. Three year outcome of children exposed prenatally to drugs. J Am Acad
Child Adolesc Psych 33:20-27, 1994.
Henderson, M.G.; McConnaughey, M.M.; McMillen, B.A. Long-term consequences of prenatal exposure to cocaine
or related drugs:effects on rat brain monoaminergic receptors. Brain Res Bull 26:941-945, 1991.
Hurt, H. et al., Inner city children with in utero cocaine exposure do not differ from controls on Wechsler Preschool
and Primary Scales of Intelligence-Revised (WPPSI-R). Ped Res 49:268A. 1996.
Spear, L. P. in Neurobehavioral consequences of gestational cocaine exposure: A comparative analysis. Advances
in Infancy Research, eds. Rovee-Collier, C. & Lipsett, L. P. Ablex Publishers, Norwood, NJ, 1995, pp. 55-105.
Vorhees, C.V. in Long-term effects of developmental exposure to cocaine. on learned and unlearned behaviors. NIDA
Research Monograph Series: Behavioral Studies of Drug-exposed Offspring: Methodological Issues in Human
and Animal Research, eds. Weatherington, C. L., Smeriglio, V. L. & Finnagen, L. P. U.S. Dept. of Hlth. and
Human Services, National Institute on Drug Abuse, Rockville, MD, 1996, pp. 3-52.
Wilson, J.G. Current Status of Teratology-General Principles and Mechanisms Derived from Animal Studies. In:
J.G. Wilson and F.C. Fraser eds. Handbook of Teratology, vol 1. Plenum Press, NY. 1977, pg 47-74.
29
SYMPOSIUM VI
DRUGS OF ABUSE, IMPULSIVITY AND RISK-TAKING
H. de Wit and G. Heyman
Department of Psychiatry, University of Chicago, Chicago, IL
Summary
Impulsivity and drug abuse are closely related. Drug abuse is believed to result from impulsive tendencies, and it is
sometimes also thought to cause impulsive behavior. Impulsive behavior may be defined as the tendency to act
without thought to future consequences. Thus. for example, some young people may experiment with drugs
without regard to the risk of future addiction and its attendant health risks. Further. it is believed that certain drugs.
such as alcohol, acutely increase lhe likelihood of engaging in risky behaviors, such as driving, without regard to
the consequences. Researchers have developed operational definitions and laboratory models of impulsive behavior
which frame the concept of impulsivity in terms of control by immediate versus delayed consequences, and in terms
of certain versus uncertain consequences. In this symposium, researchers will present their models of impulsive
behavior, and discuss lhe relationship of impulsivity to drug abuse. In addition, the possible physiological and
neurochemical mechanisms which underlie impulsive behavior with be discussed. Behavioral models of impulsive
behavior, using both humans and non-humans as subjects, will enable researchers to systematically explore the
behavioral and neural processes involved in impulsivity. Dr. Ainslie will present a quantitative model of impulsive
decision making which provides a framework for systematic study of impulsive behavior. Drs. Schuster, Johanson
and Greenwald will present results from experiments in which they have tested patients with antisocial personality
disorder on a Iaboratory-based procedure designed to measure impulsivity. Dr. Pihl will present results regarding
physiological and biochemical mechanisms which may underlie aggressive and impulsive behavior. Drs. Richards.
Sieden and de Wit will present data on the effects of abused drugs on models of impulsive behavior and risk taking
in humans and rats. As discussant Dr. Heyman will attempt to integrate lhe various approaches to impulsive
behavior discussed in the symposium.
A Picoeconomic Approach to Addiction
G. Ainslie
Veterans Affairs Medical Center, Coatesville, PA and Temple Medical School, Philadelphia,
PA
Substance abusers usually suffer from a failure to integrate their decisions over time, sometimes to the point of
actual dissociation. Conventional utilitarian analyses of substance abuse cannot lake this integration problem into
account because they assume that people discount the value of delayed goals in proportional, exponential curves.
However, there have been several experiments showing that people’s spontaneous valuations of one-lime events
decline in a hyperbolic curve as a function of delay. This finding is consistent with a large hody of animal research.
Hyperbolic discount curves suggest an innate tendency for people’s preferences at one time to differ from those of
later times. Integration among successive motivational states will then require strategic bargaining much like that
among agents engaged in limited warfare. Substances of abuse seem to be both exacerbators of intertemporal
conflict and tools in intertemporal bargaining.
30
MEASURES OF IMPULSIVITY TRAIT AND STATE CHARACTERISTICS
R. O. Pihl, P. Conrod, K. Helmers, D. Lemarquand*, S. Young, J. Pelterson*, C. Benkelfat,
J. Seguin*, P. Harden, and R. Tremblay*
Dept. of Psychology, McGill University, Montreal, Canada; * University of Montreal,
Montreal, Canada; and * Harvard University, Cambridge, MA
Studies are presented which support three points. The first point is that “impulsivity”, variously measured, is
related to drug abuse and the form of comorbid psychopathology. An assessment of 300 drug dependent women
revealed live clusters of which one, impulsivity, did not distinguish the drug abused but did differentially correlate
with a diagnosis of ASPD. The second point is that impttlsivity is a concept with many possible and frequently
used but not often non related measures. In a second study, ninety eight, young adult males completed an extensive
battery of putative paper and pencil and behavioral tests of impulsivity. For the paper and pencil tests four factors
were determined and none of them were strongly correlated with the behavioral measures. The final point is that
specific frontal cortical and serotonergic functioning is linked to impulsivity. Here the results of studies are
presented which show that a relative dysfunction in working memory predicts impulsive/aggressive behavior and
that a tryptophan depletion manipulation increases behavioral impulsivity in individuals at risk for alcoholism and
with histories of aggressive behavior.
EFFECTS OF ABUSED DRUGS ON A LABORATORY MODEL OF IMPULSlVlTY AND
RISK TAKING IN HUMANS AND NON-HUMANS
J. B. Richards and H. de Wit
Department of Psychiatry, The University of Chicago, Chicago, IL
These studies illustrate the use of a laboratory model of impulsive behavior in humans and laboratory animals. The
model is based on the concept that impulsive individuals discount the value of future consequences (rewards and
punishers) more than non-impulsive individuals. In the procedure. reinforcer magnitude is adjusted as a function of
the subjects’ choice responses. We present results of several studies in healthy young adults, psychiatric outpatients
and rats. In all studies, discounting was well characterized by a hyperbolic discount function. In healthy young
adults, discounting of reward value was moderately correlated with paper pencil tests of impulsivity, but alcohol had
no effect on this behavior. In psychiatric outpatients, individuals with a history of impulsive symptoms discounted
the value of delayed and uncertain rewards more than other patients without a history of impulsivity. In rats,
amphetamine decreased discounting whereas haloperidol increased discounting. Scrotonin lesions affected probability
discounting (made the rats more risk prone) without affecting delay discounting. Taken together, these results
indicate that discounting by delay and probability represent a similar behavioral process in humans and rats, and that
the procedure is a valid and sensitive measure of impulsivity. Parallel studies with humans and non-humans may
provide a powerful approach to studying the behavioral and biological processes which underlie impulsive decision
making.
ACKNOWLEDGMENTS: Supported by DA-09133 and DA-10588.
31
EFFECTS OF ANTISOCIAL PERSONALITY DISORDER (APD) ON RISK-TAKING
BEHAVIOR
M. K. Greenwald, R. K. Brooner*, C. R. Schuster, and C.-E. Johanson
Dept. of Psychiatry and Behavioral Neurosciences, Wayne State Univ. School of Medicine,
Detroit, MI; *Dept. of Psychiatry and Behavioral Sciences, Johns Hopkins Univ. School of
Medicine, Baltimore, MD
Antisocial drug abusers engage in high levels of risk-taking, including adverse socioeconomic activities (e.g.,
criminality) and behavior (e.g., using dirty needles, unsafe sex) that increases the likelihood of HIV transmission.
This study validates a new laboratory model of economic risk-taking (Quick Decision Task, Greenwald et al., in
preparation) in methadone-stabilized clients (50-80 mg/day) diagnosed with APD and non-APD matched Controls.
On two consecutive days, testing occurs before and after methadone dosing. On discrete trials in a mock traffic
tight situation, participants (11 APDs and 6 Controls to date; target n= 18/group) begin keyboard responding during
the green light and, during the yellow light (3-7 s), decide whether to complete different fixed ratios (FR 15 - FR
50; response cost) or stop responding before the red light appears. Probability of risk-taking (trying to complete the
FR, independent of outcome) to earn the reinforcer ($0.25 per trial) is assessed under varying punishment conditions
(12.5%, 37.5% or 100% of money loss). i.e., money is subtracted for unsuccessful risk-taking depending on the
condition. Initial results show significant linear increases in risk-taking with lower response cost and less certain
punishment, and trends toward increased risk-taking for APDs (group effect), particularly with more certain
Punishment (group x punishment interaction). At present, no systematic effects of time since methadone
administration (possibly related to early withdrawal signs) on risk-taking have emerged. APDs also report levels of
gambling behavior that are substantially greater than Controls. If these interim findings persist with the full
sample, they suggest that APDs engage in greater overall economic risk-taking and are relatively less sensitive
(i.e., their behavior is not suppressed) to possible monetary loss than their non-APD counterparts. The present
methods represent a promising new approach to study determinants of and treatment interventions for pathological
risk-taking.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 05569.
32
SYMPOSIUM VII
RECENT PROGRESS IN TRANSPORTER RESEARCH
R. Blakely, S. Jones, J. Justice, M. Kuhar, and N. Volkow
Introduction
This symposium reviews developments in neurotransmitter transporter research from molecular, cellular. system and
human level. At the molecular level, Kuhar discusses development of DAT inhibitors leading to potential new
medications for the treatment of cocaine abuse. Also at the molecular level, Justice describes studies on substrates
which help to characterize the kinetics and mechanism of the catecholamine transporters. At the cellular level, the
regulation of neurotransmitter transporters affects the temporal and spatial charactecristics of neurotransmission, by
controlling the extent uptake removes transmitters following release. Blakely discusses this regulation from a
genetic point of view. At the system level, the consequences of the absence of transporters are examined by Jones in
DAT knockout mice. In humans. the relationship between the extent of DAT transporter occupancy and subjective
feelings are examined.
TRANSPORTERS AND MEDICATIONS DEVELOPMENT
M. J. Kuhar, F. I. Carroll, L. Howell, and S. Dworkin
Neuroscience Division, Yerkes Regional Primate Center, Atlanta, GA (MJK,LH), Research
Triangle Park, NC(FIC), Bowman Gray School of Medicine, Winston Salem NC(SD)
Because the dopamine transporter (DAT) is thought to be a key “receptor” site for cocaine and other
psychostimulants, it is a key target for medications strategia. There are many kinds of medication needs.
Substitute agonists are accepted and proven in the addiction field. However, no such medication exists for cocaine
abusers and much research is directed towards this need. Key features of substitute-agonist medications include high
potency and selectivity for the transporter, a slow entry into the brain and a reasonably long duration of action.
Also, it is necessary that a high occupancy of DAT by medications is achieved under treatment conditions. Our
group has been examining a series of phenyltropane compounds that include several compounds with useful
features. RTI-113 is potent and selective for the DAT. enters the brain more slowly than cocaine and is long acting.
In studies in primates, it generalizes 100% to cocaine. Also, in primates, it causes an efflux of dopamine as
measured by microdialysis. In rats, pretreatment results in a dose-responsive reduction in cocaine selfadministration; these doses result in a high (>50%) occupancy of DATs. Thus, many phenyltropane compounds
may be useful medications for cocaine abusers.
CHARACTERIZATION OF SUBSTRATE TRANSPORT AT CATECHOLAMINE
TRANSPORTERS
J. B. Justice, J. Kable, K. Danek, and B. Reed
Department of Chemistry, Emory University, Atlanta, GA
One of the goals of NIDA is the development of medications useful in the treatment of drug abuse. A primary target
of this research effort is the dopamine transporter because it is the site at which cocaine appears to act to produce
its reinforcing effects. Thus, considerable work has been done to study inhibition of transport and structural
requirements of inhibitors. To better uderstand the mechanism of the dopamine (DAT) and the norepinephrine
(NET) transporters, we have been examining these transporters from the point of view of substrates rather than
inhibitors. Using voltammetric methods combined with transporters expressed in cell lines, the kinetics of
catecholamine transporters can be characterized with respect to uptake and efflux under a variety of conditions, using
a range of substrates. Rotating disk electrode voltammetry provides rapid mixing and a complete time course of the
33
concentration of substrates added to a medium containing cells expressing hNET or hDAT. The decreasing
concentration of electroactive substrates such as DA and NE can be followed as they are taken up from the medium
into the cells until steady state is reached, and their efflux observed when a second substrate is then added to the
medium. When two electrodes are used, it is possible to simultaneously observe the uptake of an electroactive
substrate such as tyramine and the induced efflux of dopamine.
The effects on the rate of transport of ring substituents at the para position of phenylethylamine were examined for
the series H, F, OH, CH3, OCH3, NH2, Cl, Br, and NO2 The rate was found to vary inversely with size of the
substituent. Regression coefficients above .95 were found for several measures of size used in structure activity
studies. Other structure activity parameters, such as bydrophobicity or Hammet’s sigma did not correlate
significantly with rate of transport. Evidently, as the size of the substituent increases, the substrate is less able to be
transported, either because it binds less effectively, or because the transport step is retarded. Preliminary work
suggests that binding is affected in a manner similar to the rate of transport, suggesting that it is the primary factor
affecting the observed substituent effect.
REGULATION OF COCAINE AND ANTIDEPRESSANT-SENSITIVE NOREPINEPHRINE
AND SEROTONIN TRANSPORTERS
R. D. Blakely, S. Ramamoorthy, S. Apparsundaram, and S. Schroeder
Department of Pharmacology, Vanderbilt University, Nashville, TN
The biogenic amine transporters constitute powerful modulators of DA, NE, and 5HT action by efficient clearance
of transmitter away from synaptic spaces. These transporters share structural similarity and ate encoded by separate
genes on different chromosomes. The powerful consequences of exogenous agents that alter transporter function,
including addictive agents and antidepressants, raise the question of whether nature has figured out how to regulate
transport systems using endogenous mechanisms. I will describe our recent studies to evaluate kinase-mediated acute
regulatory influences impinging on biogenic amine transporter function, focusing on studies of the cloned
norepinephrine and serotonin transporters. These studies will be placed in the light of recent findings suggesting
genetic mechanisms contributing to altered transporter function and behavior in humans.
PROBING THE PHYSIOLOGY OF DOPAMINE IN GENETICALLY ALTERED MICE
LACKING THE DOPAMINE TRANSPORTER
S. Jones, R. Gainetdinov, and M. C. Caron
Howard Hughes Medical Institute, Duke University, Durham, NC
Targeted inactivation of the dopamine transporter gene in mice produces a phenotype in which the animals display
marked spontaneous hyperlocomotion and no further increase in locomotion after psychostimulant administration
(Giros et al, 1996). The dopamine transporter plays an important role in calibrating the duration and intensity of
dopamine neurotransmission in the CNS. In mice lacking the transporter, basal extracellular concentrations of DA
in the striatum are 5-times higher than in normal mice, clearance of extracellular DA is 300-times slower and is
governed solely by diffusion. Electrically stimulated dopamine release was induced by 75% in homozygotes and
50% in heterozygotes when compared to wild type values, a finding consistent with HPLC measurements which
showed greater than a 90% decrease in striatal dopamine in homozygotes and 40% in heterozygotes. Our findings
demonstrate that the marked increase in spontaneous locomotor activity in mice without transporters, despite low
levels of dopamine and receptors, is probably due to the prolonged time that DA spends in the synapse after release.
These alterations in DA dynamics are accompanied by dramatic adaptive changes in the synthesis, storage, release
and degradation of intracellular DA. In addition. DA autoreceptor function was completely disrupted in mice lacking
the transporter. These changes uncovered previously unappreciated points of DA homeostatic regulation. Thus, the
dopamine transporter not only controls the duration of extracellular dopamine signals but plays a critical role in
regulating presynaptic dopamine function.
34
RELATIONSHIP BETWEEN COCAINE-INDUCED SUBJECTIVE EFFECTS AND
DOPAMINE TRANSPORTER OCCUPANCY
N. D. Volkow, M. Fischman, G.-J. Wang, R. Foltin, J. S. Fouler, N. N. Abumrad, S.
Vitkun, J. Logan, and C. Shea
Brookhaven National Laboratory, Upton, NY
The reinforcing effects of cocaine are generally accompaniecd by self-reports of euphoria or “high”. Although the
mechanism(s) underlying this effect has not been investigated in humans, studies with laboratory animals have
provided compelling evidence that inhibition of dopamine transporters (DAT) is involved in the reinforcing effects
of cocaine. However, the relationship between self-reports of “high” and acute DAT blockade has never been
established. Methods: Occupation of DAT by different doses of cocaine was measured with PET using
[11C]cocaine as a DAT ligand in 18 active cocaine abusers. The ratio of the distribution volume of [11C]cocaine
in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was our measure of DAT availability. In
parallel subjective effects (“high”, “rush”, “restlessness and “cocaine craving”) were measured to assess the
relationship between DAT occupancy and cocaine’s behavioral effects. Results: intravenous cocaine reduced the
binding of [11C]cocaine in the striatum but not in cerebellum. Bmax/Kd measures were significantly induced by
all doses of cocaine and the estimated DAT occupancies corresponded to: 73 % for 0.6 mg/kg; 60% for 0.3 mg/kg;
48 % for 0.1 mg/kg iv and 40 % for 0.05 mg/kg. For subjects tested twice with the same cocaine dose the testretest reproducibility of DAT occupancy measures were within 10 %. DAT occupancies were significantly correlated
with cocaine plasma concentration (r = 0.81, p < 0.0001). Cocaine also produced dose- dependent increases in selfreported ratings of “high” which were significantly correlated with the levels of DAT blockade (r = 0.55 p < 0.001).
Discussion: These results provide the first documentation in humans that DAT occupancy is associated with
cocaine induced subjective effects. They also suggest that DAT occupancies equal to or greater than 60% are
required to produce significant effects on ratings of “high”.
ACKNOWLEDGMENTS:
Supported by Department of Energy and NIDA
35
SYMPOSIUM VIII
DRUG ABUSE AND THE GENOME
G. Uhl, L. Yu, E. Simon, M. J. Kreek, and T. R. Kosten
NIDA, Indiana University, NYU Medical Center, Rockefeller University, and Yale University
Dr. Uhl indicated how the genes relatted to several abused substances have now been identified: the dopamine
transporter for psychostimulant reward, and the opiate receptor for opiate reward. Analyses of site-directed mutants
and chimeras have yielded evidence for participation of different features of these receptor proteins for intrinsic
activity, affinity, G-protein recognition and phosphorylation.
The DAT gene accounts for the pharmacologically-defined dopamine transporter. Extensive DAT structure/function
studies first identified sites at which mutations could selectively influence dopamine transport or cocaine analog
recognition, providing substantial support for development of cocaine antagonists. Availability of DAT and
VMAT2 cDNAs revealed that amphetamine reward in murine models depends on actions at synaptic vesicles as well
as at DAT, while cocaine reward does not depend on intact vesicular transporter function. They also document how
cocaine reward in murine models is sensitive to even modest, 30-50% differences in the levels of expression of
DAT.
Studies in transgenic mice, with interruption of the µ receptor gene document the absolute dependence on intact µ
receptor function for full morphine analgesia and reward Indeed, much of the analgesia that delta and kappa
agonists provide also appears to be µ dependent Active post-translational receptor regulation of the mu receptor
contrasts with little transcriptional regulation even after prolonged opiate agonist treatment.
Neuropeptide neurotransmitter genes are often subject to extensively regulated expression. Some of this regulation
can be. mimicked through use of relatively short heavily-regulated promoter elements. Transcription factor genes
can also be regulated in response to synaptic activities and drugs. Transcription factor regulation can display
striking adaptive changes with chronic drug regimens, but drug receptor genes, including those for opiates and
psychostimulants, are often minimally regulated by drug administration.
We believe that identification of each of the genes regulated by abused substances, characterization of the patterns
of regulation, and mimicking this regulation in model systems provides one of the most powerful currentlyavailable tools to identify potential candidate molecular underpinnings for addiction.
Dr. Yu summarized how drugs of abuse affect brain neurotransmitter systems, thereby exerting their CNS effect.
Molecular cloning and cellular studies in the recent years have begun to unravel how drugs of abuse may influence
neurotransmitter signal transduction. This presentation provided a general overview of neurotransmitter signal
transduction, with emphasis on second messenger pathways and in channel functions, using opioid receptors and
dopamine receptors as prototype examples.
The major second messenger pathway that opioid and dopamine receptors affect is the adenylyl cyclase/cAMP
pathway. After binding of opioids or dopamine. these receptors activate specific classes of G proteins, thus
affecting the intracellular cAMP level by either increasing (D1-type dopamine receptors) or decreasing (D2-type
dopamine receptors and opioid receptors) the adenylyl cyclase activity.
These receptors also modulate neuronal excitability by regulating the activity of specific ion channels. For
example, by expressing the cloned mu opioid receptor in cells, it can be shown that opioids can inhibit certain
calcium channel activities. This suggests that one way for opioids to inhibit synaptic activity is by decreasing
presynaptic calcium channels. Furthermore, activation of the expressed mu opioid receptor results in opening of a
class of G protein-activated potassium channels (GIRK channels), causing a hyperpolarization of the cell. This
could be another cellular mechanism of neuronal inhibition.
36
One emerging paradigm of neurotransmitter signal transducdon is that protein kinases may play a major role in
regulating neurotransmitter receptor activity. For instance, when protein kinase C or calcium/calmodulin-dependent
protein kinase is activated, mu opioid receptor coupling to the GIRK channels is reduced, resulting in rapid
desensitization. This desensitization resembles the clinical phenomenon of opioid tolerance, i.e., upon repeated
opioid usage, the responsiveness of the subject is reduced. Further studies areneeded to determine whether such
protein kinase-mediated processes contribute to the onset of opioid tolerance, and may provide clues for more
effective ways of clinical intervention.
Dr. Simon dealt with several aspects of his recent studies on opioid receptors. In line with a broad interpretation of
the Symposium title, they all relate to opioid receptor genes (or cDNA). The first portion summarized studies by
Dr. Matthew Andria on the promoter region of the human receptor gene. Dr. Andria has cloned the genomic DNA
that encodes the human receptor. He has sequenced the 5’ terminal portion and has concentrated his studies on the
DNA upstream of the start codon for protein synthesis. He has made constructs in which this sequence or portions
thereof, were used to promote the expression of a luciferacc indicator gene, when the plasmid wastransfectwd into
differentiated SK-SY5Y cells. He has demonstrated that two short segments of approximately 50 bp have promoter
activity. He has also shown that promoter activity is greatly decreased when the DNA is methylated enzymatically
in vitro. Finally, he has shown significant differences in level of methylation between cell lines that express
receptors and lines that do not. The results have led him to the hypothesis that methylation is a very important
regulator for expression or non-expression in nervous tissues, while it appears to be one of several regulators of
non-expression of the gene in non-neuronal tissues.
The second part of the lecture summarized his work on the bovine receptor including its purification to
homogeneity and its reconstitution and recoupling with G proteins in liposomes. Recent work by Ms. Irma
Onoprishvill, Dr. Sven Villem, and Dr. Andria on the cloning of the bovine receptor and its expression in HEK
293 cells was presented.
The final portion of the talk dealt with a site-directed mutagenesis study by Dr. George Ehrlich carried out on the
recombinant receptor. Two extracellular loop and six transmembrane cystcine residues were replaced by serine (or
alanine). It was found that the replacement of the transmembrane cysteines had little or no effect on opioid agonist
or antagonist binding. However, as expected from analogy with other G protein-coupled receptors, the extracellular
cysteine residues, which form a disulfide bridge, are essential for ligand binding. Their replacement resulted in
complete absence of binding. The presence of the mutant receptor in the cell membrane was demonstrated by
immunocytochemistry carried out on the cells by Dr. Boris Veksler.
Dr. Kreek gave the final presentation on molecular and clinical studies of effects of drugs on dynorphin, kappa
receptor and related gene expression and activity. The amino acid sequence of the kappa receptor is closely related to
the other two opioid receptors (mu and delta) with most differences in the N terminal (ligand binding end of receptor
protein) and the C terminal (G protein signal transduction end of the receptor protein). The kappa receptor binds
dynorphin with high aftinity, and dynorphin appears to act as a neurotransmitter between the caudate-nucleus
accumbens (NA) and the substantial nigra-ventral tegmental area (VTA). In this pathway, it acts as a feedback loop
for the dopamine system. This feedback activity is supported by direct application of dynorphin into the VTA
where it reduces dopamine release in the nucleus accumbens.
In animals given 14 days of a binge pattern of cocaine administration, both basal and cocaine stimulated release of
dopamine in the NA and caudate were reduced compared to baseline dopamine levels, and dynorphin may contribute
to this reduction through the above feedback loop. In a test of this hypothesis using molecular biology techniques,
preprodynorphin messenger RNA levels were measured in the caudate and NA. These mRNA levels were elevated
consistent with greater synthesis and release of dynorphin. This dynorphin could then reduce dopamine release
through the above feedback inhibition pathway to the VTA and substantial nigra. This rise in preprodynorphin was
blocked by administration of a D1 receptor antagonist during the 14 day cocaine hinge cycle. but was not blocked
by a D2 dopamine antagonist.
37
These molecular biological findings led to clinical studies of dynorphin effects on dopaminergic systems. Using
prolactin blood levels as a marker of dopaminergic activity, dynorphin was found to increase prolactin in a dose
dependent manner. This increase was only partially blocked by naloxone (30 mg IV) or nalmefene suggesting that
this dynotphine effect was not entirely mediated by kappa opioid receptors. Nevertheless, dynorphin and other
kappa ligands may be potential treatment agents for not only opioid but also stimulant dependence, because of its
efticacy in reducing dopaminergic activity in the brain’s reward pathway between the VTA and NA.
ACKNOWLEDGMENTS: This work was supported by grant DA-0017 from the National Institute on Drug
Abuse (NIDA) to EJS and a K-21 award, also from NIDA, to Dr. Andria.
38
SYMPOSIUM IX
COMMUNITY-BASED OUTREACH AS AN HIV RISK REDUCTION STRATEGY FOR OUTOF-TREATMENT INJECTION DRUG USERS (IDUS)
S. L. Coyle and R. H. Needle
National Institutes on Drug Abuse, National Institutes of Health, Rockville, MD
Introduction: This presentation reviews the literature on the impact of two widely used outreach models on HIV
risk and protective behaviors. The typical outreach intervention offered in NIDA’s NADR and Cooperative
Agreement programs hid indigenous community workers to meet drug users in the streets and injection settings.
provide risk reduction information and referrals to services, and distribute condoms and bleach; usually, outreach also
included making arrangements for IDUs to receive HIV antibody testing and pre- and post-test counseling. which
included demonstration and rehearsal of risk reduction skills. Behavioral and ecologic data were collected at baseline
and six months post-intervention. Methods: We reviewed 36 published studies that evaluated the effectiveness of
the outreach-based intervention in facilitating changes in risk behaviors of IDUS, using single and multiple samples
of IDUS. Results: Outreach interventions have helped IDUs reduce their risk-taking behavior, particularly drug and
needle using practices, and to a lesser extent sex risk behaviors. The following summary of published data illustrates
the magnitude of changes. Termination of drug injection: Nine of 10 studies reported significant numbers of IDUs
who stopped injecting at follow-up (between 24 and 31% of IDUs reported stopping; the median at follow-up was
26%). Reduced frequency of injection: Sixteen of 17 studies reportced significant decreases in injection frequency
(range: 11 to 62 fewer injection events per month; median was 28 fewer injection/month.). Reduced multiperson
reuse of syringes/needles: Sixteen of 20 studies reported significant decreases in multiperson reuse of injection
equipment (range: 14 to 43% fewer IDUs reused syringes; median was 19%). Reduced multiperson reuse of drug
preparation paraphernalia: Eight of studies reported significant decreases in multiperson paraphernalia reuse (range:
16 to 34% fewer reports of equipment reuse in last month; median was 27% fewer reports). Reduced HIV incidence
accompanying reductions in risk behaviors: a single study reported on both behavioral and serological outcomes and
found significant reductions in injection risk as well as HIV incidence. Conclusions: Outreach-based intervention
has been a successful risk reduction strategy. Outreach has provided access to the means for behavior change, and a
significant proportion of IDUs have changed their behaviors following exposure to outreach interventions.
DRUG TREATMENT AS AN HIV PREVENTION STRATEGY
J. L. Sorensen and A. Copeland
University of California, San Francisco, at San Francisco General Hospital
Drug abuse treatment can be a powerful tool for preventing infection with HIV. Treatment can directly prevent HIV
infection by causing patients to decrease their risky needle use and sexual behavior; treatment can indirectly prevent
HIV by assisting patients toward rehabilitation and serving as a platform for other HIV prevention services.
Recently published research on the utility of drug treatment as an HIV prevention strategy has focused primarily on
methadone maintenance treatment (MMT). Recent studies provide clear evidence that MMT reduces HIV risk
behaviors, particularly needle use. The research provides less definitive evidence that MMT reduces needle sharing
and unsafe sexual behavior. Studies of HIV seroconversion can be more conclusive than studies of self-reported HIV
risk behaviors about the prevention of HIV infection. Several studies of HIV seroconversion published in the early
1990s indicate that MMT protects against acquiring HIV infection. Thus the literature is clear that MMT has a
significant effect in preventing HIV infection. Future studies need to take into account self-selection processes,
such as treatment dropout of high-risk drug users, and they need to investigate other treatment modalities for heroin
or stimulant abuse to determine their effects on HIV risk and HIV infection.
ACKNOWLEDGMENTS: Supported by NIDA grants R01-DA08753 and P50-DA09253.
39
SYMPOSIUM X
GENETIC AND ENVIRONMENTAL INFLUENCES ON DSM-III DRUG USE AND
DIAGNOSES OF ABUSE/DEPENDENCE
M. van den Bree, E. Johnson, and R. Pickens
Division of Intramural Research, NIDA, Baltimore, MD and ‘Department of Psychiatry,
Henry Ford Health Sciences Center, Detroit, MI
Information was obtained on drug use (five times or more) and DSM-III diagnoses of abuse and/ or dependence or
dependence alone for male and female twins, recruited from addiction treatment centers. Univariate structural equation
analysis was used to estimate heritable and environmental influences from liability correlations of monozygotic
(MZ) and dizygotic (DZ) twins. Given a normally distributed liability, individuals with scores above a certain
threshold will have used drugs five times or more, or have received a diagnosis. Threshold estimates were obtained
from population prevalences of the Epidemiological Catchment Area (ECA) study (which also used DSM-III
diagnoses), and stratified for characteristics of the twin sample. The models included a second threshold, for
treatment status, to account for the clinical nature of the twin sample. Under models, including heritable (h2),
Common environmental (e2), and specific environmental (e2) influences. estimates were:
DRUG ABUSE: TOWARD A REFINED PHENOTYPE
E. O. Johnson
Department of Psychiatry, Henry Ford Health Sciences Center, Detroit MI
Substance abuse shows heterogeneous clinical expression and multiple etiologies, including genetic and
environmental influences. Efforts to estimate genetic and environmental profiles of individuals have received
relatively little attention in genetic research, although the benefits of doing so have been recognized. Without the
ability to separate relative genetic and environmental influence in individuals efforts to identify specific genes must
contend with unwanted environmental “noise.” Refining phenotypes to reduce heterogeneity has been a valuable
strategy for developing better understandings of etiology including identification of genes contributing to a variety
of diseases such as breast cancer and Alzheimer’s. Recently, we reported symptoms that distinguished relative
genetic and environmental loading in alcohol dependent individuals. Using data from a treatment-based twin study,
symptoms with significantly higher monozygotic (MZ) than dizygotic (DZ) concordance rates were assigned to a
“genetic” scale, while symptoms that did not were assigned to environmental scale(s). Genetic and environmental
scales were subsequently evaluated among alcohol dependent Caucasian men in the Epidemiologic Catchment Area
Study. Factor analyses identified a single dimension for the genetic scale items. Two factors were found among the
environmental scale items generating two scales: general environmental and dyssocial environmental. Use of these
tree scales in a hierarchical cluster analysis empirically identified three “naturally occurring” subtypes of alcohol
dependence: mild, severe and dyssocial. Only the severe subtype showed evidence of substantial genetic influence.
Most recently, preliminary analyses of the National Longitudinal Alcohol Epidemiologic Survey replicated the
empirical identification of the mild, severe and dyssocial subtypes and again indicated that only the severe subtypes
shows substantial genetic influence as measured by the genetic symptom scale developed in the twin sample.
Attempts to identify specific genes influencing alcohol dependence may benefit from focusing on the more
homogeuous and seemingly genetically influenced severe subtype. Furthermore this approach to refining
phenotypes for molecular genetic analyses may be applicable to substance abuse disorders in general.
40
SYMPOSIUM XI
ETHICAL LABORATORY RESEARCH WITH HUMANS: THE DEVIL IS IN THE DETAILS
M. W. Fischman and C.-E. Johanson
College of Physicians and Surgeons of Columbia University and Wayne State University
School of Medicine
Experimental studies with humans conducted in a laboratory setting are an important component of our field’s
research portfolio aimed at understanding, treating and preventing drug abuse. This symposium discussed a number
of issues that investigators should consider in conducting scientific studies of drug-related phenomena within a
laboratory setting with humans.
THE NUTS AND BOLTS OF SETTING UP A NEW LABORATORY
C.-E. Johanson
Wayne State University School of Medicine
In addition to the usual ethical concerns, special issues emerge in human laboratory-based research that are usually
not considered by ethical review committees. Although these issues may be Seen as practical rather than ethical
problems, satisfactory solutions have ethical overtones. A few examples are given below.
Medical Issues: While medical backup is usually required. level of coverage can vary considerably. Obtaining
medical backup is often difticult and quid pro quo issues, such as courtesy aurhorship, can raise ethical questions.
Solutions for handling medical/psychiatric problems in potential candidates and making arrangements for treatment
are not always clear and can involve violating volunteers’ expectations.
Drug Issues: Obtaining controlled substances is very complicated and differs by state and institution with many
of the “regulations” a matter of tradition. not law. Requirements for storage, inventory, access, and drug
administration are often vague with little consensus or firm guidelines.
Confidentiality Issues: Standard procedures for storage of information with identifiers (e.g., consent forms) are
available but leakages occur despite investigators’ best efforts. These limits to confidentiality are often the result of
conflict among different regulations. For instance, social security numbers are required to pay subjects and this
identifier paired with the source of the payment are readily accessible within an institution.
Treatment Issues: If non-treatment studies involve administration of abused drugs to substance abuser
participants, a decision must be made as to whether to recruiT those wanting treatment. Problems can arise if
treatment is included as there will be tensions between those conducting the research and those providing treatment.
Given that most studies are not long-ten-n, provision for referrals or continued treatment must be considered. This
can be problematic if the research involves medications that are not yet marketed.
Representativeness: The Federal Government mandates that consideration be given to the sex and ethnicity of
participants in research studies so as to insure representativeness. Although guidelines for determining what is
representative are vague, there is an implied threat that if the sample is not representative, sanctions will follow.
But what is representative varies by study as well as by city, and for studies that do not involve treatment and use a
very small sample, it is hard to fathom what is appropriate.
ETHICAL CONSIDERATIONS IN ADMINISTERING DRUGS TO HUMANS
M. W. Fischman
College of Physicians and Surgeons of Columbia University
Although excellent animal models are available to address many issues in drug abuse research, findings should be
confirmed in humans and, in addition, questions exist that can only be answered in humans. Federal regulations
mandate multiple levels of review including the local institutional review board (IRB), appropriate Federal funding
41
agencies (e.g., NIDA, NIAAA), the NIH Office for the protection of Research Risks (OPRR), and the Food and
Drug Administration (FDA). The informed consent process serves as the main protection for volunteers and it is the
investigator’s obligation to assure the integrity of the process with particular attention to addressing risks.
Other concerns related to the administration of drugs of abuse are frequently raised. These include: 1) exposure may
cause or exacerbate drug abuse/dependence; 2) individuals who abuse/ate dependent on drugs may not consider the
risks involved because of their desire to get drugs; and 3) exposure is often non-therapeutic and therefore without
benefit to the individual. However, exposure to drugs in a therapeutic context (e.g., opiates) does not generally lead
to abuse, and exposure for research purposes is unlikely to promote increased (or decreased) use after study cessation.
There is no basis to the assertion that drug abusers are so driven to obtain drug that they are incapable of weighing
the risks of participation. In fact, excepting when intoxicated by drug, these individuals can be quite capable of
participating in a consent process. As with all research with human participants, the investigator must assess an
individual’s capacity to provide consent prior to enrolling anyone in a protocol and refuse participation where
capacity is diminished regardless of the reason. In many cases the study of drugs of abuse occurs within a nontherapeutic context. Therefore, other benefits to the individual must exist. These can include: 1) contact with health
care professionals; 2) HIV/AIDS risk reduction education; 3) food, lodging and isolation from the risky lifestyle of
the drug abuser if the research is residential; and 4) referral to treatment.
participant selection criteria cannot be stated in the absence of experimental context. They are related to drug under
study, route and doses used, setting in which drug is administered, and question being asked. For example, study
drugs could be low dose oral caffeine or moderate dose i.v. cocaine administered in settings varying from inpatient
hospital to outpatient laboratory. Oral caffeine studies dictate a different (and broader) population than intravenous
cocaine, and inpatient vs outpatient settings dictate different study designs. Thus, participant criteria vary along a
continuum (e.g., non user to drug dependent individual, never in drug treatment to repeated unsuccessful treatment
attempts, etc.), and the specific study must determine the precise criteria to be used. Clearly, participant safety is of
primary importance and the investigator has the responsibility for implementing protocols that minimize risks and
maximize benefits. In summary, drug abuse research is necessary and important, and as with other biomedical
research, careful implementation of research protocols and concern for the well being of participants assures that it
can be carried out ethically.
SCIENTIFIC AND ETHICAL CONSIDERATIONS RELATED TO GENETIC STUDIES
R. Pickens
Division of Intramural Research, NIDA
Genetic knowledge has the potential for both improving and harming the individual and society. Benefits are related
to improvements in treatment (environmental modification, gene therapy) and prevention (early intervention,
avoidance). Harm is related to loss of privacy, discrimination in employment and insurance, damage to family
relationships, and anxiety due to inaccurate risk assessment (related to probability of gene expression,
environmental influences). As a result ethical, legal and social implications of genetics research are a major concern
for the Human Genome project. A number of practical issues are also involved in laboratory genetic research
Genotype studies attempt to relate genotype (genetic constitution) to phenotype (result of gene/environment
interaction). One of the most frequently used laboratory strategies is the at-risk family study, in which offspring
with a positive family history for a substance use disorder are compared to offspring with a negative family history
for the disorder. Although not actually a genetic study, recent data suggest familial alcoholism increases risk for
both alcohol dependence (OR=2.7) and drug dependence (OR=4.0). The sensitivity of family history as a method far
predicting alcohol and drug dependence is relatively low; however, with relative risk of family history on alcohol
dependence being similar to risk of drinking alcohol before age 18 (OR=2.6) and being mate (OR=2.4).
42
POPULATION-BASED HUMAN LABORATORY RESEARCH
S. Kellam
The Johns Hopkins University School of Public Health and Hygiene
The population laboratory is built within the social and political structure of the population itself. Such
laboratories can be developed within defined residential geographic areas. elementary school catchment areas, and so
forth. The ethical issues in building and maintaining such a laboratory are not unlike those faced in other areas of
human research although problems of confidentiality and representativeness of participants in the studies become
paramount. Two processes are initially important in developing a partnership between the scientists and leaders of
the community social and political structure: an analysis of the institutions and power structure within the
population and an analysis of the values, priorities and language interpretation of the constituencies and their
leaders. The goal is to define the scientific problem to the right people in a way that is understandable and
acceptable. Implementing the research also involves negotiation with specific leaders of all community
organizations whose constituencies lie within the population itself rather than within an agency “downtown”. ln
order to achieve partnership with community and institutional leaders along with teachers and parents, the process of
engagement and working through trust issues is paramount as is a deliberate negotiation around mutual selfinterests of all who are participating.
Our prevention research in Woodlawn, on the south side of Chicago. and Baltimore has used several models for this
process over the past 30 years. The research has focused on directing interventions at early antecedents along
developmental trajectories leading to problem outcomes such as drug abuse. Such designs always require
randomization to the intervention and control conditions, preferably at the level of individual children, teachers,
classrooms, and even schools. The model in use in the latest generation of trials in Baltimore involved follow-up at
age 19-21 of the 2311 first-grade children who were the total first grade population in 1985-87 of 19 schools in
Baltimore and who participated in two prevention intervention trials. The community base required for the intensive
assessment at follow-up was an extension of the prior base involving the Johns Hopkins School of Public Health
Prevention Research Center and the Baltimore City Public Schools. But because the participants were now making
the transition to adulthood, the Morgan State University, a traditional African American community university,
became an important newally. We were able to establish mutual interests around recruiting and developing top
undergraduates as our research assistants and interviewers through a minority supplement funded by NIH. This
minority training program provided us with needed additional resources while at the same time provided an
opportunity to develop a program of advanced training in order to help minority undergraduates develop strengths for
application to graduate education in public health. Morgan, joining together with the Baltimore City Public
Schools Board of School Commissioners and the Johns Hopkins School of Public Health allowed for a strong
community base in addition to a useful undergraduate training program. A community board comprised of leaders
within these institutions and overlapping with other community organizations provides the authority for the
research to move ahead with continual negotiations, understanding, and acceptance.
DISCUSSANT
E. M. Sellers
Addiction Research Foundation
The principles of bioethics include autonomy (the morality of mutual respect) and beneficience (the morality of
achieving good and avoiding harm). In other words “do not do to often that which they would not have done unto
them, and do for them that which one has contracted to do” and “do to others their good.” The principle of
autonomy requires, as a condition of mutual respect, that individuals be protected against both deception and
coercion. The principle of beneficience requires that there be a net benefit to others. Therefore, one should consider
the good from the research and the harm from not doing the research.
In many cases. human research is congruent with moral authority. However. what is actually done or required may
not be derived from moral authority. Successful “population laboratory” research must incorporate the principles of
bioethics since it derives from the social and political structure of the studied population and requires a partnership
which embraces the values and priorities defined in terms of the population good and harm. Population laboratory
43
research, therefore, has an advantage that direct and indirect good and harm must be clear and have the approval of
the constituency with whom the research is done. In contrast, at the institutional level, individual attitudes and
beliefs can be particularly powerful in shaping the application and interpretation of the bioethical principles of
autonomy and beneticience. Such variation probably accounts for why institutional decisions on similar issues can
be different. To offset idiosyncratic views, researchers must deliberately and systematically anticipate issues and
educate review committees since, in a secular pluratistic society, consensus needs to be developed among informed
and representative individuals on these committees. As researchers in this field, we can contribute to the evolution
of bioethical considerations by sharing our innovations and involving trainees in bioethical issues. We need to
persuade colleagues and trainees lhat a body of knowledge exists mnceming bioethical issues and that bioethics not
only informs the quality of research but also enhances its success.
44
SYMPOSIUM XIII
NOVEL APPLICATIONS OF HUMAN DRUG DISCRIMINATION FOR UNDER-STANDING
THE EFFECTS OF ABUSED DRUGS
C. R. Rush, J. B. Kamien, K. L. Preston, B. J. Smith, K. A. Perkins, and C. E. Johanson
University of Mississippi Medical Center, Jackson, MS; Addiction Research Foundation,
Toronto, Ontario, Canada: National Institute on Drug Abuse, Addiction Research Center,
Baltimore, MD; University of Vermont School of Medicine, Burlington, VT; University of
Pittsburgh, Pittsburgh, PA; and Wayne State University, Detroit, MI
Between 1985 and 1995, there has been a striking, positively-accelerating increase in the use of drug discrimination
procedures to examine the effects of commonly abused drugs in humans, with approximately 100 publications to
date. Human drug discrimination researchers ate now beginning to apply these procedures in novel ways to
understand the behavioral and pharmacological effects of commonly abused drugs. For example, it has long been
thought that the discriminative-stimulus and subjective-effects of drugs covary (Preston and Bigelow, 1991;
Schuster and Johanson, 1988; Schuster et al., 1981). Recent studies have demonstrated that the discriminativestimulus and subject-rated effects of drugs overlap, but clearly they are not isomorphic (e.g., Perkins et al., 1994;
Rush et al., 1995). In fact, human drug discrimination procedures may be more sensitive than the more commonly
used subject-rated drug-effect questionnaires, especially to the effects of low doses of drug (Perkins et al., 1994).
Finally, antagonism studies using drug discrimination procedures have begun to explore receptor mechanisms
underlying the discriminative stimulus effects of drugs in humans (e.g., Smith et al., 1996).
The papers presented in this symposium reviewed recent empirical data from studies that used human drug
discrimination procedures. The goats were to highlight: 1) the utility of human drug discrimination, 2) novel
applications of these procedures, and 3) that the use of human drug discrimination procedures in conjunction with
other measures (e.g., subject-rated drug-effect questionnaires) will further our understanding of the behavioral and
pharmacological underpinnings of drug abuse. Below are abstracts prepared by each of the participants.
USING HUMAN DRUG DISCRIMINATION PROCEDURES TO STUDY THE
PHARMACOLOGY AND ABUSE OF OPIOIDS
K. L. Preston and G. E. Bigelow
As part of a program to study the pharmacology and receptor activity of mixed agonist-antogonist opioids in
humans, our laboratory developed a method for testing drug discrimination in human subjects analogous to the
methods widely used in animal laboratory research. In a series of studies testing marketed opioid analgesics,
methodological aspects of the drug discrimination procedure were systematically varied and evaluated. Eight studies
have evaluated the effects of varying tbe training drugs, the dose of the training drugs, the number of training drugs,
the available response alternatives, and the type of pharmacological pretreatrnents. Subjects were experienced opioid
abusers, and dependent variables were measures of discrimination and subjective effects. Discrimination measures
differentiated among the agonist/antagonists, though training condition clearly altered discrimination responding.
Three-choice procedures and two-choice procedures with an “other” response alternative appeared to be more sensitive
for differentiating among drugs with different but overlapping pharmacological profiles than simple drug/placebo
two-choice procedures. There was general concordance between discriminative and subjective measures. The results
show drug discrimination to be a useful tool for evaluating the pharmacology of opioids in humans.
ACKNOWLEDGMENTS:
Supported by NIDA grants R01 DA-04089, K05 DA-00050, and the NIDA
Intramural Research Program.
45
STUDYING ETHANOL PHARMACOLOGY USING HUMAN DRUG DISCRIMINATION
PROCEDURES
J. B. Kamien
Drug discrimination procedures have not been used to study the human behavioral pharmacology of ethanol.
Establishing ethanol discrimination by humans begins to fill this research gap. In the present study, fourteen
healthy male and female volunteers (20-38 years) were trained to discriminate drinks containing 0.32 g/kg ethanol
(e.g., Drink A) from placebo drinks (e.g., Drink B) to which very small amounts of ethanol were added to mask
possible olfactory and gustatory stimuli. During the first four daily sessions, subjects were informed of the drink
label at the time of administration. During the next 4 to 12 sessions, subjects received Drinks A and B in
randomized block fashion, were not informed of drink labels and earned money for correctly identifying which drink
they had received. Seven of fourteen subjects met the criterion for discrimination (accurate drink code identification
on 4 consecutive or 5 of 6 consecutive sessions). Subsequently, the dose-response function for ethanol was
determined by administering drinks containing 0.1, 0.17, 0.32 and 0.56 g/kg. Ethanol produced dose-related
increases in ethanol-appropriate responding and on several measures of subjective effects characteristic of ethanol.
Over-ah, this research established ethanol discrimination by humans, providing a baseline for studying ethanol’s
mechanism(s) of action related to alcohol abuse. Further, ethanol discrimination by humans promises to provide a
robust model in which to evaluate possible medications for the treatment of alcoholism and alcohol abuse.
USING HUMAN DRUG DISCRIMINATION AND THE NOVEL-RESPONSE PROCEDURE
TO INVESTIGATE FUNCTIONAL VERSUS COMPETITIVE ANTAGONISM
B. J. Smith and W. K. Bickel
The novel-response procedure provides a response altemative appropriate for stimulus effects unlike either training
condition (i.e., placebo or drug). Previous studies demonstrated that drugs occasioning full substitution for placebo
or triazolam under a two-response procedure were distinguishable under the novel-response procedure. Drug
combination data assessing the effects of triazolam alone (0, 0.10, 0.32 and 0.56 mg/70 kg; triazolam-placebo), and
each dose in combination with 560 mg/70 kg caffeine (i.e., triaxolam-caffeine) under both a two-response and novelresponse procedure have been gathered in 12 participants. Participants were trained to discriminate 0.32 mg/70 kg
triazolam from placebo, and then were tested under the two-response and novel-response procedures. Under the tworesponse procedure, the triazolam-placebo dose effect curve was indistinguishable from triazolam-caffeine
combinations, with full substitution for triazolam occurring in both cases. Under the novel-response procedure,
triazolam-placebo combinations occasioned similar effects. In contrast, 0.10 mg/70 kg triazolam-caffeine
occasioned 55% novel-appropriate responding and no triazolam-appropriate responding; at 0.32 mg/70 kg triazolamcaffeine 45% novel-and 55% triazolam-appropriate responding were occasioned; and at 0.56 mg/70 kg triazolam
caffeine, 75% triazolam- and 2590 novel-appropriate responding occurred. That is, when triazolam-caffeine
combinations were. administered, triazolam-appropriate responding increased, while novel-appropriate responding
decreased, as a function of triazolam dose. These results indicate that the novel-response procedure is useful for
distinguishing relative effects of drug combinations in situations where the two-response procedure appears
insensitive.
NICOTINE DISCRIMINATION AND SELF-ADMINISTRATION
K. A. Perkins
Relative to the animal research on nicotine discrimination and the human research on discrimination of other drugs.
there has been very little research on human nicotine discrimination. This is largely due to methodological
difficulties in administering rapid,fixed doses of nicotine atone to human participants. We have conducted a series
of nicotine discrimination studies employing a nasal spray nicotine dosing procedure that administers in fairly rapid
46
fashion fixed doses of nicotine in isolation. In these studies, we have found mat: 1) smokers and nonsmokers can
discriminate nicotine from placebo nasal spray; 2) nonsmokers show greater sensitivity in discrimination at higher
nicotine doses, suggesting tolerance; 3) discrimination responding of women is less sensitive than that of men
across dose; 4) discrimination behavior depends partly on initial training dose and does not reflect an inherent
characteristic of the drug; 5) mecamylamine, a central and peripheral nicotine antagonist, attenuates nicotine
appropriate responding but trimethaphan, a peripheral only antagonist, does not; and 6) behavioral discrimination of
nicotine appears to be more sensitive across doses than traditional subjective effects measures, demonstrating a clear
advantage to the use of drug discrimination procedures in humans, Results of this research are very similar to
findings in animal studies of nicotine discrimination, showing strong cross-species generalization. Across studies.
nicotine-appropriate responding is consistently associated with the subjective response of “head rush” hut only
inconsistently with ottriaxolamher responses. We have only recently begun to compare nicotine discrimination with selfadministration; findings so far do not show a direct relationship, although subjective responses to nicotine may
predict magnitude of self-administration. Future research will examine common environmental manipulations (e.g.
physical activity, other acute drug intake) that may alter nicotine discrimination and possibly influence nicotine selfadministration.
STUDYING THE RELATIONSHIP BETWEEN THE DISCRIMINATIVE-STIMULUS AND
SUBJECT-RATED EFFECTS OF ABUSED DRUGS IN HUMANS
C. R. Rush and S. H. Kollins
The discriminative-stimulus and subject-rated effects of commonly abused drugs are generally thought to covary. In
a traditional human drug-discrimination experiment, volunteers are trained to discriminate between drug and placebo.
Following acquisition of the discrimination, other drugs are tested. Drugs that increase drug-appropriate responding
generally produce subject-rated drug effects similar to those observed with the training drug. For example, in a
recent experiment we examined the discriminative-stimulus and subject-rated effects of methylphenidate, bupropion
and triazolam in d-amphetamine-trained humans. Metbylphenidate occasioned dose-dependent increases in drugappropriate responding, and produced subject-rated effects that were indistinguishable from those observed with damphetamine. Bupropion. a dopamine uptake blocker, occasioned intermediate levels of drug-appropriate
responding, and produced subject-rated drug effects that were both similar and dissimilar to those observed with damphetamine. Triazolam, by contrast, occasioned low levels of drug-appropriate responding, and produced subjectrated drug effects that were different from those observed with d-amphetamine. These results suggest a high degree
of concordance between the discriminative-stimulus and subject-rated rated effects of drugs.
In another experiment we examined the influence of training dose on the discriminative-stimulus and subject-rated
effects of d-amphetamine. Four subjects were trained to discriminate between 10 mg d-amphetamine and placebo
(i.e., low-dose group), while 4 other subjects were trained to discriminate between 20 mg d-amphetamine and
placebo (i.e., high-dose group). Following acquisition of the discrimination, a range of doses of d-amphetamine
(1.25-20 mg) was tested in each group. d-Amphetamine increased drug-appropriate responding as a function of dose
and produced clear dose-related stimulant-like subject-rated drug effects (e.g., “Like Drug”) in the low-dose group,
The dose-response functions for discrimination performance and subject-ratings were virtually identical, further
supporting the notion that the discriminative-stimulus and subject-rated effects of drugs covary. In the high-dose
group, d-Amphetamine also generally increased drug-appropriate responding and subject-rated drug effects as a
function of dose. However, the dose-response functions for discrimination performance and subject-ratings were
somewhat dissimilar. These findings suggest that the discriminative-stimulus and subject-rated effects of abused
drugs are not isomorphoric, and that discrimination performance in humans is not based solely on “subjective” drug
effects. Continuing to use the human drug discrimination paradigm in novel ways will allow us to more clearly
determine the conditions under which the discriminative-stimulus and subject-rated effects of drugs covary or
dissociate.
References: Available upon request.
ACKNOWLEDGMENT:
Supported, in part, by NIDA grant R01 DA-10325.
41
SYMPOSIUM XIV
PTSD AND SUBSTANCE ABUSE: EPIDEMIOLOGY, GENETICS AND NEUROBIOLOGY
R. K. Price 1 , N. Breslau2 , H. D. Chilcoat2 , E. Triffleman3 , W.R. True 4 , and T. R. Kosten1
1
Washington University School of Medicine; 2 Henry Ford Health Science Center; 3 Yale
University School of Medicine; 4 St. Louis University School of Public Health and St.
Louis VA Medical Center; and 5 Yale University School of Medicine and VA Connecticut
Healthcare System
A NOSOLOGIC AND ETIOLOGIC OVERVIEW
Dr. price began with an introduction to the symposium. The literature on post-traumatic stress disorder (PTSD)
and PTS symptoms has shown their associations with a number of factors including substance abuse. However.
causality involving PTSD and substance abuse is far from established. In 1980, the symptomatology of PTSD
in DSM-III was delineated in four groups: exposure, reexperience of event, avoidance and numbing, and increased
arousal. The duration, onset, and clinical significance and impairment were added in DSM-III-R and DSM-IV.
Some observed associations, such association with suicide risk and depression, may he a result of symptom
overlap, but they could also be causal. Associations with substance abuse and childhood behavior problems. on the
other hand, may be etiological, but there may be underlying forces, such as shared genetic susceptibility. Finally,
even if tbe causal relationship between PTSD and substance abuse is evidenced, it is critical to understand the
neurobiological mechanism for effective treatment of comorbid PTSD and substance abuse.
CHARACTERIZING TRAUMA EXPOSURE AND PTSD AMONG TREATMENT-SEEKING
SUBSTANCE ABUSERS
Dr. Triffleman presented results from an on-going, longitudinal study of Axis I and II disorders among treatmententering substance abusers. At baseline, 370 patients were enrolled in the study through two outpatient addiction
clinics and another addiction treatment inpatient unit. The two clinics were primarily cocaine treatment sites. The
subjects were administered the ASI, the SPSE, a 14-item checklist of stressful events, and the SCID PTSD
module. The mean age was 32.6 years old and 56% were female. The sample included 56% white, 35% AfricanAmerican and 9% Hispanic. A majority met at least one lifetime substance dependence disorder: 74% cocaine, 59%
alcohol, 52% opioids, 37% marijuana, 14.9% sedatives, and 10% stimulants. The mean first age of regular
substance use was 15 years of age. The level of traumatic exposure was high: 95% bad been exposed to at least one
form of trauma The mean total types of exposures was 4.3. The lifetime diagnosis of PTSD was met in 19.9%
of the sample and 6.7% had current PTSD. The mean age of onset was 17.3 years old. Of those with lifetime
PTSD, 76% were female. While both genders experienced exposure to multiple traumatic events, female patients
endorsed more traumatic events, and exposures tended to occur at an earlier age. The prevalence of lifetime PTSD
was also significantly different by gender. In the multivariate analysis, witnessing family violence, childhood
sexual abuse which occured prior to the onset of regular substance use, and gender were independent significant
predictors of the lifetime PTSD. The presence of criminal victimization, exposure to physical illness, rape and
gender, but not lifetime PTSD, were significant predictors of the current drug severity. Although the study was
limited by a retrospective design and tbe convenience sample, results are consistent with those from general
community samples.
48
TESTING CAUSAL PATHWAYS BETWEEN PTSD AND DRUG USE DISORDERS
Dr. Chilcoat’s presentation set out to test three hypotheses about the causal pathways between PTSD and drug use
disorders: self medication of PTSD; drug abuse as a risk factor for exposure (high-risk); and drug abuse as a risk
factor for PTSD following exposure (susceptibility). Data were collected as part of a longitudinal study of young
adults, randomly selected from a list of 400,000 health maintenance organization members in southeast Michigan.
Of the 1,200 members randomly selected at baseline in 1989 when they were 21-30 year old, 1,007 (84%)
participated. At the follow-ups in 1992 and 1994, 979 (97%) and 971 (97%) respondents, respectively, completed
interviews. The demographic characteristics of the study respondents were generally representative of the
geographic areas from which the sample was drawn: 63% were female, 81% white, and 45% married. Psychiatric
disorders were measured by the NIMH DIS-IIIR. Drug abuse or dependence (A/D) was determined according to
DSM-IIIR criteria for stimulants, sedatives or tranquilizers, marijuana, cocaine, heroin or other opiates, PCP.
hallucinogens and prescribed medication. In the PTSD section, each respondent could have up to three distinct
episodes at each of the three follow-up intervals. The earliest traumatic event and onset of PTSD were used for this
analysis. The qualifying stressors were limited to those defined by DSM-IIIR. To account for temporal
sequencing of traumatic events, PTSD and drug A/D. Cox proportional hazardl models were used with time
dependent covariates. Results from the Cox regression models for the drug A/D outcome provided support for the
self medication model: adjusted for race, sex and education, individuals with PTSD had a 4.5 fold increase in the
risk of onset of drug A/D compared to those who were not exposed to a traumatic event. On the other hand,
exposure to a traumatic event without PTSD was not associated with increased risk of drug A/D. Further analyses
showed that early conduct problems and depression prior to PTSD also signaled increased risks for drug A/D.
PTSD without prior depression signaled a four-fold increase in the risk of drug A/D, with an even greater risk
when PTSD followed the onset of depression, suggesting independent contributions of PTSD and depression to
the risk of drug A/D. Strongest evidence for self-medication was found for prescribed drugs. No evidence was found
to support the high-risk hypothesis. The evidence for the susceptibility model was weak: drug A/D signaled a
small and insignificant increase in risk of PTSD following exposure. Overall, evidence supports the selfmedication model. However, the results are consistent with the possibility that there is a shared vulnerability for
PTSD and drug A/D.
PTSD AND DRUG ABUSE: TIME SEQUENCE AND EARLY PREDICTORS
Dr. Price presented a first set of results from her on-going follow-up study of Vietnam War soldiers. Half of the
veteran respondents were drawn randomly from the Army list of “drug-positives” based on urine testing at the time
of departure. Another half, the “general” sample, was randomly drawn from the population. A total of 942
veterans were surveyed in 1972; of them, 571 were re-interviewed in 1974, along with 284 civilian comparison
respondents who were chosen from the Selective Service lists and matched to the general sample. The follow-up
study respondents are all males who are reaching mid to late 40’s. Among the drug-positive sample, 30% are
African Americans. After two decades of hiatus, 90.5% of the 1,092 eligible and surviving members were
contacted. The presentation utilized data from the first 276 cases available for data analysis. This subsample is
under-represented by D+ veterans. The time sequence of hard drug use, traumatic events, and, PTSD syndrome
were examined. along with causal relations among “early” predictors and subsequent hard drug use and PTSD
syndrome. Three time periods for the event variables were constructed from two questions about the most traumatic
events: T1, from early childhood to the service induction date; T2 from the induction to September 1971
(departure); and T3, from October 1971 to present. The measures of PTSD and drug use were constructed
separately for each time period. The sum of PTSD syndrome criteria were used for path analysis, and the threshold
of meeting all four criteria was set to create dichotomous variables which approximate DSM-IV criteria without
duration requirement. The number of hard drugs used within a period was used for path analysis, The results
showed that the PTSD syndrome level is high when it is compounded by drug use. The current estimates of an
approximation of the lifetime PTSD syndrome without the duration requirement are 41.7% among D+ veterans.
and 20.9% among D- veterans. When multiple traumas are assessed for different time periods, PTSD is found to
be relatively common in this age group; however, war-time trauma was most intensely experienced and most likely
to lead to PTSD. The results regarding the relationship between drug use and exposure were equivocal. Overall,
49
PTSD appears more likely to affect subsequent hard drug use than the opposite; however. the evidence was
Inconclusive. A small set of predictors included in this analysis failed to predict PTSD well. The current results
are limited by the small sample size available, retrospective assessment of PTSD, and different durations
represented by the three time periods.
COMMON RISK FACTORS FOR POST-TRAUMATIC STRESS DISORDER AND DRUG
ABUSE/DEPENDENCE: BIVARIATE TWIN ANALYSES
Dr. True, using a behavior genetic paradigm, investigated the issues regarding shared genetic and environmental risk
factors for the co-occurrence of PTSD and illicit drug abuse. The data for the current analyses was derived from the
Vietnam Era Twin Registry. The Registry compiled records of approximately 4000 identical and fraternal male
twins in which both siblings served in the military during the Vietnam Era (1964-1975) from over 7,300 twins
ascertained from the computer tape of 5.5 million veterans. Twins were matched based on the last name, social
security number and the date of birth; zygosity was determined from similarity questions and blood group typing.
The diagnostic data were obtained from telephone interviews conducted in 1992-93 using the DIS-IIIR. The
prevalence of PTSD was 9.6% among this analysis sample. The prevalence rates for drug abuse/dependence (D/A)
was 7.2% for marijuana, 4.3% for stimulant and 10.1% for any illicit drug. The rates are approximately three
times as high among those with PTSD compared to those without . Using MX and PRELIS2, univariate and
bivariate analyses examined the degree to which the observed associates between PTSD and illicit drug abuse are
due to shared and unique genetic influences, and experiences shared and not shared by twins. The analyses were
based on 1.842 MZ pairs and 1.474 DZ pairs. The tetrachoric correlation of PTSD among MZ pairs was .38
compared to .14 among DZ pairs, suggesting a dominance genetic effect. The MZ/DZ correlation ratios were
smaller for stimulants and marijuana. The univariate estimates under the best fitting models showed somewhat
ambiguous results: for PTSD, additive genetic variance was 17.4% (C.I. 0-45%), nonaddictive genetic variance
was 20.2% (C.I. 0-49%) and the unique environmental error variance was 62.3% (C.I. 51-73%). About a third of the
variance was explained by the additive genetic component for any illicit drug A/D, and marijuana A/D, while
53.5% (C.I. 41-66%) of the variance was explained by the additive component for stimulants. The bivariate
analyses showed significant additive genetic effects common to PTSD and drug A/D with non-significant shared
environment effects. The bivariate models showed that common additive genetic effects explained 42.1% of the
variance in risk for any illicit drug A/D, 42.0% of the variance in risk for marijuana A/D, and 54.9% for
stimulant A/D. However, the low prevalence rates for marijuana and stimulant A/D may be a reason for
ambiguous results of the shared environmental effect.
NEUROBIOLOGY OF PTSD AND DRUG ABUSE
Dr. Kosten provided an overview of the current knowledge on the neurobiology of PTSD relevant for substance
abuse. Psychophysiological findings in PTSD support increased sympathetic nervous system reactivity including
excessive sweating, tachycardia shortness of breath and anxiety. Biochemical correlates of PTSD such as 24 hour
urinary cateholamines, have also supported increased sympathetic activity. Low levels of 24 hours urinary cortisol.
however, have been found in veterans with PTSD, which may be a result of chronic noradrenergic activation and
decreases the release of corticotropin releasing hormone (CRH) and ACTH. Beta endorphinm (coreleased with
ACTH) levels are also low and may lead to relapse to opioid abuse in former abusers. This delayed pattern of drug
abuse in humans with PTSD has a parallel in drug self-administration by animals after inescapable shock exposure
(IS), which is a model of PTSD. After an IS exposure, animals self-administer drugs such as alcohol in a delayed
pattern that is distinct from use during acute stress. Finally, drug withdrawal states often exacerbate PTSD
symptoms by activation of central noradrenergic systems, and treatment of withdrawal may provide simultaneous
reduction in stress related symptoms. Thus, increased adrenergic activity might well lead to substance abuse for
acute self-medication, although chronic use of these substances worsen the underlying PTSD. In the future, the
animal models of PTSD may help clinicians to select the most promising medications with the least abuse
potential for clinical testing of efficacy in PTSD.
50
DISCUSSANT
Dr. Breslau highlighted the findings common to the studies presented earlier, and discussed them in the light of the
genetic and neurobiological findings presented by Drs. True and Kosten. Despite the differences of sample.
similarities were found between Dr. Triffleman’s study from a treatment-seeking sample and Drs. Chilcoat and
Breslau’s findings from a general population study. These included: a high prevalence of trauma but a much
smaller prevalence of PTSD; a higher prevalence of PTSD in women; a small ratio of the current to lifetime
PTSD; and no evidence of association between exposure, per se, and psychiatric problems. Neither Dr. Chilcoat
nor Dr. Price’s study found evidence supporting the role of drug abuse in increased risk for exposure to trauma.
There appears to be weak evidence of drug abuse increasing the vulnerability of PTSD. The evidence is stronger
for the self-medication hypothesis given the findings of PTSD increasing the risk of drug abuse. However, Dr.
True’s paper suggests a strong genetic contribution to the co-occurrence of PTSD and drug use disorders, Dr.
Kosten’s summary also leads to the possibility that distinct abnormality in patients with PTSD might represent
pre-existing vulnerabilities. These findings together suggest the importance of identifying pre-existing
vulnerabilities that may be common to substance abuse and PTSD.
Authors and Titles of Presentations:
R. K. Price. A nosologic and etiologic overview. E. Triffleman, J. Poling, B. Rounsaville. Characterizing trauma
exposure and PTSD among treatment-seeking substance abusers. H.D. Chilcoat, N. Breslau. Testing causal
pathways between PTSD and drug use disorders. R. K. Price, B.D. Li. E.L. Spitznagel. PTSD and drug abuse:
Time sequence and early predictors. W. R. True, S. A. Eisen, H. Xian, J. Scherrer, M. Lyons, A.C. Heath.
Common risk factors for post-traumatic stress disorder and drug abuse/dependence: Bivariate twin analyses. T. R.
Kosten. Neurobiology of PTSD and drug abuse. N. Breslau. Discussant.
51
SYMPOSIUM XV
SUMMARY - CPDD SYMPOSIUM ON HIV IN THE BRAIN
B. J. Hoffer1, H. E. Gendelman2, S. J. O’Brien3, N. Sacktor4, and C. A. Wiley5
1
National Institute on Drug Abuse; 2University of Nebraska; 3National Cancer Institute;
Johns Hopkins University School of Medicine; and 5University of Pittsburgh Medical Center
4
Dr. Ned Sacktor provided a comprehensive review of HIV dementia HIV dementia affects 15-20% adults and
children with AIDS. HIV dementia is rare during the asymptomatic phase. It is an indicator of AIDS in only 3%
of cases. Risk factors for the development of dementia include lower CD4 count, anemia, low weight, and
constitutional symptoms. Progression of HIV dementia is variable with 30% cases having a slow course. Rapid
progression is associated with lower CD4 count and evidence of CNS immune activation. The protective effect of
combinations of antiretroviral medications and protease inhibitors is uncertain. In one longitudinal cohort of
homosexual men, the Multicenter AIDS Cohort Study (MACS). with the past 1 1/2 years, the incidence seems to
be decreasing.
The most common presenting symptoms are problems with memory, gait difficulty, mental slowing, and
depressive symptoms. Early symptoms affect behavior, cognition. and motor function. Late features include severe
apathy, psychomotor retardation, poor insight, delirium, and increased tone and reflexes. Frequently associated
conditions include myelopathy, peripheral nerve disease, and seizures. Cognitive decline, specifically in tests of
psychomotor speed that is sustained in a subsequent follow-up visit, is an excellent indicator of an increased risk of
developing dementia, AIDS, and death.
In intravenous drug users (IVDU), cognitive impairment may be HIV-related. due to the effect of chronic
drug/alcohol use, or due to non-specific reasons such as fatigue, mood changes, insomnia medication side effects, or
systemic disease. Dr. Sacktor compared neuropsychological testing in 2 longitudinal cohorts, a cohort of IVDU’s,
and a cohort of homosexual men. ln the IVDU cohort, HIV- and HIV+ IVDU’s scored lower on neuropsychological
tests compared to age and education matched norms in the homosexual cohort. At the baseline visit, there was no
difference between HIV+ and HIV- IVDU’s on any neuropsychological test after adjusting for education. In a longterm 4-year follow-up, there was no difference between AIDS-free HIV+ and HIV- IVDU’s on any
neuropsychological test after adjusting for education. However, HIV+ IVDU’s who had progressed to AIDS had
mild decline in cognitive performance compared to asymptomatic HIV+ IVDU’s. This pattern in IMU’s is similar
to longitudinaI studies in homosexual men. Therefore, it is concluded that intravenous drug use is not a risk factor
for progression of cognitive symptoms in HIV infection.
In terms of mechanisms, HIV virus does not infect neurons directly. Rather, HIV infects macrophages causing
macmphage activation, expression of endothelial adhesion markers, blood-brain barrier damage, and with induced
inhibitory control of macrophage activation, macrophages release a cascade of neurotoxins which stimulate, astrocyte
proliferation causing neuronal death. Potential neurotoxins include cytokines, such as TNF-alpha, arachidonic aid
and its metabolites, platelet activating factor, free O2 radicals, nitric oxide (NO), glutamate, and quinolinic acid.
Recently, Immunological nitric oxide synthase (iNOS). an important enzyme for the generation of NO in the CNS,
was found to be increased in patients with severe dementia in postmortem cortical tissue. Furthermore, gp 41
induced iNOS in primary cultures of mixed rat neuronal and glial cells. and iNOS killed neurons through an NOdependent mechanism. Thus, gp41 induced NO formation may contribute in part to the pathogenesis of HIV
dementia. It is unlikely that any one of these neurotoxins acts alone: rather, it is probably a cascade of many of
these neurotoxins that lead to the problems in HIV dementia
Recent controlled drug trials suggest that cognitive impairment associated with HIV dementia is in part reversible,
suggesting that there may be reversible and irreversible components to the pathophysiology of HIV dementia. In
the reversible component, there is limited CNS macrophage infection, macrophage activation with release of
cytokines. pIatelet activating factor, and free O2 radicals causing astrocytic reaction and neuronal dysfunction. In the
52
irreversible component, there is productive CNS macrophage infection with intense macrophage activation. With
decreased CD4 inhibitory control, there is a release of more inflammatory mediators and NO, causing astrocytic
reaction, blood-brain barrier disturbance, and neuronal death.
Dr. Clayton Wiley also presented a comprehensive review of HIV encephalitis. Infection with Human
Immunodeficiency Virus (HIV) is followed by a chronic and abundant systemic replication of HIV. While
macrophage tropic virus appears to be particularly important in transmission, during the decade of so-called “latentphase” infection, cells within lymphoid structures produce the majority of virus. Late in infection severe
immunosuppression accompanies depletion of the host CD4 t-cells. Where the virus resides al this stage of
infection is unknown, however, patients surviving for extended periods of time with immunosuppression do have a
large amount of virus within me brain. While there has been some controversy regarding the association between
HIV encephalitis and the neurobehavioral symptomatology, clearly patients with a high central nervous system
(CNS) viral load are more likely to exhibit neurocognitive abnormalities.
One reason for the controversy associating brain viral load and clinicaI symptomatology is that CNS viral load can
only be assessed through post-mortem analysis. A systemic surrogate marker of brain viral load would
substantially aid clinical studies. Because of the blood brain barrier (BBB), levels of virus in the blood would not be
expected to be concordant with CSF viral loads. Unfortunately, even CSF which is within the BBB is frequently
discordant with the brain parenchyma with respect to a wide variety of markers.
Dr. Wiley has found that elevated HIV RNA levels in post-mortem CSF samples is associated with high viraI load
in brain tissue at autopsy. Analysis of longitudinal samples showed that this relationship was only true in Iater
stages of life. If, as he has hypothesized, elevated HIV load in the brain is a substrate for HIV neurocognitive
disorders then his findings would suggest that antemortem-CSF HIV-RNA would be a useful clinical surrogate
marker for neurocognitive disorders only in the later stages of disease
The close correlation between CSF and brain tissue viral loads suggests that in the months preceding death, there
may be significant utility to assaying viral copy number in CSF, not only to guide clinical therapy for
neurocognitive disorders but also to help in assessment of efficacy of experimentalanti-viral therapies. The
hypothesis is that elevated brain viral load precedes the development of these Iate stage neurocognitive abnormalities
and neuropathology. Therefore, identifying patients with elevated CSF viral load offers a window of opportunity,
during which treatment of CNS HIV infection might prevent the development of a fixed neurologic lesion. Having
the CSF as a surrogate marker for brain viral load will expedite me development of effective CNS therapies.
Dr. Howard GendeIman’s presentation focused on celluIar and molecular mechanisms of HIV infection in me CNS.
The neuropathogenesis of central nervous system (CNS) HIV infection revolves around mononuclear phagocytes,
brain macrophage/microglial infection and immune activation in brain. Macrophages secrete neurotoxic factors that
elicit neuronal injury and lead to neural ceII death associated with the significant cognitive and motor impairments
seen during progressive neurologic disease Neurotoxic factor production requires virus entry and replication. the
evolution and selection of neurovirulent and HIV strains and the production of viral and cellular immune factors
injurious to human neurons. The Ievels of viral replication are not always associated with cognitive and molor
impairments. This has led to the notion that viral replication induces autocrine/paracrine production of cellular viral
factors leading to metabolic encephalopathy. Dr. Gendelman’s lab has developed in vitro, ex vivo, and animal
model systems to study the effects of HIV-1 replication in brain tissue. The isolation/propagation of primary
microglials, astrocytes, and human endothelial cells combined with cellular immune assays that demonstrate the
effects that viral replication has on the secretion of immune neurotoxic factors, has enabled his laboratory to
establish laboratory models of AIDS-dementia complex. Recently, his development of bIood-brain barrier model,
the isolation of neurovirulent, microglial tropic viraI strains and the improvement murine animal models for
neurological impairments has further permitted the laboratory to develop novel potential therapeutic approaches. A
key hypothesis is that viral infection allows passage of monocytes into the brain.
53
Dr. Stephen J. O’Brien discussed genetic factors in AIDS resistance. A portion of the epidemiologic heterogeneity
that is characteristic of the HIV-AIDS epidemic is Iikely to be the consequence of variation of genes whose products
play a role in HIV pathogenesis. To identify such genes, Dr. O’Brien’s group assembled lymphoblastoid cell
lines from nearly 10,000 patients enrolled in prospective AIDS cohort studies. Genomic DNA from these
individuals were screened for departures in population genetic equilibrium among population subdivisions of the
cohorts with different infection or disease outcomes. Human polymorphisms for both candidate genes (e.g.,
immune response, genes, cytokines, receptors, HLA, oncogenes) and anonymous polymorphic marker loci were
screened for aIlelic, genotypic and paired haplotype disequilibrium in cohorts of different risk groups, Ascertainment
of previously unknown loci linked to anonymous markers was enhanced by using a new method termed Mapping by
Admixture Linkage Disequilibrium (MALD). Genetic associations wee detected for two loci, HLA and CCR5 in
AIDS cohorts for both infection effects and disease progression effects in HIV-1-infected patients. HLA contains
several loci that mediate immune recognition and clearing of HIV infected cells. CCR5 encodes a chemokine
receptor molecule. that serves a second co-receptor required for HIV infection of macrophage and monocyte lineage
cells. Identification of “restriction genes”, which delimit HIV infection and spread, provide important opportunities
for drug, peptide and gene therapy by targeting cellular functions required for HIV infection and disease pathogenesis.
54
SYMPOSIUM XVI
COMBINED COCAINE AND OPIOID ABUSE: FROM NEUROBIOLOGY TO THE CLINIC
J. K. Rowlett 1 , S. S. Negus 2 , T. S. Shippenberg 3 , N. K. Mello 2 , S. L. Walsh4 , and R. D.
Spealman1
1
Harvard Medical School, NERPRC, Southborough, MA and 2 ADARC/McLean Hospital,
Belmont, MA; 3 NIH/NIDA, DIR, Baltimore, MD; and 4 Behav. Pharmacol. Res. Unit, Johns
Hopkins University School of Medicine, Baltimore, MD
INTRODUCTION
Many intravenous polydrug abusers inject cocaine in combination with heroin either by injecting the two drugs
serially or by combining the drugs in solution and taking them simultaneously (commonly know as a “speedball”).
The increasing use of speedballs has led to their widespread inclusion in recent epidemiological studies of drug
abuse in the United States. It has heen reported that speedball abusers exhibit a more severe psychopathology
compared to other cocaine abusers, are more likely to fail in drug abuse treatment and are al increased risk of
contracting HIV infection. Despite the prevalence of speedball abuse, the interactions between cocaine and opioid
drugs are not well understood at either the clinical or preclinical level. This symposium examined current research
on the pharmacological interactions between cocaine and abused opioids in order to provide a synthesis of current
knowledge and to suggest potential directions for future research.
Neurobiology of cocaine and opioid abuse
The rewarding effecls of cocaine have been attributed to an increase in the functional activity of mesolimbic
dopamine (DA) neurons. Evidence that endogenous as well as exogenous opioid agonists modulate the activity of
this DA system has also been presented. This talk reviewed neurochemical data regarding the effects of cocaine
administered alone or in combination with opioids upon mesolimbic DA neurotransmission as well as the role
endogenous opioid peptide systems play in regulating the activity of mesolimbic neurons. The influences of
cocaine upon opioid peptide gene expression and the dynamics of endogenous opioid peptide systems also were
reviewed along with the relevancy of these findings for the developmenl of therapeutic agents to treat speedball
abuse.
Discriminative stimulus effects of cocaine/opioid combinations
Drug discrimination procedures have been used extensively to characterize the pharmacological mechanisms of
action mediating the abuse-related effects of cocaine and mu opioids, as well as between those drugs. In most of
these studies, subjects were trained to discriminate either cocaine or a mu agonisl from vehicle and the effects of
cocaine alone, mu agonists alone, and cocaine/mu agonisl combinations were examined. An important goal of
these studies has been to evaluate the hypothesis that cocaine and mu agonists potentiate each other’s discriminative
stimulus (DS) effects. The results have been variable across studies, and in many instances, across subjects within
a study. In subjects trained to discriminate cocaine from vehicle, mu agonists sometimes produce high levels of
cocaine-appropriate responding and/or enhance the DS effects of cocaine. Similarly, in subjects trained to
discriminate mu agonists, cocaine sometimes generalizes to the training stimulus and enhances the DS effects of
the mu agonist. In many subjects, however, cocaine and mu agonists do not cross generalize and either do not alter
or attenuate the other’s DS effects.
Another approach for examining the DS effects of speedballs is to train subjects to discriminate a mixture of
cocaine and a mu agonist from vehicle. We recently trained rhesus monkeys to discriminate a 10:1 mixture of
cocaine and heroin (0.4 mg/kg cocaine + 0.04 mg/kg heroin). Increasing doses of the 10:1 mixture produced a
dose-dependent generalizalion to the training stimulus, and both cocaine and heroin alone generalized completely to
the training stimulus. In addition, many cocaine-like drugs (CFT, amphetamine, bupropion) and heroin-like drugs
(alfentanil, fentanyl, morphine) produced high levels of speedball-appropriate responding, The DS effects of the
55
cocaine/heroin mixture could be antagonized by combined treatment with the DA antagonist flupenthixol and the
opioid antagonist quadazocine, but either antagonist atone was less effective. These findings suggest that the DS
effects of the cocain/heroin mixture includes aspects of both cocaine and heroin and that the mixture did not
produce DS effects that were qualitatively different from either cocaine or heroin alone.
Reinforcing effects of cocaine/opioid combinations
Because both cocaine and mu opioid agonists function as reinforcers, it is possible that the reinforcing effects of
cocaine and opioid combinations are enhanced compared to either cocaine or mu agonists alone. To examine this
possibility, rhesus monkeys were trained to respond under a progressive-ratio (PR) schedule of intravenous drug
injection. Under this schedule, the response requirement for obtaining an injection of drug is increased until
responding stops and a measure of reinforcing efficacy can be defined as the maximum response requirement a
subject will complete to obtain an injection. Using this procedure, cocaine dose-effect curves for injections/session
typically are monophasic, i.e., responding increases with dose until an asymptote or a peak is reached. Heroin
dose-effect curves, by contrast, are biphasic functions, i.e., increase to a peak and then decrease. When cocaine was
combined with heroin, low doses of cocaine and heroin that did not maintain behavior when tested alone did so
when tested in combination. Furthermore, combination with heroin resulted in a leftward shift in the cocaine doseeffect curve, indicating that heroin increased the potency of cocaine as a reinforcer. However, maximum
injections/session for cocaine combined with heroin were not different from cocaine alone. suggesting that the
relative reinforcing efficacy of combinations of cocaine and heroin were not greater than that of cocaine alone. The
enhanced potency of the reinforcing effects of cocaine by combination with heroin may be a contributing factor to
the abuse of speedballs.
Medications development for the treatment of combined cocaine-opioid abuse
The combined abuse of pharmacologically dissimilar drugs complicates the search for effective treatment
medications. We have found that buprenorphine, an opioid mixed agonist-antagonist, significantly reduced both
cocaine and opioid self-administration by rhesus monkeys and human polydrug abusers. We recently studied the
effects of buprenorphine on self-administration of cocaine/heroin combinations using a model of speedball abuse
developed in our laboratory. In this procedure, drugs and food (1 gm banana pellets) were available in four daily
sessions on a second-order FR4 (VR16:S) schedule of reinforcement. Each heroin/cocaine combination was
available for 10 consecutive days, and monkeys were treated daily with either saline or buprenorphine.
Daily treatment with 0.237 mg/kg/day buprenorphine shifted the speedball dose-effect curves for heroin+0.001
mg/kg/inj cocaine downward and to the right. Buprenorphine also decreased self-administration maintained by
speedball combinations of heroin+0.01 mg/kg/inj cocaine and heroin+0.1 mg/kg/inj cocaine. However,
buprenorphine was less effective in decreasing self-administration maintained by heroin in combination with 0.1
mg/kg/inj of cocaine than with 0.01 mg/kg/inj of cocaine. Thus, buprenorphine’s effectiveness in decreasing
speedball self-administration decreased as the dose of cocaine increased. These findings suggest the usefulness of the
speedball model for evaluation of the effectiveness of medications for the treatment of speedball polydrug abuse.
Our findings in rhesus monkeys are concordant with clinical trials, which found that buprenorphine decreased both
cocaine and heroin abuse in polydrug abusers.
Human laboratory studies on cocainel/opioid combinations
Recent studies by Foltin, Fischman and colleagues and by Walsh and colleagues have evaluated the acute subjective
and physiological effects of cocaine in combination with opioid mu agonists. The subjective effects of various
dose combinations of mu agonists and cocaine were greater than those produced by either drug alone on measures
such as “drug liking” and “high”. The qualitative profile of subjective effects produced by the opioid/cocaine
combination was toughly equivalent to the sum of effects produced by the two drugs singly, rather than producing
novel or unique subjective effects. The cardiovascular effects of cocaine, including tachycardia and pressor action,
were enhanced when cocaine was administered in the presence of the mu agonist. Other studies have compared the
effects of cocaine in opioid-dependent subjects during chronic maintenance on mu opioid agonists. In studies of
methodone-maintained patients, the subjective response to cocaine (e.g., “magnitude of drug effect”, “good effect”)
56
was significantly greater compared to control subjects. Similarly, some studies in buprenorphine-maintained
patients reported that the subjective response to cocaine was either enhanced or not appreciably altered compared to a
control condition. Enhanced cardiovascular responses to cocaine were also observed under these chronic opioid
dosing conditions. These and other fmdings suggest that administration of mu agonists generally enhances the
effects of cocaine in humans, particularly the positive subjective responses to cocaine. This enhancement of
subjective effects has been observed following pretreatment with opioids under both acute and chronic dosing
procedures. Whether or not enhancement of physiological responses is observed appears to depend upon the specific
opioid agonist chosen for testing as well as the range of test doses. The observed enhancement of subjective
responses produced by speedball combinations may account for the high prevalence of speedball abuse as well as the
persistent abuse of cocaine in patients enrolled in opioid maintenance therapy programs.
Summary and Future Directions
This symposium has provided a synthesis of recent research aimed at understanding the interactions between
cocaine and abused opioids. Dr. Shippenberg described neurobiological evidence that both exogenous and
endogencus opioids can modulate the actions of cocaine in the mesolimbic DA system. There is also evidence for a
reciprocal influence of cocaine on the endogenous opioid peptide system. Understanding the interplay between these
two systems continues to be a major challenge facing research in this area. The escalation of dual cocaine-opioid
abuse has prompted renewed interest in the interactions between these drugs in relevant animal models of addiction.
As discussed by Drs. Negus, Rowlett, and Mello, an important, though still elusive, goal of this research is to
characterize the complex effects that combinations of cocaine and opioids can have in behavioral experiments.
Growing evidence indicates that prominent individual differences exist in the DS effects of cocaine-opioid
combinations, yet virtually nothing is known about their neurobiological correlates. Along similar lines, studies
involving i.v. drug self-administration in monkeys suggest that low doses of cocaine and heroin, which fail to
maintain self-administration when tested singly, do so if combined under a progressive-ratio schedule of drug
injection. However, this appears not to be the case under other conditions, where self-administration of cocaine
may be reduced by the addition of high doses of heroin. Human laboratory studies reviewed by Dr. Walsh have
generally shown that opioids enhance the positive subjective effects of cocaine, although the findings do not fit
easily within any simple model of drug interaction. Given the prevalence of cocaine use among untreated opioid
abusers and methadone-maintained patients, there is a critical need to identify pharmacological mechanisms
underlying speedball abuse in order to develop effective therapeutic strategies. By providing a state-of-the-field
review of multidisciplinary research, this symposium has helped lay the groundwork for achieving this goal.
ACKNOWLEDGEMENTS: Supported by USPHS grants DA05625, DA00499, DA11054, DA01533,
DA00101, DA02519, DA04059 and RR00168.
57
WORKSHOPS
MAKING AUDIENCES AMAZED, NOT GLAZED: TECHNIQUES FOR IMPROVING
PRESENTATIONS
R. Eisenberg and F. George
University of Minnesota, Duluth, School of Medicine, Department of Pharmacology, Duluth,
MN and Amethyst Technologies, Inc., Scottsdale, AZ
During the last CPDD meeting, we were impressed with the number of presentations that suffered greatly even
though the content was good. Despite use of the traditional format - background, methods, results and conclusions the hypothesis was not always stated and then justified in the conclusions. Screen colors or design often distracted
from the data Material was often cluttered, overly abundant, and difficult to mad. Many times this appeared to be so
blatant as to suggest a total disregard of the audience. This disregard was not restricted to any particular level of
seniority or experience. It is clear that few of us cannot improve our style and method of communication. From
the presenters standpoint, better communication may result in a tangible reward. For the audience, the results are
more interesting and less tedious.
A workshop was conducted which focused on improving oral presentations. It was divided into two parts: 1)
improving screen-presented material, and an introduction to PowerPoint; and 2) suggestions for improving oral
communication, with a series of “do’s” and “don’ts.” Subjects which were covered are shown below:
Screen--presented material
An introduction to PowerPoint, an example of presentation software
Colors/Contrast/Compatibility
Text selection: type size. font, BOLD
The amount of information per screen
Limitations of the # of different templates per presentation
Built-m screen distractions
Limiting the number of graphics (and type) per screen
Presenting a full page of text OR NOT!
Complex tables
Consistency of screens
Distracting symbols/logos
Thickness of lines on graphs
Giving an Oral Presentation (Tricks of the Trade)
The Art of Speaking Well
Using a Microphone
Timing is Everything
Speaking to groups of different sixes
Body Positions, and the (not so) subtle messages they give your audience
Gesttures and Pauses
Stating the question or hypothesis; conclusion should reiterate the question and then show or not show
support for it
Restating the question from the audience when the microphone is not used
Putting it together to turn your audience On instead of Off
58
FOOD, SEX AND DRUG INCENTIVES: IMPLICATIONS OF A COMMON SUBSTRATE
FOR DEVELOPMENT OF ANTI-CRAVING MEDICATIONS
Co-Chairs: F. Vocci1 and A. R. Childress 2
Panelists: B. Gosnell 3 , A. Phillips4 , D. C. S. Roberts 5 , and A. R. Childress
Discussant: F. Vocci
1
NIDA Medications Development Division, Rockville, MD (USA); 2 University of
Pennsylvania, Philadelphia, PA (USA); 3 Neuropsychiatric Research Institute, Fargo, ND
(USA); 4 University of British Columbia, Vancouver (CANADA); and 5 Carleton University,
Ottawa, Ontario (CANADA)
NIDA MDD Workshop
SUMMARY
Cocaine and opiates activate brain systems responsible for the reinforcing properties of “naturaI” rewards such as
food and sex. This overlap in brain substrates may help explain the subjective phenomenology of drug effects: e.g.,
both male and female users describe the euphorigenic tush produced by cocaine and opiates as similar to, but several
times stronger than, sexual orgasm (cocaine can trigger ejaculation in males), and they liken the desire for cocaine
to strong sexual anticipation. Cocaine users note the ‘taste’ of the drug in the back of their throat both during use of
the drug and in anticipation of it (“I wanted it so much I could already taste it”). These kinds of parallels suggest
that research on the incentive states associated with food and sex may inform our understanding of incentive-based
drug craving, and may facilitate the search for agents which would ameliorate it. To this end, the symposium
surveyed state-of-the art knowledge on substrates of drug, food, and sexual reinforcement, and on the incentive states
(“craving”) associated with each. For each of the three areas (food, sex, and drugs), a basic scientist initially reviewed
putative brain substrates of reinforcement and offered animal models of incentive motivation, followed by a clinical
researcher (Dr. Childress) describing the human findings. The discussant and Co-Chair, Dr. Vocci, summarized
the panelists’ findings and led an open discussion on their implications for the development of anti-craving
medications
Dr. Gosnell (food) noted that though food intake is essential for the survival of all organisms, not all feeding is
in direct response to caloric needs. Foods rich in sugar or fat are generally considered quite pleasurable, and
excessive consumption of such foods is often associated with obesity and eating disorders. Several tines of evidence
indicate that endogenous opioids play a role in mediating the rewarding aspects of foods, and that the processes
mediating food reward may share some of the mechanisms mediating drug reward. Opioid agonists stimulate food
intake, and antagonists generally cause a reduction in intake. These effects are more pronounced for palatable foods
and fluids than for water or standard lab chow, and appear to be more effective in satiated animals than in hungry
animals. It has; therefore, been proposed that opioids participate more in me mediation of palatability than in the
regulation of energy balance. There is some overlap between the brain areas associated with opioid stimulation of
food intake and those associated with drug reward. and the pattern of receptor selectivity of agonists that will
stimulate ingestive behavior when injected into certain regions (mu, delta > kappa) is similar to that seen in several
other reward-relevant paradigms. Finally, the intake of sweetened food or fluids has been shown to alter the
analgesic effects of morphine and to predict the self-administration of morphine, alcohol and amphetamine. There is
a high co-morbidity for eating disorders and substance abuse, and continued research on mechanisms mediating the
rewarding aspects of food may offer new insights into the causes and treatments of both disorders.
Dr. Phillips (sex) reviewed data underscoring the importance of brain dopamine (DA) systems for sexual
behavior in the male rat. In the study of sexual behavior, a distinction is usually made between motivation and
performance. DA is implicated in both aspects, with central administration of dopamine agonists facilitating both
performance (copulatory rate, ejaculation and penile reflexes) and motivation (copulatory initiation, conditioned
anticipatory or preparatory responses). Conversely, disruption of the DA system either through lesions or chemical
59
blockade with antagonists generally often disrupts performance and blunts motivational indices. In vivo
microdialysis studies show that DA levels in the nucleus accumbens increase dramatically during the anticipatory
(as soon as the receptive female is placed behind a proximal screen) and consummatory phases of sexual behavior in
the male rat, dropping shortly thereafter. Electrovoltammetry studies confirm a similarly dynamic fluctuation in DA
signal, with increases occurring in response to cues for the female, prior to copulation. Taken together, these data
suggest a prominent role for limbic dopamine systems, particularly nucleus accumbens, in sexual incentive
motivation.
Dr. Roberts (drugs) reviewed two decades of evidence for involvement of brain dopamine systems in cocaine and
heroin reinforcement, noting that though these drugs are both powerfully rewarding, they also demonstrate some
interesting and potentially important differences. Following an initial prime, cocaine self-administering animals
will respond vigorously for the ‘next’ dose of cocaine. In contrast, heroin-trained animals receiving the first heroin
injection of the session are not “primed” to respond for the next dose -- though they will emit hundreds of lever
presses for the initial dose of the session. This difference. which may entail more than the different
pharmacokinetics of the two drugs, may explain one difficulty in attempting substitution approaches for stimulants
such as cocaine. Another difficulty in finding effective treatment agents may arise from the animal models used.
Self-administration paradigms with FR1 response requirements are relatively insensitive to changes in drug
motivation; a paradigm such as the progressive ratio (PR) schedule is more useful in this regard. Another model
which shows promise for measure of drug motivation is a discrete trials paradigm, in which animals given limited
access to drug eventually develop a circadian schedule of drug administration (administering drug during the active
phase of the light-dark cycle). Using this paradigm, pre-treatment with the GABA B agonist baclofen (at doses that
did not disrupt normal food and water intake) was found to delay onset of cocaine administration by 4-6 hours. lf
CABA B agonists reduce drug incentive motivation (potentially by modulating brain DA release), they may offer
significant promise as “anti-craving” agents in humans.
Dr. Childress offered clinical data indicating potential overlap of positive incentive states, including (male)
patients’ descriptions of the striking similarity between cocaine pleasure and sexual pleasure, and between cocaine
desire aud sexual desire. This overlap is supported by preclinical data suggesting the importance of limbic DA
systems in both states. Using in vivo brain imaging, it is now possible to study the incentive states for drugs and
other appetitive rewards directly. Dr. Childress’ recent study using positron emission tomography (PET) found a
pattern of limbic (amygdala and anterior cingulate) increases and basal ganglia decreases in relative regional cerebral
blood flow (rCBF) of cocaine users during a video which induced craving. This pattern did not occur in cocainenaive controls, and the two groups did not differ in the response of other compared brain regions. These findings
indicate limbic activation is one component of are-induced cocaine craving, and amygdalar activation to cocaine
cues has now been confirmed by two other imaging teams. Imaging is now ongoing to find whether limbic
activation is similarly involved in cue-induced desire for other rewarding drugs (opiates) and for natural rewards such
as sex. If significant overlap is demonstrated, agents found helpful in one arena might show significant benefit in
the other. On the other hand, significant overlap in positive incentive substrates would present the challenge of
ending agents which can effectively modulate drug incentive motivation, but without completely blunting the
ability either to experience, or to anticipate, normal pleasures.
ACKNOWLEDGMENTS:
This workshop was supported by NIDA Medications Development Division.
60
WORKSHOP: FIGHTING BACK—COMMUNITY INTERVENTIONS TO REDUCE DRUG
ABUSE
R. S. Schottenfeld, A. Spickard*, and C. Winick
Department of Psychiatry, Yale University Medical School, New Haven, CT; *Department of
Medicine, Vanderbilt University Medical Center, Nashville, TN; and City University of New
York Graduate School, New York, NY
PROGRAM DESCRIPTION
The Robert Wood Johnson Foundation (RWJF) Program, “Fighting Back— Community Initiatives to Reduce
Demand for Illegal Drugs” was born in 1989 out of a concern that the national issue of drug and alcohol abuse was a
serious epidemic in our nation’s communities. The Foundation M realized that alcohol and drug abuse seriously
affected its national health programs for the elderly, the homeless, and the school based health initiatives. At the
inception of Fighting Back, a National Program Office at Vanderbilt University Medical Center was established to
oversee the program and a National Advisory Committee of specialists in substance abuse was recruited to assist in
choosing the grantees.
Using a rigorous grant review process, 14 communities of 100,000 to 250,000 persons were chosen to develop
community-wide strategies to change the use and abuse patterns of illegal drugs and alcohol in their areas. The
Fighting Back (FB) communities chosen were sometimes an entire city, such as Vallejo, CA; Santa Barbara CA;
Little Rock, AR; Worcester, MA; New Haven, CT; and Columbia SC; and parts of larger communities, such as
Oakland, CA; Northwest, NM; San Antonio, TX: Kansas City, MO; Milwaukee, WI; Charlotte, NC; Washington,
DC; and Newark, NJ.
Each FB community was required to define the nature and extent of its alcohol and drug abuse problem before it
developed strategies. Each community was to organize a Citizens Task Force to engage all persons in the
community affected by the problem. City officials, the police, judges, and neighborhood groups were all involved
from the start., A Consortium of Providers, those who provided services to persons with substance abuse problems,
was also required.
Funds were provided for two years of planning and five years of implementation. Each FB community developed its
own set of programs following a set of guidelines. These included a public awareness campaign to keep the public
informed, a prevention program targeted at children, youth, and young adults, and a broad range of accessible options
for treatment and relapse prevention.
At each juncture of the planning and implementation process, the FB communities were required to review the
progress of each initiative and submit a complete proposal to the reviewers. If a FB site made substantial progress.
funds for the implementation were provided. This meant that some sites had funds withheld until satisfactory
progress could be. demonstrated. At the mid-course of the implementation period, all sites submitted a revised
proposal which was reviewed with the NPO, the National Advisory Committee, and the Foundation staff. At each
major review period, the RWJF Board reviewed the recommendations by the staff before the additional funds were
allocated. This process of refinement and review contributed to improved approaches as all of the participants
involved in the FB programs became more experienced.
In eight years of implementation, the FB communities have organized a broad array of initiatives to counter the
plague of alcohol and illegal drug use and abuse. One of these important initiatives is “Insure the Children” in
Little Rock, AR. “Insure the Children” provided insurance for treatment of substance abuse or addiction to every
student in the Little Rock school system. Those children identified by principals, teachers, or parents as having a
problem with illegal drugs or alcohol were given an array of options, including inpatient and outpatient treatment.
Evaluation showed that those treated had improved behavior both in the classroom and at home.
61
Gallup, NM, the site of Northwest New Mexico Fighting Back, or “Drunk Town, USA”, developed a
comprehensive approach for treatment of the intoxicated Navajos. Previously, the Navajos were placed in a ‘drunk
tank” to recover. No care of any kind was provided. Gallup started a humane treatment program at the Na’Nizooshi
Treatment Center which has become the model for treatment of the Navajo alcoholoc/drug addict. Readmissions to
this facility and admissions for alcohol/drug related injuries and illnesses in the Indian Health Service Hospital
nearby have fallen steadily.
In Charlotte, NC, the “Stop the Killing” campaign (a church based program to reduce the drive-by shootings and
cocaine purchasing in District II in Charlotte) has had significant impact on the perceptions of the community
residents about neighborhood safety. The involvement of the community in making a difference in their lives and
the lives of others has drawn the community together and made the streets safer.
In some of the FB communities, the effect of community policing has been particularly noticeable. In LittlIe Rock,
Kansas City, New Haven, and Columbia. police stationed in neighborhood precinct buildings work collaboratively
with the neighborhood residents to watch for crack cocaine sales in abandoned buildings and on corners. In Little
Rock, a Codes Enforcer is part of the team provided by the city government to hold absentee Iandlords accountable
for their dilapidated property. Neighborhood organizations work with the community police and the Codes Enforcer
to monitor the activities of liquor store owners and drug dealers.
In three of the FB communities, the programs have been funded by the passage of taxes to sustain them. In
McKinley Country, NM, the citizens passed a liquor tax. Kansas City passed a sales tax to fund alcohol and illegal
drug reduction initiatives. In Little Rock, citizens passed a sales tax for the “future of Little Rock” which assures
funding for the FB programs. In addition, the combination of citizen feedback and the passage of sales tax
contributed to a revision to the plan for the Neighborhood Alert Centers. The number of planned centers was
increased from 8 to 15 as part of the tax initiative.
Further programs created and sponsored by FB include reductions of billboard advertising in minority communities,
in Milwaukee and San Antonio, and in mentoring programs for youth in Santa Barbara, Oakland, VaIlejo,
Columbia, and San Antonio. Drug court diversion efforts by the judges in Santa Barbara and Worcester moved
youth offenders from jail to treatment while treatment in the criminal justice system was popular in Columbia and
Vallejo. Over 300 innovative initiatives like these have been started in the Fighting Back communities.
PROGRAM EVALUATION
As part of the Fighting Back program, a set of outcome-oriented evaluation studies of the program was designed to
measure changes over time in community wide measures of substance use, abuse, and harm. Four types of studies
were Iaunched: 1) surveys of adults and youth to assess drug and alcohol use and attitudes; 2) assessment of social
indicators of harm caused by substance abuse; 3) ethnographic studies of the communities’ response; and 4)
systematic tracking of the program implementation in each community. The evaluation compares each FB site
with two or three sites within each state.
The survey will be conducted every two years, starting in 1995, with respondents aged 16 to 44. The questions
derive from previously validated national surveys. A meta-analysis of school surveys supplements the FB survey.
The indicators include data from the Uniform Crime Reports, deaths related to substance use, deaths from single
vehicle auto accidents, and trends in treatment. The indicator data will go back to 1980.
Ethnographic studies of the communities assess the social processes and development of the community coalitions.
These extended case studies clarify the dynamics and context of the life cycle of each program interpreted in the light
of changes in the larger community, the region, and the country. Tracking the many strategies employed by the FB
communities permits analysis in terms of their relative attention to dimensions like substance supply, the
individual, the environment, and the life cycle of the program.
To date, significant differences in outcome between FB and the comparison communities have not emerged.
62
Among the factors contributing to these interim findings are the confounding of the comparisons by CSAP and
other funding of the comparison sites, and the complexity of the substance abuse system, so that long term efforts
are requited to bring about changes in both physical and social environments. An additional comparison will be
made between the progress of the eight communities that have been selected for an additional five years of refunding
and the six communities for which funding was terminated after five years.
WORKSHOP DISCUSSION
Discussion at the workshop identified some critical limitations of the evaluation studies and some possible
alternative approaches. The current evaluation strategy was developed after implementation of the Fighting Back
initiatives began, and this has led to many of the difficulties. One major limitation is that “head to head"
comparisons of the Fighting Back cities with comparison sites within the same state, conducted many years after
program initiation, might not detect the actual impact of Fighting Back, if, as is likely, the comparison cities also
implemented the successful initiatives developed by Fighting Back cities. Dissemination of effective strategies (or
diffusion of effective strategies) to the control cities would ordinarily be considered a positive outcome of a
community-wide experimental approach, but in the evaluation approach being utilized, dissemination or diffusion
serves to “contaminate” the research and decrease the likelihood of demonstrating positive effects of the initiatives.
A second but related limitation is that considerable new resources were made available to both the control and
Fighting Back cities during the period of Fighting Back implementation. The resources available to cities under
Fighting Back were relatively small ($3 million), especially in comparison to the resources available through
combinations of federal block grant funds and other special initiatives (e.g., HUD grants, empowerment zones.
CSAP and CSAT projects. etc.). The cumulative effects of these resources may have dwarfed the impact of
Fighting Back, making it more difficult to evaluate its impact. Some of these resources were modeled after
Fighting Back (e.g., Community Partnership Grants) and only became available to control cities because of
Fighting Back, hut the current evaluation strategy would not “credit” Fighting Back for having this effect.
A third limitation of the evaluation methodology is that it does not account for the considerable variability of
Fighting Back interventions. Fighting Back supported many activities within each of the cities, and it supported a
different set of activities in each of the cities. Assuming that some, but not all of the interventions were effective,
the evaluation methodology would not be able to ascertain which components were effective, which were
ineffective, and which were counterproductive.
Some alternative evaluation strategies and models were then discussed. One conceptual model would view Fighting
Back as developing a platform supporting demand reduction, and evaluation of the impact of Fighting Back should
then focus on whether the platform was constructed and whether it supported demand reduction. Data from the
current evaluation activities could be used in correlation analyses to address these issues. Rather than comparing
Fighting Back to control cities, the data collected through the evaluation could be used to identify which of the
many and various community initiatives and activities undertaken in all of the cities studied were associated with
reductions in substance abuse, which initiatives appear to have no relation to substance abuse indices, and which, if
any, appear counterproductive.
In addition to helping to identify potentially useful community initiatives, this strategy could also help to answer
the question of whether Fighting Back had any impact. If, for example, community policing is identlfied as highly
correlated with reductions in substance abuse (regardless of whether community policing was initiated in a Fighting
Back city or a control city), it might be possible to assess Fighting Back’s impact by evaluating whether
community policing was implemented earlier or more successfully in Fighting Back cities compared to control
cities.
Another approach to evaluation could be to examine what has happened in the 300+ communities that originally
submitted proposals to the Foundation and were not funded. Comparing their programs to combat substance abuse
with what has taken place in the FB sites could be fruitful. These 300+ communities had carefully considered what
they wanted to do to cope with their substance abuse problems, and it is important to know what happened after
their self-survey, in terms of any implementation, without outside Foundation funding.
63
ORAL COMMUNICATIONS I
REINSTATEMENT AND SPONTANEOUS RECOVERY OF NICOTINE-SEEKING IN RATS
W. A. Corrigall 1 , L. K. Adamson, S. Grocki, and Y. Shaham 2
Biobebavioral Research Department, ARF, and Departments of Physiology1 and Psychology’,
University of Toronto, Toronto, ONT
Reinstatement and spontaneous recovery of previously extinguished nicotine-taking behavior were examined in rats,
Male subjects were trained to self-administer nicotine (30 µg/kg per infusion, IV; one 60-mm session per day for
three weeks). Extinction sessions were then given for 5-10 days during which saline was substituted for nicotine.
Subsequently, in the first set of tests for relapse to nicotine-seeking, the reinstatement of lever presses that
previously delivered nicotine was examined after priming injections of saline and nicotine (75, 150 and 300 µg/kg,
SC; and 30 and 60 µg/kg. IV). In the second set of tests for relapse, rats were tested for nicotine-seeking after an
additional 21-day drug-free period during which they were not exposed to the self-administration chambers (a test for
the spontaneous recovery of drug-seeking), and after priming injections of nicotine (150 and 300 µg/kg, SC).
Reinstatement of extinguished food-reinforced behavior after exposure to nicotine was also determined. Priming
injections of nicotine reinstated nicotine-seeking regardless of the route of administration. In addition, previouslyextinguished nicotine-seeking recovered spontaneously after a 21-day period during which rats were not exposed to
the drug-taking environment. Nicotine also reinstated extinguished food-reinforced behavior in rats with a history of
nicotine self-administration, but not in drug-naive rats. The present results extend previous work with opioid and
stimulant drugs on reinstatement of drug-seeking by the self-administrated drug. It also appear that, as with other
positive reinforcers. the mere passage of time is a sufficient condition for the spontaneous recovery of extinguished
nicotine-seeking.
ACKNOWLEDGMENT:
Supported by ARF.
RECEPTOR MEDIATION OF THE DISCRIMINATIVE AND REINFORCING EFFECTS OF
NICOTINE
L. K. Chambers, C. C. Rovetti, and R. S. Mansbach
Department of Neuroscience, Pfizer Central Research, Groton CT
Central nicotinic cholinergic receptors, specifically of the high-affinity
subtype, are thought to mediate the
primary psychoactive effects of nicotine. To examine the importance of the
receptor in nicotine’s subjective
antagonist erysodine (a DH E analog) was administered to rats trained to
and reinforcing properties, the potent
discriminate or self-administer nicotine. In rats trained to discriminate injections of nicotine in a two-lever procedure
of food-maintained behavior, erysodine dose-dependently blocked the effects of the training dose. In addition,
erysodine produced rightward shifts in the nicotine dose-response curve. Given alone erysodii had few nicotine-like
effects and did not affect response rate. Eryscdine also appeared to reverse adverse effects associated with high doses
of nicotine. Erysaline was also examined in rats trained to intravenously self-administer nicotine under a fixed ratio
schedule. Noncontingent nicotine injections before test sessions resulted in dose-dependent decreases in drug intake
that were. not due to generalized decreases in response rate. Like nicotine (and mecamylamine), acute pretreatment
with erysodii produced decreases in nicotine intake that were not due to a general decrease in response rate. Chronic
treatment with mecamylamine or etysodine produced decreased intake over time similar to that observed in rats
undergoing nicotine extinction over a seven day period. Taken together, these results suggest a critical role for the
receptor in both the discriminative stimulus effects of nicotine and its reinforcing properties.
64
EFFECTS OF PRICE INCREASES AND BRIEF ABSTINENCE ON CIGARETTE SMOKING:
BEHAVIORAL ECONOMlC ANALYSIS
G. J. Madden and W. K. Bickel
Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT
We investigated in the behavioral economics laboratory the combined effects of two public policy initiatives
designed to reduce cigarette smoking: tax increases and bans on public smoking. Human subjecls responded to earn
money which could be spent on cigarette puffs or taken home at the end of each 3.5-hour session. The price of
cigarette puffs was changed between sessions (1-60 cents/puff). Before half of the sessions, subjects abstained for
approximately 6 hours (analogous to a workplace smoking ban). Subjects smoked ad-lib before the remaining
sessions. Independenl of abstinence effects, price increases produced significant decreases in smoking. Demand for
cigarettes shifted from inelastic (i.e., insensitivity to price changes) to elastic as prices increased. Pre-session
abstinence increased demand intensity for cigarettes (i.e., total intake al low prices). However, demand was more
elastic when subjects had abstained before the session. The latter result reflects a price x abstinence-condition
interaction: cigarette consumption was less affected by abstinence as prices increased. These findings suggest that
the beneficial effects of public and workplace smoking bans are likely to be eclipsed by the reductions in cigarette
smoking that would be produced by significantly increasing the excise tax imposed on cigarette purchases.
ACKNOWLEDGMENTS:
Supported by NIDA Grants DA06526 and T32 DA07242.
MECHANISMS OF ACUTE TOLERANCE TO NICOTINE IN MICE
M. I. Damaj, G. S. Patrick, and B. R. Martin
Department of Pharmacology/Toxicology, Virginia Commonwealth University, Medical
College of Virginia, Richmond, VA
Desensitization to nicotine’s effects is believed to play an important role in the development and maintenance of
dependence to this drug. The objective of this study was to investigate the mechanisms of acute tolerance to
nicotine’s antinociceptive effect after intrathecal (i.t.) injection. Male ICR mice were pretreated i.t. with different
doses of nicotinic agonists 10 min prior to a second i.t.injection of agonist (ED84) and the effect on the tail flick
response was measured. An ID50 value (dose that decrease the effect of agonist by 50%) was determined. Acute
tolerance developed to agonists such as (+)- and (-)-nicotine isomers, m-nicotine, isonicotine and ABT-418 with
ID50 values that did not produce agonists effects when administered alone. On the other hand, tolerance did not
develop to other agonists such as DMPP, (+)- and (-)-epibatidine, lobeline and N-MCC. Cross-acute tolerance to
nicotine was investigated by pretreating mice with different nicotinic ligands and then challenging them with
nicotine. Interestingly, cross-tolerance was seen only with agonists which developed acute tolerance by
themselves. However, no relationship was found between receptor affinity and degree of acute tolerance. Finally,
although acute tolerance developed to (+)-BN. a rigid analog of nicotine with low affinity to [3H]-nicotine binding
sites, cross tolerance to nicotine was not observed. These results suggest that multiple mechanisms are involved in
the cholinergic desensitization of spinal nicotinic responses in mice.
ACKNOWLEDGMENT:
Supported by PHS grant #DA-05274.
65
ALTERED COGNITIVE TASK-INDUCED BRAIN ACTIVATION DURING NICOTINE
WITHDRAWAL: A HUMAN FMRI STUDY
A. S. Bloom, J. Wright, J. Pankiewicz*, S. M. Rao † , J.-K. Cho*, H. H. Harsch*, S. A.
Fuller*, Y. Wang ‡ , L. L. Sperry*, and E. A. Stein*
Departments of Pharmacology, *Psychiatry, ‡ Biophysics and † Neurology. Medical College of
Wisconsin, Milwaukee, WI
Chronic use of nicotine products such as cigarettes produces physiological and/or psychological dependence.
Smoking cessation is associated with a withdrawal syndrome consisting of alterations in mood along with an
impairment of attention and cognitive performance. To better understand the biological substrates of nicotine
dependence, we examined the time course of nicotine withdrawals effects on brain activation induced by cognitive
tasks using functional magnetic resonance imaging (FMRI). Chronic smokers (ages 24 - 43) agreed to abstain from
nicotine use for three weeks. They performed three different cognitive tasks (delayed match to sample, visuospatial
working memory and concept formation) while undergoing whole brain FMRI scanning. Scanning was performed
prior to smoking cessation and at one day, one week and three weeks of abstinence. While each task produced a
characteristic activation pattern, all tasks produced activation in frontal cortex and strong activation in parietal and
visual cortical areas. While the FMRI signal magnitude. did not change, the area of activation and task performance
were decreased at day one of withdrawal. Brain activation and task performance returned to pre-withdrawal levels at
one week, suggesting that the decrease in cognitive performance during nicotine withdrawal may be related to
localized associated decreases in brain activity.
ACKNOWLEDGMENT:
Supported by DA-09465.
TREATMENT OF NICOTINE DEPENDENCE WITH FLUOXETINE, NICOTINE PATCH,
AND GROUP THERAPY
K. K. Downey, L. M. Schuh, M. E. Tancer, J. A. Hopper, and C. R. Schuster
Wayne State University School of Medicine, Department of Psychiatry and Behavioral
Neurosciences, Clinical Research Division on Substance Abuse
Smoking cessation attempts are often complicated by dysphoria/ depression, weight gain, craving, and other
nicotine withdrawal symptoms. Fluoxetine’s antidepressant and anorectant properties, along with its capacity to
attenuate compulsive behavior, suggest that this medication might facilitate smoking cessation treatment. In this
pilot study, we examined the effect of pretreating smokers with fluoxetine and maintaining them on the medication
throughout a standard, state-of-the-art smoking cessation program including group cognitive-behavioral therapy (6
weeks) and transdermal nicotine patches (10 weeks). Ten daily-smokers were assigned to either placebo (n=3),
20mg (n=4), or 40mg fluoxetine (n=3). Only 50% of subjects correctly guessed whether they had been taking
fluoxetine versus placebo. Fluoxetine was well-tolerated by all subjects. All 7 fluoxetine subjects achieved initial
abstinence; only one had relapsed just prior to 3 month follow-up; and 3 of 7 (43%) remained abstinent by 6 month
follow-up. Of those on placebo, 2 failed to achieve initial abstinence. although, after 1 week on patch, 1 was able
to achieve and maintain abstinence up to 3-month follow-up. The third placebo subject relapsed just prior to
discontinuation of nicotine patch treatment (9 weeks post quit-date). At six months, 1 of 3 assigned to placebo
remain abstinent (33%). Confirmation of fluoxetine’s apparent efficacy to facilitate smoking cessation and the
mechanisms underlying this effect await availability of a larger sample size.
66
QUITTERS AND NONQUITTERS DIFFER IN THEIR PRETREATMENT REACTIVITY TO
SMOKING
A. Droungas, R. N. Ehrman, A. R. Childress, E. L Erney, and C. P. O’Brien
Addiction Treatment Research Center University of Pennsylvania Medical School,
Philadelphia Veterans Affairs Medical Center, Philadelphia PA
We examined whether pretreatment reactivity to smoking cues differed between quitters and nonquitters who
completed 8 weeks of nicotine patch treatment. Smoking status was determined by self-report of the number of
cigarettes smoked on weeks 8 and 9 using the Time-Line Followback method. Smokers were categorized as quitters
if they reported smoking no cigarettes, and nonquitters if they reported smoking at east 10 cigarettes on each of
weeks 8 and 9. Self-reports were confirmed with week-9 urine cotinine levels which were lower than 100ng/kg for
all quitters and higher than 500ng/kg for all nonquitters. Although quitters and nonquitters did not differ in
demographic characteristics, pretreatment smoking characteristics (e.g., Fagerstrom score, Shiffman and Jarvic
withdrawal scales) and incidence of Axis I diagnoses, they differed in pretreatment reactivity to smoking cues.
ANOVAs showed that although both quitters and nonquitters reported increases in “craving”, and “withdrawal" in
response to the smoking cues, quitters showed a larger increase. Furthermore, the nonquitters reported less “high”
following the smoking cues than at the beginning of the session, while the quilters did not exhibit a similar
reduction. Given that smokers bad been required to smoke a cigarette prior to the pretreatment session, the quitters’
report of strong “high" following the cues indicates that the cues helped preserve a nicotine-like effect. These
results corroborate similar findings with cocaine addicted patients.
ACKNOWLEDGMENTS:
Research Service.
Supported by NIDA grant DA3008 and Department of Veteran’s Affairs Medical
PRELIMINARY EXPERIENCES WITH OPIATE ABUSERS SEEKING SMOKING
CESSATION TREATMENT
D. L. Frosch, S. Shoptaw, M. E. Jarvis, R. A. Rawson, and W. Ling
Los Angeles Addiction Research Consortium, UCLA Dept. of Psychiatry, W.L.A. VAMC
The prevalence of tobacco smoking among opiate abusers is extremely high, with estimates ranging from 70-100%.
There is evidence that tobacco smoking is correlated with illicit substance abuse, through biological mechanisms as
well as social and behavioral linkages. This study describes preliminary experiences with opiate abusers
participating in a smoking cessation trial evaluating Relapse Prevention and Contingency Management in
conjunction with transdermal nicotine patches. Comparing study applicants who were randomized to participate in
the trial with applicants who did not complete screening procedures we found a greater likelihood of opiate use
among unsuccessful applicants ( 2(1)=5.71, p<.05). In addition. unsuccessful applicants showed significantly higher
urine cotinine values (t(39)=2.37, p<.05). suggesting greater severity of nicotine dependence. By the end of the 12
week treatment episode, 7 (31.82%) of the first 22 study participants were confirmed non-smokers. Criteria
consisted of serum thiocyanate below 100 UMOL/L, expired carbon monoxide below 8ppm, and self-report of nonsmoking for the last week of treatment. In treatment. urine toxicology data suggest a strong association between
cocaine use and inability to stop smoking tobacco. Replicating our findings from a previous pilot study subjects
that did not stop smoking were much more likely to be using cocaine compared to subjects confirmed to be nonsmokers at the end of treatment ( 2(1)=4.02, p<.05). These findings suggest that opiate abusers are able to use
available methods for smoking cessation and achieve similar preliminary success as found in the general population.
Our findings support common pathways involved in tobacco and other substance abuse.
67
THE EFFECT OF SUBSTANCE ABUSE TREATMENT HISTORY, CURRENT ALCOHOL
USE, OR MARIJUANA USE ON SUCCESS IN QUITTING SMOKING
G. Humfleet1 , S. Hall1,2 , V. Reus 1 , K. Sees 1 , and R. Muñoz1
‘Department of Psychiatry, University of California, San Francisco and ‘San Francisco
Veterans Affairs Medical Center
Previous research suggests higher rates of smoking, and smoking cessation failure, in alcohol and drug abusing
populations. The relationship is not as clear in a non-abusing population. The present study examined the
relationship of alcohol/drug treatment history and current alcohol and marijuana consumption with success in
smoking cessation treatment in a smoking clinic population. Subjects were 199 smokers participating in a smoking
cessation clinical trial. Subjects were 55% female. Mean age =40.7 years. Mean daily cigarettes = 22.5. Mean
years smoking = 22.2. History of alcohol/drug problems, treatment. and current use was assessed prior to study
entry. Any potential subject reporting current alcohol or drug problems was excluded from the study resulting in a
population with low to moderate levels of alcohol and marijuana use. Current alcohol/drug consumption was also
reported at monthly intervals during treatment and at follow-up assessments. Twenty three percent reported a history
of an alcohol/drug problem and 12.6% reported a history of drug treatment. Seventy-eight .7 percent reported alcohol
use and 21.3% reported marijuana use during treatment. Analyses examined abstinence rates at the end of treatment
and 3. 6, and 12 months post-treatment as well as continuous abstinence. Results indicate no significant differences
in abstinence rates at any assessment based on history of alcohol/drug problem or treatment. Differences were found
for any current alcohol use but not marijuana use. Both alcohol use at baseline and any alcohol use during
treatment predicted abstinence at all follow-up points with alcohol users having significantly lower quit rates than
those reporting no use. Neither use of marijuana at baseline or during treatment predicted outcome. Although past
alcohol/drug problems do not appear to predict treatment outcome, these findings suggest that even low to moderate
levels of alcohol consumption during smoking cessation may decease treatment success. Contrary to an earlier
report, marijuana use was not related to relapse.
ACKNOWLEDGMENT:
Supported by NIDA grants DA02538 and P50-DA0923.
ORAL COMMUNICATIONS II
THE EARLIEST STAGE OF MARIJUANA INVOLVEMENT: INITIAL OPPORTUNITY TO
USE
M. L. Van Ellen, Y. D. Neumark, and J. C. Anthony
Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins
University, Baltimore, MD
A renewed American interest in marijuana has coincided with our research group’s focus on the earliest stages of
drug involvement. Here. we have studied the transition from an initial opportunity to try marijuana to the
subsequent use of this drug. We analyzed self-report interview data gathered from nationally representative samples
of the United States National Household Surveys on Drug Abuse, 1979-94. The evidence indicates that the
estimated prevalence of initial opportunities to try marijuana has been rather stable for 15 years. However, there are
recent increases in the probability of rapidly progressing from first marijuana opportunity to first marijuana use,
among persons given an opportunity to use. As age of first marijuana opportunity increases, the likelihood of
marijuana use decreases. Also, male-female differences in marijuana use appear to be due to differences in
opportunity to use rather than differences in likelihood of use once an opportunity has occurred. This
epidemiological evidence on the transition from marijuana opportunity to marijuana use, the first to be published
based on a nationally representative U.S. sample, highlights directions for future research and a focus for prevention
efforts.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA07292 and DA08199.
68
PREDICTORS OF CESSATION OF MARIJUANA USE
D. B. Kandel1,2 and K. Chen1
1
Columbia University and
2
New York State Psychiatric Institute, New York, NY
In contrast to the initiation of marijuana use, little is known about the predictors of cessation. Event history
analysis was applied to monthly life and drug histories of a representative community sample of 706 marijuana
users, followed from ages 15-16 to 34-35, to investigate factors associated with cessation of marijuana use from
adolescence to adulthood. In addition to gender, the most important determinants of cessation are the
phenomenology of marijuana use, social role participation, depressive symptoms and deviance. Frequent users,
those who started using early and those who use illicit drugs other than marijuana are more likely to continue using
marijuana. Using marijuana for social reasons accelerates cessation, using to change one’s mood reduces cessation
for women only. Becoming a parent is the most important social role leading to marijuana cessation. There is also
a very important experimental effect of the interview itself on the reported timing of cessation. One-third of the
effect of age observed at the univariate level is explained by the factors included in the model. The effect of social
context favorable to marijuana use. appears to reflect a selection effect rather than social influence. Postponing onset
into marijuana use. reducing extensiveness of use, increasing commitment to conventional social roles, and reducing
delinquent participation are likely to be important interventions that would shorten a marijuana-using career.
Supported by NIDA grants (DA01097, DA02867, DA03196 and DAO4866) and
ACKNOWLEDGMENTS:
Research Scientist Award (DA00081).
ASSESSMENT AND TREATMENT OF ADULT MARIJUANA DEPENDENCE:
COMPARISON TO COCAINE AND OPIOID DEPENDENCE
A. J. Budney, K. J. Radonovich, S. T. Higgins, and W. K. Bickel
Department of Psychiatry, University of Vermont. Burlinton, VT
The prevalence rate of marijuana dependence is the highest of any illicit drug in the general population, yet clinical
research on marijuana dependence is sparse. The aim of the present research is to extend prior findings regarding the
characteristics of individuals who seek treatment for marijuana-related problems and examine the efficacy of three
behaviorally-based interventions, (1) brief motivational enhancement, (2) motivational enhancement plus behavioral
coping skills therapy, and (3) motivational enhancement, behavioral coping skills therapy plus reinforcement
contingent on marijuana abstinence. Marijuana-dependent individuals (n=62) averaged 21.8 ± 9.9 days of marijuana
use during the 30 days prior to treatment and smoked 4.0 ± 3.5 times per day. This marijuana group reported druguse histories and impairment comparable to cocaine- and heroin- dependent individuals seeking treatment in the same
clinic. Notable significant differcences observed between groups included more education, less employment
problems, less depressive symptomatology. and lower prevalence of cigarette smoking among the marijuana
abusers. A readiness-to-change measure suggested that marijuana abusers may enter treatment less motivated to
discontinue their use than cocaine or heroin abusers. To date, 33 marijuana-dependent individuals have entered the
clinical trial. Preliminary outcome data indicate that 58% completed treatment, and 42% reported a greater than 50%
reduction in days of marijuana use at the end treatment. In summary, these data suggest that marijuana abusers
present for treatment with substantial psychosocial problems. Clinical research focused on the development of
efficacious treatments for this population appears warranted.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-08655, DA-09378, DA-06969.
69
THE EFFECTS OF A MONETARY ALTERNATIVE ON MARIJUANA SELFADMINISTRATION
A. S. Ward, S. D. Comer, M. Honey, R. W. Foltin, and M. W. Fischman
NYS Psychiatric Institute and Columbia University, New York, NY
Availability of alternative reinforcers can reduce drug self-administration. This 21-day study investigated the effect
of monetary alternatives on marijuana self-administration. Seven participants (3F, 4M) performed computer tasks
(baseline) in the morning prior to smoking a sample marijuana cigarette (0.0, 1.8, or 3.9% THC) and receiving the
sample alternative ($5 voucher). In the afternoon, participants had five opportunities to choose to receive either of
the earlier alternatives. Participants were required to meet a criterion level of task performance to obtain each choice.
The monetary performance criterion varied from day to day (80, 100, or 120% of baseline); the marijuana
performance criterion remained constant at 100% of baseline. Choices were delivered in the evening, after task
completion. Marijuana choice varied as a function of THC concentration and criterion to earn money. Active
marijuana was always chosen more often than placebo, and active and placebo marijuana were chosen over money
when the criterion to earn money was high. Task performance improved when criteria were imposed, even after
participants had smoked the sample marijuana cigarette. Subjective ratings of drug effects increased with increasing
THC concentration, but did not predict choice. Results indicate that the availability of a monetary alternative was
effective in shifting choice to self-administer marijuana, and that marijuana choice was sensitive to contingency
manipulations. Results further suggest that contingency manipulations may override the performance-impairing
effects of marijuana.
ACKNOWLEDGMENT:
Supported by NIDA grant DA03476.
CHANGES IN AGGRESSIVE BEHAVIOR FOLLOWING DISCONTINUATION FROM LONGTERM MARIHUANA USE
E. M. Kouri; H. G. Pope, Jr.; and S. E. Lukas
ADARC, McLean Hospital/Harvard Medical School, Belmont, MA
Most studies investigating the relationship between marihuana smoking and aggression have concluded that acute
administration of marihuana decreases aggressive behavior in humans (Myerscough et al., 1985). However, there
are no published studies on the effects of withdraw from chronic marihuana use on aggressive behavior in humans.
This represents a serious omission in the research literature because it has been shown that the abrupt
discontinuation of marihuana after long-term use can result in a syndrome characterized by insomnia, restlessness
and irritability within 24 hours after discontinuation of the drug (Compton et al., 1990; Mendelson et al., 1984).
Our study was conducted to characterize the duration and pattern of changes in aggressive behavior in long-term
marihuana users after a 28-day abstinence period verified by daily urines. Our subjects were 4 women and 13 men
who had smoked marihuana on at least 5,000 occasions (the equivalent of smoking daily for approximately 14
years) and who were smoking regularly when recruited. Subjects were studied on day 0 (when they were still
smoking), day 1 (during acute withdrawal), days 3, 7 and 28 of a 28-day detoxification period. Aggression was
measured with the Point Subtraction Aggression Paradigm (PSAP, Cherek, 1981). There was a significant increase
in aggressive responding on days 3 and 7 of withdrawal as compared to day 0. These increases in aggressive
responding returned to pre-withdrawal levels after 28 days. Our findings confirm previous reports of an abstinence
syndrome associated with chronic marihuana use and suggest that aggressive behavior should be an additional
component of this syndrome.
ACKNOWLEDGMENTS:
NIDA DA10346, DA03994 and DA00115.
70
MARIJUANA SLOWS SMOOTH PURSUIT EYE TRACKING AND REDUCES LIGHT
REFLEX
W. B. Pickworth and R. V. Fant
NIDA, Division of Intramural Research, Addiction Research Center, Baltimore, MD
Marijuana continues to be the most commonly abused illicit drug in the United Slates. Because many people abuse
marijuana during the evening and on weekends and then go to work or school the next day, more research is needed
on the residual effects of marijuana. The current study sought to examine both acute and residual subjective,
physiologic, and performance effects of smoking a single marijuana cigarette. Ten healthy male volunteers who
reported recent use of marijuana resided on a residential research ward. On three separate days, subjects smoked one
NIDA marijuana cigarette containing either 0%, 1.8%, or 3.6% 9-tetrahydrocannabinol (THC) according to a paced
puffing procedure. Subjective, physiologic, and performance measures were collected prior to smoking, five limes
following smoking on that day, and three times on the following morning. Smooth pursuit eye tracking was
measured at 15°/sec through the central (0-22°) and peripheral (22-45°) visual fields. The response to a sustained
light stimulus at two intensities (8 and 20 ftcd) were recorded using a computer-based video system. Subjects
reported robust subjective effects following both active doses of marijuana which returned to baseline levels within
3.5 hr. Heart rate increased and the pupillary light reflex decreased following active dose administration with return
to baseline on that day. The mean constriction amplitude of the light reflex decreased from 1.8 to 0.9 mm (8 ftcd)
and 2.8 to 1.8 mm (20 ftcd). Marijuana smoking produced decrements in smooth pursuit eye tracking that persisted
for 1.75h after smoking. Tracking speed was reduced from 11.5 to 6.5 °/see (central field) and 6 to 2 °/sec (peripheral
field). Although robust acute effects of marijuana were found on subjective and physiologic measures, and on
smooth pursuit eye tracking performance, no effects were evident the day following administration indicating that
the residual effects of smoking a single marijuana cigarette are minimal, the acute effects of marijuana to impair
smooth pursuit tracking and the light reflex may be involved in workplace and traffic accidents associated with its
use.
MOTOR COORDINATION AND BALANCE ARE IMPAIRED BY ACUTE MARIJUANA
ADMINISTRATION
S. J. Heishman, R. C. Taylor, and D. J. Crouch*
Clinical Pharmacology Branch, IRP, NIDA, Baltimore, MD and *Center for Human
Toxicology, University of Utah, Salt Lake City, UT
In two studies. we investigated the effect of smoked marijuana on four standardized field sobriety tests (FST) that are
used to determine whether a person can safely operate a motor vehicle. Subjective effects and 9 tetrahydrocannabinol (THC) plasma concentrations were also measured to correlate with behavioral impairment. In
a residential study. 12 volunteers participated in six experimental sessions. At each session, subjects smoked ad lib
two half-cigarettes containing 0 or 3.58% THC. Placebo, low, and high doses consisted of two placebo halfcigarettes, one placebo and one active half-cigarette, and two active half-cigarettes, respectively. Subjects received
each marijuana dose twice in random order. Marijuana impaired performance on only one FST, the One Leg Stand,
by increasing number of hops and times the elevated foot touched the floor to maintain balance. In a nonresidential
study. 20 subjects participated in three experimental sessions. At each session, subjects smoked two cigarettes (16
paced puffs) containing 0, 1.75, or 3.55% THC. Marijuana impaired performance on two FST, One Leg Stand and
Finger to Nose. The number of times subjects put their foot down and raised their arms to maintain balance and
amount of body sway were increased by marijuana in the One Leg Stand test. A dose-dependent increase in number
of misses was observed in the Finger to Nose test. In both studies, marijuana produced orderly dose-relaled increases
in subjective ratings of intoxication. THC plasma concentrations peaked immediately after smoking and bad
declined to 15-28 ng/ml at time of FST testing (15 min postsmoking). These data suggest a threshold plasma THC
level in the 20-25 ng/ml range for marijuana to impair behaviors critical for safe driving.
71
MARIHUANA AND ETHANOL EFFECTS ON COGNITION, HEART RATE AND
SUBJECTIVE MOOD
S. Orozco and S. E. Lukas
ADARC, McLean Hospital/Harvard Medical School, Belmont, MA
Researchers using electrophysiology as a measure of cognitive processing following ethanol and maribuana
challenges have suggested that the N100 and P300 event-related (ERP) components can reflect two aspens of
selective attention, stimulus set and response evaluation, respectively. However, few have studied ERP responses to
combined ethanol and marihuana Eighteen healthy male recreational drug users were randomly assigned to one of
three groups: placebo marihuana (0.001% 9-THC), low-dose marihuana (1.26% 9-THC) and high-dose marihuana
(2.53% 9-THC). the marihuana dose was held constant and each subject drank three different doses of ethanol on
three different days: placebo, 0.35 g/kg or 0.70 g/kg. Thirty minutes after drinking they smoked a maribuana
cigarette. Subjects were presented with an auditory “oddball” ERP task and measurements were obtained at baseline
and at 20, 40, 60 and 80 minutes after smoking. Blood samples, heart rate and subjective mood ratings were also
analyzed. A MANOVA revealed a reduced P300 amplitude 70 minutes after drinking and at 60 minutes after
smoking, a high dose of maribuana and ethanol produced a longer P300 latency. Both high and low dose maribuana
produced longer N100 latencies at 80 minutes after smoking. Heart rate remained increased for an hour after
smoking. Subjects reported feeling “high” until 50 minutes after smoking, and “drunk” until 90 minutes after
drinking. these findings suggest that an acute dose of marihuana and ethanol may alter cognitive processing in
healthy individuals long after the physiological and subjective states have disappeared.
ACKNOWLEDGMENTS:
Supported by NIDA Grants DA00115 and DA00115
ORAL COMMUNICATIONS III
CONSERVATION OF CONFORMATIONAL TOPOGRAPHY AT FIVE GABAA/BENZODIAZEPINE RECEPTOR SUBTYPES
Q. Huang, X. He, T. Gan, and J. M. Cook*
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI
The synthesis and in vitro affinities of a series of optically active pyrrolo or azetidinylimidazobenzodiazepines at
five recombinant GABAA/BzR subtypes expressed from human cell lines are described Examination of in vitro
binding data indicates thaat (S)-enantiomers of these ligands are much more potent than their corresponding (R)isomers. Binding affinities of three framework constrained (rigid) ligands provide evidence for the first time which
indicates the conformational preference for BzR ligands is highly conserved at these five recombinant receptor
subtypes. The contigurational preference for (S)-enantiomers in both series of ligands suggests that
pharmacophoric descriptors H1, H2 and L1 are the same in these five receptor subtypes in agreement with previous
modeling studies. In addition, these framework constrained (S)-pyrroloimidazobenzodiazepines 1, 2, 3, and
azetidinyl analog 4, were 45 to 57 times more selective for the
subtype in comparison to the
isoform. Data from the present study should be useful for understanding conformational requirements of
GABAA/BzR subtypes as well as providing some insights into the conservation of binding site topography across
a series of BxzR subtypes.
72
APPARENT pA 2 VALUES OF PARTIAL AND SELECTIVE GABA A ANTAGONISTS
WITH MIDAZOLAM IN MONKEYS
C. A. Paronis and J. Bergman
Harvard Medical School, ADARC / McLean Hospital, Belmont, MA
Drugs that bind to benzodiazepine recognition sites of GABAA receptor complexes may function as agonists in
some behavioral assays while functioning as antagonists in other behavioral assays. The present studies compared
the effects of the imidazodiazepines midazolam, Ro 41-7812, and Ro 42-8773 and the -carboline -CCt under two
different procedures of schedule-controlled responding. One group of squirrel monkeys (N=4) responded under a
multiple fixed-ratio schedule of food presentation involving suppressed and nonsuppressed behavior. Another group
of monkeys (N=3) responded under a fixed-ratio (FR30) schedule of stimulus-shock termination. Midazolam (0.03 0.3 mg/kg) and Ro 42-8773 (0.01-1 mg/kg) dose-dependently increased rates of suppressed responding, and
flumazenil (0.3 mg/kg) surmountably antagonized these antisuppressant effects. Ro 41-7812 and -CCt bad no
effects on behavior maintained under the suppressed- responding schedule. Under the schedule of stimulus-shock
termination, only midazolam decreased responding (ED50 = 0.3 - 0.1 mg/kg), and these effects were surmountably
antagonized by Ro 41-7812 (0.3-10.0 mg/kg), Ro 42-8773 (0.1-3 mg/kg), and -CCt (3-30 mg/kg). Schild plot
analysis revealed tbe following mean values (with 95% C.L.): Ro 41-7812 pA2= 7.06 (5.67, 8.44) witb a slope
of -0.76 (-1.31, -0.20); Ro 42-8773 pA2= 6.81 (6.26, 7.37) with a slope of -1.11 (-1.66. -0.57). Apparent pA2
values were not calculated for -CCt because the confidence limits of the slope of the Schild plot included positive
values, these results demonstrate that Ro 42-8773 has both agonist and antagonist properties in squirrel monkeys,
whereas -CCt and Ro 41-7812 have predominantly antagonist effects in monkeys. Furthermore. these results
indicate that apparent pA2 values can he obtained for benzodiazepine ligands that are either full antagonists or partial
agonists.
ACKNOWLEDGMENTS:
Supported by USPHS Grants DA 03774, DA 05653. MI-I 07658 and RR 00168.
DISCRIMINATIVE STIMULUS EFFECTS OF FLUMAZENIL IN RHESUS MONKEYS
TREATED CHRONICALLY WITH DIAZEPAM
L R. Gerak and C. P. France
Department of Pharmacology, Louisiana State University Medical Center, New Orleans, LA
One consequence of long-term treatment with benzodiazepine agonists is the development of physical dependence.
The purposes of the current study were to establish a procedure for evaluating benzodizepine dependence and
withdrawal in nonhuman primates and to assess the effects of other drugs for their ability to modify dependence or
withdrawal. Four thesus monkeys were treated daily with 5.6 mg/kg of diazepam (p.o.) while discriminating 0.32
mg/kg of flumazenil (s.c.) from vehicle under a fixed ratio 5 schedule of stimulus-shock termination. Flumazenil
(0.0032-0.32 mg/kg) dose-dependently increased responding on the flumazenil lever with doses larger than 0.1
mg/kg producing 80% flumazenil- appropriate responding. Discriminative stimulus effects of 0.32 mg/kg of
flumazenil were evident 10 mm after injection and bad a duration of 60 min. The benzodiazepine receptor inverse
agonist Ro 154513 produced 80% flumazenil- lever responding in all monkeys whereas the benzodiazepine
receptor inverse agonist ethyl -carboline-3-carboxylate and the GABA receptor antagonist pentylenetetrazole
produced 80% flumazenil-appropriate responding in only some monkeys; drugs from other pharmacological classes
produced vehicle-appropriate responding. Temporary suspension of diazepam treatment resulted in a time-related
switch in responding to the flumazenil lever; 75 hr after the last dose of diazepam, flumazenil-lever responding was
reversed by 1.0 mg/kg of diazepam. In diazepam-treated monkeys, there was no apparent change in effectiveness of
the training dose of flumazenil even when it was administered daily. This procedure appears to be pharmacologically
selective for antagonists and inverse agonists at the benzodiazepinelGABAA receptor complex. To the extent that
the discriminative stimulus effects of flumazenil are related to benzodiazepine withdrawal, this procedure should
prove useful for studying dependence and withdrawal in a manner that will be predictive of subjective effects in
humans.
ACKNOWLEDGMENT: Supported by USPHS Grant DA09157.
73
ZOLPIDEM PHYSICAL DEPENDENCE ASSESSED ACROSS INCREASING DOSES
UNDER A ONCE-DAILY DOSING REGIMEN
E. M. Weerts, D. M. Grech, N. A. Ator, and R. R. Griffiths
Johns Hopkins University School of Medicine, Baltimore, MD
Zolpidem (ZLP) is an imidazopyridine hypnotic with selectivity for BZ1 receptor subtypes. Previously,
discontinuation of ZLP after chronic self-administration suppressed food intake indicating that baboons may have
been physically dependent (Griftiths et al. 1992). The current study examined the behavioral effects and possible
development of physical dependence after once-daily bolus doses of ZLP (0, 1, 3.2, 10, 32 mg/kg) in 3 baboons.
Each dose was administered i.g. for 17 days and then the dose was increased. Chronic dosing was discontinued after
the 32 mg/kg condition. Baboons had access to pellets for 20 h/day beginning 15 min after dosing. Baboons were
presented with a motor task 1 h after dosing, and tremor, incoordination, and time to complete the task were
recorded. Behavioral observations were conducted 1 h after dosing on days 1, 10, 12 and 14 of each dose and after
dosing was terminated. On days 10 and 14 of each dose, vehicle and flumazenil (FLZ, 5 mg/kg) were administered
i.m., respectively. ZLP increased pellet intake in 2 of 3 baboons. At 3.2 and 32 mg/kg ZLP, 1 baboon vomited
and a 2nd baboon showed head-lower-than-torso posture (often associated with nausea and vomiting). Time to
complete the motor task was increased in 3 baboons, and incoordination was observed at 10 and 32 mg/kg ZLP.
FLZ produced behavioral signs of withdrawal including vomit/retch (2 of 3 baboons) and tremors/jerks (3 baboons)
at 32 mg/kg ZLP. Discontinuation of ZLP resulted in suppression of pellet intake for 15 days in 2 baboons, and
signs of withdrawal in all 3 baboons. These data indicate that ZLP produced physical dependence under once-daily
dosing conditions. References: Griffiths, R.R.; Sannerud, C.A.; Ator, N.A.; Brady, J.V. (1992) Zolpidem
behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal. J Pharmacol Exp
Ther 260: 1199-1208.
ACKNOWLEDGMENT:
Supported by NIDA grant DA01147.
SELECTIVE EFFECTS OF ZOLPIDEM ON HUMAN MEMORY FUNCTIONS
M. Z. Mintzer and R. R. Griffiths
Johns Hopkins University School of Medicine, Baltimore, MD
Zolpidem (ZOL) is an imidazopyridine hypnotic with selective affinity for the benzodiazepine receptor subtype.
It has been suggested that ZOL may produce less memory impairment than classic benzodiazepines due to its
relatively low affinity for the receptor subtypes found in areas of the brain which are involved in learning and
memory. The present double-blind, placebo-controlled study evaluated the effects of orally administered ZOL (15
mg/70 kg) on a battery of memory tasks with word and picture stimuli in 16 normal human volunteers. Relative to
placebo, ZOL significantly impaired memory for material presented after drug administration when memory was
assessed directly by referring subjects back to the prior study episode (explicit memory: recall and recognition) but
not when memory was assessed indirectly by evaluating subjects’ ability to identify degraded versions of studied
stimuli (implicit memory: fragment completion). ZOL did not impair explicit memory for material presented
before drug administration or memory for previously acquired knowledge (semantic memory: categorization). There
was evidence suggesting that ZOL enhanced explicit and implicit memory for material presented before drug
administration and that ZOL produced a specific deficit in the acquisition of contextual information about material
presented after drug administration. The results of the present study document selectivity in the memory-impairing
effects of zolpidem. The extent to which zolpidem’s selectivity differs from that of classic benzodiazepines remains
to be explored.
ACKNOWLEDGMENT:
Supported by NIDA grant DA03889.
74
CHRONIC BENZODIAZEPINE THERAPY DOES NOT RESULT IN BRAIN
ABNORMALITIES AS MEASURED ON COMPUTERIZED TOMOGRAPHY (CT) SCANS
V. E. Busto, K. Bremner, K. Knight, K. terBrugge, and E. M. Sellers
Biobehavioral Research Department, Addiction Research Foundation, Toronto, Ont.;
Departments of Pharmacology, Psychiatry, Medicine, Neurology and Faculty of Pharmacy,
University of Toronto, Toronto, Ont.
Studies on the association between chronic benzodiazepine use and chronic brain abnormalities have yielded
conflicting results. The computerized tomography (CT) scans of 20 chronic benzodiazepine users (65% male; age,
± SD [range] = 42.2±12 yrs [23-59], mean daily benzodiazepine dose, diazepam equivalents = 21±18 mg, [2.5-70],
mean cumulative benzodiazepine exposure = 55.2 g, [1.8-198]) were compared to 36 age (±2 yrs) and sex-matched
controls. Controls were prospectively recruited from 120 patients attending a neurology clinic, and interviewed to
screen for alcohol and substance use disorders and other conditions possibly leading to brain atrophy. Three
neurologists blindly assessed each CT scan for atrophy and measured ventricles (V1, V2, V3), sulci, fissures,
cisterns and folia. Reliability among raters ranged from 0.92 to <0.1, in which case, deleting one rater raised all
reliabilities to >0.45. No difference in atrophy was found between bcnzodiazcpine users and controls, V1 measures
were significantly higher for benzodiazepine users than controls (x±SD = 12.1±1.3 vs. 11.1±2.0, p=0.02) but
measures of 3rd and 4th largest sulci were significantly higher in controls than in benzodiazepine users. Right 3rd
and 4th largest sulci (x±SD) were: controls, 0.72±0.4 and 0.74±0.7; benzodiazepine users, 0.51±0.3 and 0.46±0.3
p<0.02). Left 3rd and 4th largest sulci were: controls, 0.77±0.6 and 0.65±0.3; benzodiazepine users, 0.53±0.3 and
0.5±0.3 (p<0.02). Chronic benzodiazepine therapy does not result in brain abnormalities.
FLUNITRAZEPAM ABUSE POTENTIAL IN RELATION TO RATE OF ONSET OF
EFFECTS AND DOSE ADMINISTERED
M. Farré, P. N. Roset, M. Mas, E. Menoyo, R. de la Torre, C. Hernández, and J. Camí
Dept. of Pharmacology and Toxicology, Institut Municipal d’lnvestigació Mèdica (IMIM),
Universitat Autònoma de Barcelona. Barcelona, Spain
Drug abuse potential seems to be related to intensity and rate of onset of effects. Thus, benzodiazepines with fast
absorption might be preferred by drug abusers because of rapid and intense obtention of pleasurable feelings, the
manipulation of rate of delivery has been a useful method to study differences in onset of effects. For diazepam 20
mg, a fast administration schedule showed higher ratings in ARCI-MBG scale, more behavioral signs of
intoxication, and greater psychomotor impairement than a slow administration. In a previous study, we failed to
demonstrate differences between fast and slow 2 mg flunitrazepam (FNZ) administration. Twelve male healthy
volunteers participated in a randomized, double-blind, double-dummy, crossover study. Drugs were administered in
6 capsules, ingested at 30-min intervals over 2.5 h. Conditions were: placebo, FNZ SLOW (6 doses of 0.25 mg),
and FNZ FAST (5 doses of placebo and a single last dose of 1.25 mg). Variables included: vital signs, subjective
effects (VAS, ARCI, POMS), psychomotor performance (simple reaction time, DSST. Maddox-wing) and blood
samples. Both active conditions induced an impairment of performance tasks and sedative effects, and produced
increases in scales related to pleasurable effects (“high”, “good effects”) compared to pIacebo. Both active conditions
produced similar psychomotor impairment and sedative effects, while FAST administration induced significantly
increases in drug-related euphoria (“high”, “good effects”, “liking”, ARCI-MBG) in comparison to SLOW. Peak
plasma concentrations were similar between both FNZ conditions. This results, taken together witlh the previous
study with FNZ 2 mg, seems to support the influence of rate of onset of effects and dose in drug abuse liability.
ACKNOWLEDGMENTS:
Supporting grants FIS 95/231, CIRIT-95SGR-432, ISC-III 97/4344 and
CITRAN.
75
EXPECTANCIES IN BENZODIAZEPINE (BZ) DEPENDENCE
J. D. Roache*, J. M. Schmitz*, J. Grabowski*, and K. Kirby&
*University of Texas - Houston HSC and &Allegheny University HSC
Thirty-seven males and females with iatrogenic BZ dependence were enrolled in an outpatient treatment program
providing clonazepam substitution and gradual dose reduction under double-blind conditions. Over the course of
weekly clinic visits, patients initially were stabilized on their intake BZ (Wk#1) and then were stabilized on an
equivalent dose of clonazepam (Wks #2-4). Thereafter, clonazepam doses were reduced weekly by 1/2 of a log, unit.
We assessed patient expectations regarding treatment, BZ use, and self-efficacy with questionnaires and attempted to
experimentally manipulate expectations through a dose-reduction instruction that was given prior to Wk #5 of
treatment. The manipulation involved a balanced-expectancy design in which withdrawal instructions were balanced
with the actual dose reduction condition. A 2x2 factorial design generated 4 differ-em groups wherein patients either
were or were not informed that their doses were being reduced (2 levels of Instruction) when they in fact were or
were not aetually being reduced (2 levels of dose reduction). Symptoms of anxiety/BZ withdrawal were assessed
over the next 3 weeks. After Wk #8, subjects, previously maintained at constant clonazepam doses, also began dose
reduction. Outcome measures were treatment retention, achievement of placebo dose, and anxiety/withdrawal
symptom levels. Counter to our hypothesis, the withdrawal instructions had no consistent effect on anxiety
symptoms in the initial 3-week period or on ultimate treatment outcome. However, initial “desire to quit” predicted
longer retention in treatment and intake assessments of general self-efficacy, low “fears of withdrawal”, and greater
ratings of “ability to manage anxiety without medication” predicted success in achieving placebo doses. Thus, we
failed to gain experimental control over anxiety levels and expectation but did find that initial assessment of patient
self-efficacy and expectation may be useful predictors of treatment outcome.
ACKNOWLEDGMENT:
Supported by NIDA Grant DA-07431.
ORAL COMMUNICATIONS IV
COCAINE TREATMENT AGENTS: SYNTHESIS AND PHARMACOLOGY OF NMETHYLPHENIDATE ANALOGS
H. M. Deutsch, X. Ye, B. Ojo, M. M. Schweri#, and S. Holtzmnn*
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA;
#School of Medicine, Mercer University, Macon, GA; *School of Medicine, Emory
University, Atlanta, GA
The long term objective of this research is to develop treatment agents for cocaine abuse. An important site of the
molecular action of cocaine is the binding site associated with the dopamine transport complex. The specific aim of
this work is to make drugs which will selectively attenuate the effects of cocaine at this site, but minimally
Interfere with the transport of dopamine. A number of N-substituted analogs of methylphenidate have been
synthesized and evaluated for inhibition of [3H]WIN 35,428 binding and [3H]dopamine uptake and in various animal
behavioral tests. Whereas N-aLkyl and N-aIkenyl groups uniformity lower the binding affinity, some N-benzyl
groups actually increase the binding potency. Analysis
of the in vitro data by looking at the ratio of inhibition
R = alkyl, alkenyl,
alkynyl and benzyl
of uptake to binding indicated that the some of these
compounds might have potential as possible cocaine
Methylphenidate
partial agonists or antagonists. The results of drug
R=H
discrimination and locomotor stimulation testing in rats,
and the synthesis and pharmacology of compounds will
be discussed in detail.
76
TRANSPORTER AFFINITY OF HYDROXYLATED DERIVATIVES OF COCAINE AND THE
PHENYLTROPANES -CIT AND FP-CIT
J. L. Neumeyer, R. J. Baldessarini, N. S. Kula, G. Tamagnan*, and A. Anderson*
ADARC and MRC, McLean Hospital—Harvard Medical School, Belmont, MA; and *Research
Biochemicals International (RBI), Natick, MA
The 3’-hydroxy (2) and 4’-hydroxy derivatives (3) of cocaine (1) have been identified as metabolites but their
neuropharmacology remains poorly characterized. -ClT (4) and FP-CIT (6) are stable phenyltropane analogs of
cocaine with high affinity for the cocaine binding site on cerebral dopamine transporter (DAT) that can be used for
imaging the DAT with PET or SPECT, and might also undergo aromatic hydroxylation in vivo. We synthesized
the hydroxy metabolites of cocaine (2,3) and potential hydroxylated metabolites of the phenyltropanes (4, 6, 5, 7)
and evaluated their affinity to DAT as well as transporters for serotonin (5-HTT) and norepinephrine (NET) in
corpus striatum tissue from rat forebrain, in comparison with the parent compounds (1, 4, 6). Synthesis of the
compounds and modification of transporter affinity and selectivity by hydroxylation will be reported.
ACKNOWLEDGMENTS:
Supported by grants MH-34006, MH-47370, MH-49533 and DA-04060 and an
award from the Royal Danish School of Pharmacy (to A.A.).
COCAINE ANTAGONISTS FROM DIRECTED COMBINATORIAL CHEMISTRY
J. R. Cashman, G. Underiner, L. Xu, A. Janowsky, and B. Levant
Seattle Biomedical Research Institute, Seattle, WA; Oregon Health Science University,
Portland, OR; and University of Kansas School of Medicine, Kansas City, KA
The dopamine transporter (DAT) and related modulation of dopamine function have been identified as the relevant
bio-macromolecules for initiating cocaine self-administration behavior. A correlation has been observed between the
drug potency al inhibiting ligand binding to DAT and replacing cocaine in a self-administration paradigm.
Previously, others have proposed that binding to and uptake inhibition of the DAT was highly correlated. As part of
a comprehensive program to develop antidotes to cocaine abuse, we used high yield solution phase chemical
synthesis to create chemical libraries that were screened for inhibition of DAT binding, dopamine uptake and release.
In addition, the selectivity of action of the antagonists for the dopamine receptor versus the DAT was examined in
the presence of rat dorsal striatal membranes. From a modest sized library, one sublibrary was chosen for more
extensive study and individual members were chemically synthesized. For the chemical sublibrary that was examined
as individual members, a very poor correlation between binding and uptake inhibition at the human DAT was
observed. For the sublibrary examined, one member showed essentially no binding to the DAT but significant
inhibition of uptake. The data suggest that binding and inhibition of [3H]-DA uptake may have different
mechanisms. The use of chemical libraries in drug discovery of medications to combat drugs of abuse overuse may
provide unique entities that may otherwise not have been anticipated.
ACKNOWLEDGMENT:
Supported by NIDA grant DA00269
77
8-OXATROPANES: POTENT NON-NITROGEN INHIBITORS OF MONOAMINE
TRANSPORT SYSTEMS
P. C. Meltzer, A. Y. Liang, M. D. Gonzalez, P. Blundell, Z. Chen, and B. K. Madras
Organix Inc, Woburn, MA and Harvard Medical School
Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing and stimulant properties
have been associated with its propensity to bind to the dopamine transporter (DAT). The binding interaction
between the tropanes and their biological target at the molecular level is still uncertain, It has always been assumed
that an 8-amino nitrogen is required for binding between the DAT and ligands in the tropane series, We now report
that substitution of the amine by an ether can result in potentligands for the DAT. We now describe the design,
synthesis, and biology of a family of potenl inhibitors: 2-catbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes. In this
family of 8-oxa compounds, a 3,4-dichloroaryl compound has proved to be a particularly potent inhibitor of the
dopamine and serotonin transporters (DAT= 3.08 ± 0.07 nM and SERT=64.5 ± 10.3 nM). An interesting aspect of
the binding of the 8-oxa compounds is that they are potent in both the chair and boat conformations.
ACKNOWLEDGMENTS:
Supported by NIDA (DA4-8309; DA09462; DA06303) (RR 00168).
A 3 -(DIPHENYLMETHOXY)TROPANE
DOPAMINE TRANSPORTER
BASED
PHOTOAFFINITY
LABEL
FOR
THE
1
2
G. E. Agoston1 , A. H. Newman1 , S. Izenwasser , and R. Vaughan
NIDA-DIR, Psychobiology Section1 and Molecular Neurobiology Branch,2 NIH, Baltimore, MD
The dopamine transporter (DAT) is believed to play a central role in cocaine addiction. Many cocaine analogs are
known to bind to the DAT. inhibit the reuptake of dopamine and demonstrate a cocaine-like behavioral profile in
animal models. In contrast, while 3 -(diphenyhnethoxyhropane analogs show analogous binding and uptake
characteristics they demonstrate a non-cocaine-like behavioral profile. The structural and behavioral distinctions
between these classes of dopamine uptake inhibitors suggest a dissimilarity in their binding interaction with the
DAT protein. Recently, it was reported that photoaffinity labels based on the structures of GBR 12909 and RTI 55
bound to different regions on the DAT. Based on this information, we have prepared a photoaffinity label
containing the 3 -(diphenylmethoxy)tropane core to explore its interaction with the DAT. Our studies to date have
revealed that the N-(4-n-butylphenyl)-4',4''-difluoro-3 -(diphenylmethoxy)tropane demonstrates potent DAT binding
affinity (Ki = 8.3 nM). The phenyl ring in this ligand may serve as an anchor in which an azido and 125I group can
be attached. The butyl azido/iodophenyl tropane photoaffinity label may be a useful ligand that will further reveal
structure / function relationships at the DAT.
78
BRIDGED PIPERAZINES AND PIPERIDlNES RELATED TO GBR12909 AS DOPAMINE
UPTAKE INHIBITORS
Y. Zhang, R. B. Rothman*, C. M. Dersch*, J. S. Portilla*, D. B. Joseph, W. D. Bowen, and
K. C. Rice
LMC, NIDDK, NIH, Bethesda, MD and *Clinical Psychopharmacology Sect., IRP, NIDA,
NIH, Baltimore, MD
Current studies on the treatment of cocaine abuse have focused on the development of selective dopamine transporter
(DAT) ligands as dopamine uptake inhibitors. Among the different classes of ligands identified, the disubstituted
piperazines including GBR12909, have demonstrated high affinity and selectivity for the transporter, A drug ad
food self-administration study showed that GBR12909 suppresses the cocaine-maintained responding without
affecting normal food intake in rhesus monkeys. Recent studies on a decanoate ester of a benzylic hydroxyl
derivative of GBR12909, a prodrug formulated To be a long acting dopamine uptake inhibitor, showed that a single
dose resulted in a sustained and selective decrease of cocaine self-administration for almost 30 days in rhesus
monkeys (J. R. Glowa, et. al., I. Med. Chem., 39, 4689-91). As a continuation of the SAR study, we have
modified the piperazine moiety and the ether linkage of the diphenylmethylether of GBR analogs, In the first series,
the diphenyhnethylamine derivatives of bridged piperidine GBR analogs, all 6 compounds showed moderate to low
aftinity for the dopamine transporter, indicating that an ether linkage is probably necessary to maintain a high
binding affinity for the transporter. The second series of compounds is composed of N-methyl and N-(3phenyl)propyl derivatives of bridged homopiperazine GBR analogs. The synthesis of this series requires the
preparation of a bridged homopiperazine moiety via a Schmidt reaction on 3-tropinone followed by an LAH
reduction of the lactam. Biological studies of this series is currently underway.
4-PHENOLIC ANALGOS OF NALTRINDOLE AS DELTA-SELECTIVE OPIOID LIGANDS
A. Coop, J. Pinto, C. M. Bertha, K. McCullough † , C. Dersch † , H. Xu † , R. B. Rothman † ,
and K. C. Rice
LMC, NIDDK, NIH, Bethesda, MD and † Clinical Psychopharmacology Sect. IRP, NIDA,
NIH, Baltimore, MD
Naltrindole (1), a selective opioid antagonist (µ/ 150 in binding assays), is widely used as a pharmacological
tool and has many potential clinical applications. The 6,7-fused indole group is known to be essential for delta
selectivity, however changes in functionality in the opioid nucleus have been shown to have a marked effect on
selectivity. We decided to systematically introduce groups known to lessen µ affinity into the opioid nucleus of 1,
with the aim of discovering a group which would lessen µ affinity but not . It was shown that masking the 3phenol of 1 as a methyl ether gave JP45 which had reduced aftinity at both µ and , however the loss in affinity at
µ was far greater than at . giving an increased selectivity (µ/ 576). Introduction of a 4-phenolic group into 1
gave a compound (AC621) of both reduced affinity and selectivity (µ/ 117). The corresponding compound
lacking a 14-hydroxy group (AC673) also showed reduced affinity compared with 1, but like JP45, µ affinity was
reduced to a far greater extent than , giving the most selective morphinan based ligand yet described (AC673,
µ / >950).
79
DESIGN AND SYNTHESIS
OF
ANTAGONIST NALTRINDOLE
DERIVATIVES
OF
THE
-SELECTIVE
OPIOID
L. Wang. A. Coop, C. Dersch*, H. Xu*, R. B. Rofhman*, K. McCullough*, and K. C. Rice
LMC, NIDDK, NIH, Bethesda, MD and *Clinical Psychopharmacology Sect. IRP, NIDA,
NIH, Baltimore, MD
Naltrindole is a nonpeptide -selective opioid receptor antagonist which has become a very useful pharmacological
tool in opioid research. The conformationally rigid indolic benzene moiety of the naltrindole affords higher
selectivity by increasing affinity and reducing affmity for µ opioid receptor sites (Portghese 1990). Recent studies
have shown that 14-alkoxy substituents on morphinans increase selectivity (Schmidhammer 1997). Also,
unpublished biological dam of our group showed that replacing me A ring 3-phenol with a 3-methoxy group greatly
increases the -selectivity. As part of our program to develop -selective opioid ligands, we synthesized 14isopentylhydrocodeinone indoles and 14-isopentylhydromorphone indole with different substituents on indolic
benzene ring. Preliminary binding studies indicated that 14-isopentylhydrocodeinone indole wilhout substituents on
indollc benzene ring provided higher -selectivity µ/ ratio = 1050) than those with substituents on indolic benzene
ring (R =Me, µ/ ratio = 65.4 and R= F, µ/ ratio = 14.5). Also, 14-isopentylhydrocodeinone indole had the same
binding affinity as and higher -selectivity than 14-isopentylhydromorphone indole (IC50 = 5.85 nM and 5.36
nM; µ/ ratio = 1050 and 63.2). On the basis of our results, we propose that a 3-methoxy group in A ring
decreased the µ-affinity and increased selectivhy (3-OMe/3-OH = 16) and the 14-isopentyl group may interact with
an active binding site for the receptor (µ/ ratio of 14-isopenlyl/14-OH = 2).
DESIGN AND SYNTHESIS OF SNC80-BASED AFFINITY LABELING ANALOGS FOR
DELTA OPIOID RECEPTORS
X. Zhang, C. Dersch*, K. McCullough*, H. Xu*, R. B. Rothman*, and K. C. Rice
Laboratory of Medicinal Chemistry, NIDDK, NIH, Bethesda, MD and *Clinical
Psychopharmacology Section, NIDA, Addiction Research Center, Baltimore, MD
Affinity labels are useful pharmacological tools to study receptor structure and function. As part of our program to
develop highly selective, nonpeptide opioid receptor ligands, we recently designed and synthesized a series of
affinity labeling analogs based on the structure of SNC80, (+)-4[( R -{(2S,5R )-4-allyl-2,5-dimethyl-1piperazinyl}-3-methoxybenzyl]- N,N-dietbylbenzamide). We utilized a stereoselective version of Katritzky’s tertiary
amine synthesis to prepare an amino analog of SNC80 (L=NH2). Different electrophilic labeling moieties (i.e.
isothiocyanate and -haloacetamide) were then introduced via the amino functionalized aromatic ring. The binding
affinities of the new analogs 1-3 for µ and receptors were determined by inhibition of binding of [3H]DAMGO
and [3H]DADLE at rat brain membranes. Compounds with the stereochemistry same as that of SNC80 showed
higher potency and selectivity for the receptors than their enantiomers. Compounds 2 and 3b-c were found to
produce wash-resistant inhibition of [3H]DADLE binding at receptors. Further pharmacological studies of these
compounds are in progress.
80
PHARMACOLOGICAL PROPERTIES OF THE STEREOISOMERS OF A 14 -CINNAMOYLAMINO CODEINONE DERIVATIVE
J. M. Bidlack, D. J. Cohen, K. P. Hill, A. D. Pechulis, and S. Archer
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY and
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY
In an attempt to determine whether codeinone derivatives, containing a 14-cinnamoylamino group, bind covalently
to the opioid receptor, the cis and trans isomers of 14beta-[cinnamoytamino]-7,8-dihydro-N-(cyclopropylmethyl)norcodeinone (N-CPM-H-CACO) were evaluated for their affinity. selectivity, and ability to produce washresistant inhibition of opioid binding to bovine striatal membranes. The trans isomer produced wash-resistant
inhibition of mu and kappa binding, but not delta binding, to membranes pretreated with the compound. At least a
It-fold higher concentration of the cis isomer was needed to obtain wash-resistant inhibition binding. Saturation
binding experiments showed a decrease in the Bmax value for both mu and kappa radioligands in membranes that had
been treated with the trans isomer. These in vitro results suggest that the trans isomer of N-CPM-H-CACO
preferentially binds covalently to both the mu and kappa opioid receptor in comparison to the cis isomer. The trans
isomer was about 50-fold more potent than the cis isomer in producing antinociception in the mouse 55° warmwater tail flick test. Surprisingly, both compounds were equipotent in producing long-term antagonism of
morphine-induced antinociception.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA03742 and DA01674.
ORAL COMMUNICATIONS V
EFFECT OF THE “CRACK” COCAINE PYROLYSIS PRODUCT, METHYLECGONIDINE,
IN SHEEP
M. A. Plessinger and R. W. Wood
Department of Obstetrics and Gynecology, University of Rochester School of Medicine and
Dentistry, Rochester, NY
Methylecgonidine (MEG) is a component of “crack” cocaine smoke and a noncompetitive antagonist of
acetylcholine possessing biologic activity in guinea pigs and squirrel monkeys. Since crack cocaine continues to be
consumed by pregnant women, one concern is the effect of crack upon the mother and its fetus, Since sheep are
most appropriate for reproductive toxicology studies, we investigated the systemic effects of MEGfumarate (MEG)
on blood pressure, heart rate, skin temperature, and core temperature and compared these responses to cocaine HCI
in the same nonpregnant sheep. After implanting polyvinyl catheters in the femoral artery and vein of two sheep,
MEGfumarate was administered intravenously on alternate days at 3.0, 5.6, and 10.0 mg/kg. After MEG
administration, there was a dose-dependent, transient decrease in mean arterial blood pressure and heart rate, followed
by a marked increase above baseline in both measures. The transient decrease in blood pressure after MEG was not
observed after intravenous cocaine HCI, 1.8 mg/kg, however, marked hypertension and tachycardia occurred. Skin
temperature was elevated after MEG with no alteration in core body temperature. In contrast, skin temperature
decreased after cocaine administration, reflective of vasoconstriction, and core temperature increased. These results
demonstrate that MEG has characteristics of an initial vasodilatative action not seen with cocaine atone.
ACKNOWLEDGMENT: Supported by NIDA grant DA05080.
81
PET IMAGING IN AWAKE RHESUS MONKEYS: EFFECTS OF COCAINE ON REGIONAL
CEREBRAL BLOOD FLOW (rCBF)
L. L. Howell 1 , J. M. Hoffman2 , J. R. Votaw2 , and A. M. Landrum 1
1
Yerkes Regional Primate Research Center and
University, Atlanta, GA
2
Emory University PET Center, Emory
Positron emission tomography (PET) imaging techniques were used in awake rhesus monkeys as an innovative
approach to investigate cocaine-induced functional changes in CNS activity. An effective restraint device was
developed that attaches to a commercially-available primate chair to facilitate immobilization, and subsequently
attaches to the end of a scanning table to allow for proper orientation in the tomograph. Function changes in
regional cerebral blood flow (rCBF) were characterzed with the positron-emitting tracer 15O water following acute
i.v. administration of cocaine (0.1, 0.3 and 1.0 mg/kg). Regions of interest were defined on MRl scans and then
transformed into the coordinate system of the PET scans with a high degree of accuracy. Cocaine had pronounced
dose-related effects on blood flow at 5 min postinjection that diminished markedly by 25 min postinjection. The
most obvious regions of increased blood flow were localized to the frontal lobes and corresponded tolimbic areas.
This study documents the successful development of an effective restraint device that will allow for the acquisition
of reliable PET images in awake monkeys following acute administration of cocaine.
ACKNOWLEDGMENTS:
Supported by USPHS grants DA-05346 and RR-00165.
EFFECTS OF COCAINE AND AMPHETAMINE ON EXTRACELLULAR DOPAMINE IN
THE MACAQUE
M. A. Taffe and R. Kuczenski
Department of Psychiatry, University of California, San Diego
The present study utilized intracerebral microdialysis techniques to determine to what extent locally administered
cocaine HCl (COC) and d-amphetamine (AMP) increase extracellular dopamine levels in the awake macaque. 2-3
mictodialysis probes were acutely placed into the caudate nucleus, nucleus accumbens and anterior cingulate cortex
of two unanaesthetized cynomolgous monkeys via implanted guides during each of several different sessions. Eight
dialysate samples of 40 min duration were collected during a given experimental session, and analyzed via HPLCEC for concentrations of dopamine and its metabolites 3-MT, DOPAC and HVA. Changing the perfusate to 50
µM AMP for a single 40 min sample produced pronounced increases over baseline dopamine and 3-MT
concentrations in caudate (1,500%; 400%) and nucleus accumbens (2.700%; 400%) followed by a gradual return to
baseline levels. 50 µM COC produced similar increases in caudate (1, 100%; 300%) followed by a return to baseline
levels. Modest and unreliable increases in dopamine concentrations were observed in anterior cingulate cortex.
DOPAC and HVA concentrations did not change after AMP or COC perfusion in any brain region. Chronic daily
administration of Haloperidol (0.03 mg/kg. i.m.; n=1) or Risperidone (0.03 mg/kg. i.m.; n=1) had a tendency to
enhance the response of DA and 3-MT to infused AMP or COC in the caudate after 12 (Hal, Risp) and 21 (Risp)
days. This study demonstrates the feasibility of measuring increases in extracellular dopamine following local
administration of dopamine indirect agonists in the awake monkey. This preparation provides an assay for changes
in dopamine availability following chronic systemic administration of neuroleptic drugs in a subject population that
is similar to man in terms of the dopamine system anatomy, receptor subtype distribution and structure as well as
similar in pharmacokinetic parameters of drug clearance and penetration.
ACKNOWLEDGMENT: Supported in part by U.S.P.H.S. grant MH 19934.
82
GENETIC VARIATION IN COCAINE- AND AMPHETAMINE- REGULATED TRANSCRIPT
(CART) EXPRESSION BETWEEN LEWIS (LEW) AND FISCHER (F344) RATS
P. Couceyro, K. McGirr, and M. J. Kuhar
Yerkes Regional Primate Research Center and Emory University, Atlanta, GA
Cocaine- and Amphetamine-Regulated Transcript (CART) is a brain enriched cDNA that encodes for a novel protein.
Its regulation by psychostimulants, distribution in the brain and putative protein sequence suggests that it may be
involved in drug reinforcement and reward. We have started examining CART’s expression pattern in the
histocompatible inbreed Fischer (F344) and Lewis (LEW) rat strains because they show differential behavioral
sensitivities to drug of abuse. Furthermore, in comparison to LEW rats, the F344 strain exhibits a depressed
hypothalamic-pituitary-adrenal axis responses to stress, a higher susceptibility to arthritis and a depressed immune
system. CART mRNA levels from 60 day old male rats were measured by Northern blot analysis. CART mRNA
was undetectable in the hippocampus of F344 rats but present in the hippocampus of LEW rats. F344 rat CART
mRNA levels were 14% lower (p<0.03) in the nucleus accumbens (nAcc), 75% higher in the hypothalamus (p<le5). and 50% higher (p<0.01) in the thalamus. The pituitary of F344 rats exhibited 29-fold less CART mRNA than
that of LEW rats. No differences in CART mRNA levels were noted in the olfactory bulb, caudate putamen. cortex,
and midbrain; CART was not detected in the cerebellum of either strain. The genetic variation in nAcc CART
expression strengthens previous data on a role of CART in drug reinforcement and reward. We also have data
demonstrating an effect of CART peptide(s) and CART antisera on cocaine-induced locomotor activity and feeding
behaviors. CART expression in LEW and F344 brains and pituitary is strikingly different in selected areas. These
areas implicated in immune function, HPA axis and responses to drugs where LEW and F344 exhibit differences. It
is plausible that CART may mediate some of these differences and is therefore physiologically relevant.
“BINGE” COCAINE ADMINISTRATION ALTERS PREPROENKEPHALIN mRNA LEVELS
IN THE GUINEA PIG BRAIN
K. S. LaForge, V. Yuferov, Y. Zhou, K. Pham, A. Ho, and M. J. Kreek
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY
An initial study in this laboratory on the effects of “binge” cocaine administration on gene expression in the guinea
pig brain suggested that preproenkephalin mRNA levels were altered by seven days of cocaine administered in a
“binge” paradigm (three daily i.p. injections, spaced at hourly intervals with the first injection given 30 min. after
the start of the light cycle). We have repeated and extended these studies in this report. Male Hartley guinea pigs
were administered saline or cocaine (45 mg/kg/day) in the “binge” paradigm for seven days. Animals were sacrificed
30 min. following the final injection, and mRNA isolated from dissected brain regions of individual animals,
Solution hybridization-RNase protection assays were performed on the isolated RNA to determine preproenkephalin
MRNA and total RNA content. Data from this and the previous study were combined to provide increased statistical
power. Differences between cocaine and control groups were analyzed by two-way analysis of variance unless a
significant Group by Study interaction was observed; in this case, a t-test was performed to assess statistical
signiftcance. In the cocaine-treated animals, we observed increased levels of preproenkephalin mRNA in the frontal
cortex [F(1,31)=23.5, p<0.00004] and amygdala [F(1.31)-10.7, p<0.003] when compared to saline-treated animals.
Preproenkephalin mRNA levels were lower in the nucleus accumbens [F(1.33)=5.61, P<0.03] and hypothalamus
[F(1,32)=9.84, p<0.004] of the cocaine group. No differences between preproenkephalin mRNA levels were
observed in the caudate putamen, hippocampus, thalamus or cerebellum. These findings differ from similar studies
performed in the rat and underscore me importance of studying more than one species.
ACKNOWLEDGMENTS:
Supported by NIDA grants P50-DA05130 and DA00049.
83
THE ROLE OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II IN
BEHAVIORAL SENSITIZATION TO COCAINE
R. C. Pierce and P. W. Kalivas
Alcohol and Drug Abuse Program, Washington State University, Pullman, WA
Repeated injections of amphetamine-like psychostimulants result in an enhancement in the ability of these drugs to
increase behavioral activation and extracellular dopamine in the medial nucleus accumbens. Calcium plays an
important role in this process, suggesting that the repeated drug treatment regimen induces a calcium requirement for
the augmented dopamine release. This represents a shift in the mechanism of action of amphetamine since the
increase in exttacellular dopamine induced by this drug is normally calcium-independent. The following
experiments assessed the potential role of calcium/calmodulin-dependent protein kinase II (CaM-KII) in the enhanced
increase in extracellular dopamine induced by amphetamine in the medial nucleus accumbens of rats sensitized to
cocaine. In addition, the behavioral relevance of these changes in the mechanism of action of amphetamine were
assessed. The results indicate that the CaM-KII inhibitor, KN-93, eliminated the amphetamine-induced enhanced
increase in accumbal dopamine in cocaine-pretreated rats, while having no influence on the ability of this drug to
increase dopamine in saline-pretreated animaIs. Consistent with these data, the intra-accumbal microinjection of
KN-93 produced a dose-dependent reduction in the sensitized behavioral response to a cocaine challenge in rats
previously administered repeated daily cocaine, while having no effect on the behavioral response to cocaine in
control animals. Taken together, these results indicate that CaM-KII plays a critical role in the expression of
behavioral sensitization to cocaine.
Supported in part by the Washington State Alcohol and Drug Abuse Program and
ACKNOWLEDGMENTS:
U.S. Public Health Service grants MH-40817, DA-03906, Research Career Development Award DA-00158
(P.W.K.) and National Research Service Award DA-05589 (R.C.P.).
EFFECTS OF ANTI-COCAINE ANTIBODIES UNDER DIFFERENT COCAINE SELFADMINISTRATION CONDITIONS
K. M. Kantak, S. L. Collins, C. A. Amendola, and B. S. Fox*
Department of Psychology, Boston University, Boston, MA and *ImmuLogic Pharmaceutical
Corporation, Waltham, MA
In a recent report (Fox et al., 1996), 4 mg of an anti-cocaine monoclonal antibody (mAb) were shown to extinguish
responding maintained by 1 mg/kg/infusion cocaine over a 5-day block of daily 2 hr sessions in rats. Drug delivery
was controlled by a second order schedule and infused at a rate of 0.6 ml/min, resulting in a baseline average of 8
infusions per hr. For the present study, reinforcement schedule, drug delivery rate and mAb dose were varied in
separate groups of rats in order to more clearly define the range of conditions for antagonizing the reinforcing effects
of cocaine by passive transfer of an anti-cocaine mAb. Under a fixed-ratio 1 schedule, cocaine infusions (14 per hr)
were not altered after treatment with 4 mg of the anticocaine mAb in the four rats tested. Under the secondorder
schedule when drug delivery rate was increased to 1.2 ml/min, cocaine infusions (8 per hr) were extinguished over 5
days in only one of four rats. By increasing the dose of the anti-cocaine mAb to 12 mg under these same conditions,
cocaine infusions (9 per hr) were extinguished for 3-5 days in five of the six rats tested. These findings suggest that
the cocaine antagonizing effects of the anti-cocaine mAb can be blunted by increasing the frequency and rapidity of
cocaine delivery. Under these conditions, a larger dose of antibody was necessary to obtain an effective blockade.
Active immunization with a cocaine vaccine will need to induce a high titer antibody response in order to be capable
of long-term blockade of the reinforcing effects of cocaine under a wide range of conditions.
ACKNOWLEDGMENT:
Supported by NIDA grant DA08979.
84
ORAL COMMUNICATIONS VI
ANTINOCICEPTIVE PROPERTIES OF A SERIES OF 2-CHLOROACRYLAMIDO
DERIVATIVES OF 7,8-DIHYDROMORPHINANS
K. P. Hill, I. Hutchinson*, S. Archer*, and J. M. Bidlack
University of Rochester, Rochester, NY and *Rensselaer Polytechnic Institute, Troy, NY
The purpose of this study was to identify compounds that act as short-term -selective opioid agonists and longterm µ-selective antagonists; such compounds have been shown to exhibit substantially less drug abuse potential
and may prove effective in treating addiction. Antinociceptive effects of 6 -(2chloroarrylamido)-4,5-epoxy-3hydroxy-17-methyl(cyclopropylmethyl)morphinan (N-CPM-6-CLAMO), its N-cyclobutylmethyl analog (N-CBM-6CLAMO), and its tetrahydrofurfuryl analog (N-FURAN-6-CLAMO) were studied in the mouse tail-flick and aceticacid writhing assays. In the acetic-acid writhing test. the compounds had D50 values ranging from 4.9-5.4 nmol,
after i.c.v. administration. The antinociception induced by the compounds was blocked by the antagonist norBNI, but not by µ or antagonists. Pretreatment of mice with the compounds produced a time- and dose- defendent
antagonism of morphine-induced antinociception but failed to antagonize antinociception induced by and
agonists. The µ antagonistic effect of 1 nmol of the compounds appeared at 60 min and lasted up to 72 hr, with a
maximal effect at 16 to 24 hr after i.c.v. administration. In summary, N-CPM-6-CLAMO, N-CBM-6-CLAMO,
and N-FURAN-6-CLAMO are all short-term -selective agonists of equipotency and long-term p-selective
antagonists in the mouse antinociceptive tests.
ACKNOWLEDGMENTS:
Supported by USPHS grants DA03742 and DA01674.
FUNCTIONAL EVIDENCE OF KAPPA OPIOID RECEPTOR SUBTYPES IN RHESUS
MONKEYS: IN VIVO APPARENT pA2 ANALYSIS
M.-C. Ko, E. R. Butelman*, M. Zhang, and J. H. Woods
Dept. of Pharmacology, University of Michigan, Ann Arbor, MI and *Rockefeller
University, New York, NY
The potency of naltrexone (NTX) in displacing the specific binding of [3H]U69,593 (putative k1-selective ligand)
was approximately 10-fold higher than [3H]bremazocine (non-k 1-selective ligand) in monkey brain membranes. This
led us to test the hypothesis that NTX could display in vivo antagonist selectivity for k1- versus non -k 1-mediated
effects. Six opioid agonists were characterized by in vivo apparent pA2 analysis in the warm water (50°C) tailwithdrawal procedure in rhesus monkeys. Naltrexone constrained pA2 values (95% C.L.) in this assay were:
alfentanil, 8.66 (8.5-8.9); EKC, 7.97 (7.9-8.0); U69,593, 7.64 (7.5-7.8); U50,488, 7.55 (7.4-7.7); bremazocine,
6.92 (6.7-7.1); CL-977(enadoline). 6.87 (6.7-7.1) (n=4). Naltrexone apparent pKB values obtained from another
group of three subjects were similar to the range of pA2 values reported above. Clocinnamox (C-CAM), an
irreversible mu opioid antagonist, shifted the dose-effect curves of alfentanil, a mu-selective agonist, and EKC by
10- and 3-fold, respectively; but it did not shift those of U69,593, U50,488, bremazocine, and CI-977. In the
presence of C-CAM, the pKB value for NTX in combination with EKC was reduced to 6.89 (6.8-7.0) (n=7).
Together with previously obtained data, results of this study suggest that U69,593 and U50,488 produced
antinociception by acting on k1 receptors, hut bremazocine and CI-977 probably on non- k 1 receptors. In addition,
both mu and kappa receptors mediate the antinociceptive effect of EKC. The current study provides functional
evidence of kappa opioid receptor multiplicity in primates.
ACKNOWLEDGMENT:
Supported by USPHS Grant DA00254.
85
BEHAVIORAL EFFECTS OF THE NOVEL DELTA OPIOID AGONIST SNC80 IN RHESUS
MONKEYS
S. Negus 1 , M. Gatch1 , N. Mello 1 , X. Zhang 2 , and K. Rice 2
1
ADARC, McLean Hospital - Harvard Medical School, Belmont, MA and *Laboratory of
Medicinal Chemistry, NIDDK, NIH, Bethesda, MD
The behavioral effects of recently developed non-peptidic delta opioid agonists were examined in assays of schedulecontrolled behavior and thermal nociception in rhesus monkeys. In the assay of schedule-controlled behavior,
monkeys were trained to respond for food under a FR30 schedule of reinforcement. The putative delta agonists
SNC86, SNC67, SNC80, SNC121 and SNC162 produced dose-dependent decreases in response rates. The potency
of these compounds in decreasing rates of responding correlated with their affinity for delta but not mu opioid
receptors. The effects of SNC80 were reversibly antagonized by the delta-selective antagonist naltrindole (1.0
mg/kg) but not by the mu-selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist nor-BNI
(3.2 mg/kg). In the assay of thermal nociception, latencies to tail-withdrawal were measured following immersion
of the tail in water heated to various temperatures (42, 46, 50 and 54°C). SNC80 produced weak but dose-dependent
and naltrindole-reversible antinociceptive effects. BW373U86 was ineffective in this assay of nociception; however,
BW373U86 antagonized the effects of SNC80, suggesting that SNC80 has higher efficacy than BW373U86 at delta
receptors. Moreover, in contrast to BW373U86, doses of SNC80 up to 32 mg/kg did not produce convulsions.
These results suggest that SNC80 is a relatively safe, selective and high efficacy agonist at delta opioid receptors in
primates.
ACKNOWLEDGMENTS:
Supported in part by grants DA02519, DA04059 and DA00101.
INVESTIGATING THE ROLE OF DELTA RECEPTORS IN THE REINFORCING EFFECTS
OF HEROIN USING 5'-NTII
T. J. Martin, S. A. Kim, D. G. Cannon, G. M. Sizemore, and J. E. Smith
Dept. Physiology and Pharmacology, Bowman Gray Sch. of Med. of Wake Forest University,
Winston-Salem, NC
Recent evidence suggests that some of the pharmacology of heroin may be mediated through delta-opioid receptors
as well as mu-opioid receptors. This study investigated the role of delta-opioid receptors in the reinforcing effects of
heroin using a selective delta-opioid receptor-alkylating antagonist. Rats were trained to self-administer heroin (5.4,
9, 18 or 30 µg/infusion) under an FR10 schedule of reinforcement and given either 0, 1, 5, 10 or 40 nmol of 5’NTII i.c.v. 5'-NTII attenuated heroin self-administration in a dose-dependent manner. Administration of 5 or 10
nmol of 5'-NTII decreased the number of infusions taken at the lower doses of heroin, whereas administration of 40
nmol attenuated the self-administration of all doses. Administration of vehicle or 1 nmol 5’-NTII was without
effect. The effects of 5 and 10 nmol 5'-NTII lasted for 4 days, and the number of infusions gradually returned to
control levels from days 4 to 10 after i.c.v. administration. The effects of 40 nmol 5’-NTII persisted for 11 days,
and the number of heroin infusions gradually returned to control values from days 14 to 18 after 5’-NTII
administration. Examination of the full dose-effect curve for heroin following 5’NTII demonstrated that 10 nmol icv
shifted the dose-effect curve approximately 0.5 log units to the right with a slight downward shift. Administration
of 40 nmol of 5’NTII produced a dramatic downward shift and shifted the dose-effect curve approximately 1.25 log
units to the right. Administration of 40 nmol of 5’-NTII i.c.v. to rats trained to self-administer cocaine (0.17, 0.33
or 0.67 mg/inf) had little effect. Therefore, delta-opioid receptors appear to be involved in the reinforcing effects of
heroin. The effects of these doses of 5’-NTII on delta- and mu-opioid receptor binding are currently being assessed to
compare with the effects on heroin self-administration.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-00247 (TJM) and DA-01999 (JES).
86
STUDIES OF SELECTlVE OPIOID ANTAGONISTS AND AGONlSTS AFTER SPlNAL
ADMINISTRATION IN AMPHIBIANS
C. W. Stevens and L. C. Newman
Dept. of Pharmacology, Oklahoma State University, College of Osteopathic Medicine,
Tulsa, OK
The pharmacological effect of -FNA (an irreversible mu opioid antagonist), naltrindole (NTI, delta selective
antagonist) and norBNI (kappa selective antagonist) was tested against mu, delta, and kappa selective opioids after
spinal administration in unanesthetized leopard frogs, Rana pipiens. Analgesic effects were measured using the
acetic acid test. Acute -FNA (20 nmol) did not produce analgesia, and concurrent injection of the mu opioid.
fentanyl (30 nmol) and -FNA (20 nmol) produced a significant block of fentanyl analgesia. Fentanyl analgesia was
antagonized for up to 10 days after -FNA pretreatment. Twenty-four hour pre-treatment with -FNA also blocked
morphine, but not delta (DADLE, DSLET) or kappa (bremazocine, U50488) opioid analgesia. NTl (0.1 nmol/frog)
was selective for DPDPE antagonism and concurrent injection blocked DSLET, DPDPE, and morphine analgesia.
NTI potentiated fentanyl and DADLE effects and had no effect on DELT, DAMGO or kappa selective opioids.
norBNI (0.1 nmol) was selective for GR89696 (kappa) analgesia and concurrent injection blocked equieffective
doses of U50488, but also blocked morphine, fentanyl, DPDPE, and DELT, norBNI potentiated DADLE analgesia
but bad no effect on DSLET. In light of previous studies showing that systemic, spinal and icv administration of
mu, delta, and kappa opioids produces analgesia in amphibians in the same rank order of relative potency as in
mammals but that binding studies show only one predominant kappa-like opioid site, these present results suggest
that norBNl may block analgesic effects of mu, delta, and kappa-selective opioids in amphibians and support a
“unireceptor hypothesis” of opioid analgesia which may be relevant to opioid analgesia in humans.
ACKNOWLEDGMENTS:
Supported by NIH-NIDA (DA07326) and the Whitchall Foundation.
THE d-ISOMER OF METHADONE HAS NMDA RECEPTOR ANTAGONIST ACTIVITY
C. E. Inlurrisi, N. Shimoyoma, M. Shimoyama, A. L. Gorman, and K. J. Elliott
Dept. of Pharmacology, Cornell University Medical College, New York, NY
dl-Methadone and its d- and l- isomers exhibit low micromolar affinities for the [3H]MK-801-labeled noncompetitive
site of the NMDA receptor in both rat forebrain and spinal cad synaptic membranes, with Ki values and
displacement curves similar to those of dextromethorphan, an established NMDA receptor antagonist (Neurosci,
Lett., 223: 5-8, 1997). To determine whether d-methadone has “functional” NMDA receptor antagonist activity, rats
were pretreated with d-methadone prior to the formalin test, a model of central sensitization. d-Methadone in a dose
of 32, 160, or 320 ug/rat or saline in a volume of 10 ul was administered intrathecally (IT) 15 minutes prior to
intraplantar formalin. In the saline-pretreated rats, formalin produced stereotypical nociceptive behaviors. dMethadone dose dependently reduced the phase 2 flinching, with the 320 ug/rat dose producing a 68% decrease.
Phase 2 licking and the phase 1 behaviors were not dose dependently affected (phase 1 licking was reduced only at
the highest dose). d-Methadone did not alter the tail-flick response. These results demonstrate that IT d-methadone is
antinociceptive. This activity may be a consequence of itsNMDA receptor antagonist activity.
ACKNOWLEDGMENTS:
and the VZV Foundation.
Supported in part by NIDA Grants DA01457, DA00198, DA07274, DA00255
87
SEX DIFFERENCES IN MORPHINE ANTINOCICEPTION
R. M. Craft, R. E. Bartok, and J. A. Stratmann
Department of Psychology, Washington State University, Pullman, WA
Several investigators have shown that male rodents are more sensitive than female rodents to morphine’s
antinociceptive effects. The present study was conducted to de&mine the generality of this sex difference by
examining morphine’s effects in female and male rats on two different thermal nociception assays, using three
different stimulus intensities, either acute or repeated dosing, and in females at various stages of the estrous cycle.
In the first experiment, a time course of antinociception was obtained on the 50, or 52 or 54°C hotplate and warm
water tail withdrawal tests. Acutely administered morphine produced greater antinociception per given dose greater peak and/or longer duration antinociception -- in males than in females at all three stimulus intensities on
each assay. In contrast, when rats were tested on all four dose conditions (one dose/week for four weeks), there were
no sex differences in morphine’s effects on either assay (52°C stimulus), suggesting that female and male rats may
develop tolerance at different rates. This hypothesis was tested in a separate experiment; however, there was no sex
diiference in rate of tolerance development in rats tested daily with 10 mg/kg morphine on the 52°C hotplate. In a
separate experiment. female rats in proestrus, estrus or diestrus-1 were tested with saline or 5.6 mg/kg morphine;
preliminary results indicate that morphine produced the least antinociception in diestrus-1 females. Thus, the fact
that no sex differences were obtained when rats were tested repeatedly may be attributable to variability of morpbine
antinociception across the estrous cycle, in addition to morphine-induced changes in estrous cyclicity.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 10284.
STUDIES ON THE ANTIPRURITIC POTENTIAL OF AGONISTS AT MU, KAPPA AND
DELTA OPIOID RECEPTORS
G. B. Kehner and A. Cowan
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA
Pain and itch are probably independent sensory modalities. The pharmacological bases of itch remain ill-defined
Scratch behavior is specific for itching and differentiates itch from pain. Kuraishi et al. (1995) recently described an
animal model of itch which involves Compound 48/80-induced scratching in mice. We have validated and
standardized this model, and studied the effects of morphine (mu), enadoline (kappa), ICI 204,448 (peripheral kappa),
SNC 80 (delta), naloxone (opioid antagonist) and saline on scratching over 30 min caused by 50 µg (100 µl) of
Compound 48/80 injected s.c into the back of the neck of albino Swiss male mice (24-27 g; n=7-10). Antiscratch50 values were obtained by nonlinear regression analysis (KaleidaGraph) for morphine (0.25-2 mg/kg s.c. given 10
min before Compound 48/80), enadoline (2.5-20 µg/kg s.c. at -5 min), ICI 204,448 (2.5-10 mg/kg s.c. at -20 min),
SNC 80 (0.25-25 mg/kg s.c. at -30 min) and naloxone (0.3-3 mg/kg s.c. at -10 min). The values were 0.38,
0.004, 2.82, 2.73 and >3 mg/kg, respectively. Enadoline is very potent against icv bombesin (another scratchinducing agent) in rats; we have therefore focused on the role of kappa receptors in mediating the sensation of itch.
Kappa receptors seem to be involved since pretreatment of mice with a behaviorally neutral dose of
norbinaltorphimine (20 mg/kg s.c. at -15 h) antagonized the antiscratch activity of enadoline (0.01 mg/kg ) (76±4%
to 37%±12%, s.e. mean). Also, our demonstration of activity for ICI 204,448 against Compound 48/80 (in
contrast to the bombesin model) affords another endpoint for structure-activity studies with peripheral kappa
agonists.
REFERENCE: Kuraishi, Y. et al. (1995) Eur J Pharmacol 275, 229-233.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-07237.
88
ORAL COMMUNICATIONS VII
A PILOT STUDY OF THREE DOSE SCHEDULES FOR THRICE WEEKLY
ADMINISTRATION OF BUPRENORPHINE
P. G. O’Connor, M. C. Chawarski, J. Pakes, and R. S. Schottenfeld
Yale University School of Medicine, New Haven, CT
Thrice weekly buprenorphine (BUP) dosing has been proposed as an altemative to daily dosing for treating opioid
dependence. To determine the optimal regimen, we compared 3 thrice-weekly BUP dose schedules (DS) (mg/70kg)
- A: 16, 16, and 32; B: 22.22, and 40; and C: 34, 34, and 44. Opioid dependent subjects were maintained on each
DS for two three-week periods during the 18 week study. Subjects and investigators were blind 10 the DS. The
outcomes were: urine toxicology (UTOX) and self reported opioid use and withdrawal symptoms. Subjects (N=21)
included 11 males and 10 females and 66% (14/21) completed the study. No complications were noted. Between
the 3 DS (A v B v C), there were no significant differences in % UTOX positive for opioids (66% v 70% v 66%)
or cocaine (33% v 30% v 36%). Similarly, mean use of opioids (bags/week) (2.5 v 2.6 v 2.9) and cocaine (0.7 v
0.5 v 1.3) did not differ across DS. Opioid use tended to be higher in all 3 DS when patients went 72 hours
without BUP. Finally, mean daily opioid withdrawal symptom scores (range: 0-88) did not differ significantly (4.6
v 3.7 v 4.5). In conclusion, thrice weekly BUP was well tolerated. High opioid use in our subjects may be based
on the short duration of treatment and frequent DS changes. No significant differences were noted between the 3
BUP DS studied. Our future research will compare thrice weekly to daily dosing.
DOSE COMPARISON OF LAAM DURING MAINTENANCE THERAPY
R. E. Johnson, T. Eissenberg, E. C. Strain. S. L. Walsh, and G. E. Bigelow
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, MD
LOAM is the most recently approved pharmacotherapy for opioid dependence. To date, there have been no clinical
trials assessing dose effectiveness of LAAM during maintenance therapy. Purpose: To assess the effectiveness of
three LAAM doses during maintenance therapy. Methods: Patients (N=180) were stratified and randomly assigned
to a 203 day double-blind clinical trial comparing three, thrice-weekly (M/W/F) LAAM dose conditions. Of the 180
patients initially enrolled, 142 entered the a priori identified maintenance phase (days 36-119). Patients in the low
(N=50), medium (N=50), and high (N=42) dose conditions recrived 25/25/35, 50/50/70, and 100/100/140 mg oral
LAAM, respectively. Urine specimens were collected and tested 3x/week. Outcome measures were: retention in
treatment, percent of opioid negative urine specimens, percent of patients who submitted 12 consecutive opioid
negative urine specimens, and self-reported heroin use (past 30 days). Results: There was no overall main effect on
retention in treatment; however, there was a trend (p<.07) for greater retention in the high dose compared to the low
dose condition. Overall, patients in the high dose condition submitted 46% opioid-negative urine specimens, as
compared to 35% in the medium, and 26% in the low dose condition (p<.05, high vs. low). Similarly, 44% of the
patients in the high dose condition submitted 12 consecutive opioid negative urine specimens, as compared to 18%
in the medium and 13% in the tow dose condition. (p<.05, high vs. low). Patients in the high dose condition
reported using heroin 3.4 out of the past 30 days, compared to 6.2 days for the medium and 9.2 days for the low
dose condition, (p<.05, high vs. low). No difference between groups was observed for cocaine use. Conclusion:
The effectiveness of LAAM during maintenance therapy is positively related to dose.
ACKNOWLEDGMENTS:
Supported by USPHS/NIH/NIDA grants P-50-DA-05273, K05-DA-0050, K20DA-00166, and T32-DA-07209.
89
EFFECTIVE MAINTENANCE TREATMENT OF OPIOID DEPENDENCE WITH TWICE
WEEKLY LAAM DOSING
P. P. Casadonte, E. O’ Donnell, and J. P. Rotrosen
Department of Veterans Affairs Medical Center, New York University Medical School, New
York, NY
The NY VA Opioid substitution Program has been prescribing LAAM since October 1994. Current prescribing
guidelines recommend three times a week dosing. In the course of regular use of LAAM, we noted that some
individuals missed a dose and returned to the clinic with no evidence of withdrawal or complaints of discomfort.
Based upon clinical observation, in September 1996. we offered twice weekly dosing to LAAM patients,
Method: Patients dosed with LAAM 3 times a week, who reported no Sunday withdrawal symptoms and
demonstrated 8 consecutive random urine drug screens negative for opiates, were invited to reduce the frequency of
clinic visits to twice/week. Total weekly LAAM doses guided adjustment of the 2 doses. During the 1996-97
Christmas and New Year Holidays, all LAAM patients were given the option of twice-weekly dosing. Results: In
January 50 LAAM patients requested twice weekly dosing, and 28 were placed on the new schedule. One of the
September and 2 of the January volunteers returned to 3 times/week due to somnolence on the 96 hour dose or
Withdrawal discomfort.) April 1997 review indicates that 26 (18%) of all LAAM patients were on twice weekly
dosing. Review of urine drug screens demonstrated that 13 (50%) used no illicit drugs, 13 used an illicit drug at least
once in the previous 4 months. Urine drug screens of the twice weekly group were compared to methadone
maintained patients (N 20) and 3 times/week LAAM maintained patients ( N 20). We found that 7% of the twice
weekly LAAM group used heroin at least once compared to 21% of the methadone group and 13% of the 3x week
LAAM group. We conclude that a selected population of motivated addicts can be successfully maintained on twice
weekly LAAM dosing.
RELAPSE TO HEROIN USE AMONG STABLE METHADONE MAINTENANCE PATIENTS
S. M. Hall1,2, D. A. Wasserman1,2, and B. E. Havassy1
University of California, San Francisco, CA and San Francisco Veterans Affairs Medical
Center, San Franciso, CA
Use of illicit opioids is high among methadone maintenance treatment (MMT) patients, and such use brings with it
continued involvement in illegal activities and the risk of HIV infection. We studied psychological variables
predicting relapse to illicit opioids among 74 MMT patients, all of whom had been in treatment for 3-18 months.
This time period was selected because it allowed for completion of the induction phase of treatment, and also
excluded subjects who had remained in treatment for such an extended length of time that relapse would be unlikely
Sixty percent of the subjects were men. Sixty-one percent were Caucasian, 20% were African-American, 12% were
Latino, and 7% were members of other racial groups. At induction into the study, all subjects reported at least two
weeks of abstinence from opioids. All subjects also maintained biochemically verified abstinence two additional
weeks, and were abstinent during the baseline data collection week of the study which followed. Based on social
learning models. and previous work by our group, we predicted that: (1) more stringent abstinence goats. higher
positive moods, greater optimism, and higher frequency of pleasant events would predict abstinence from illicit
opioids; (2) lapses to heroin would be followed by retrospective reports of poor mood, and more life stress, but
these variables would not prospectively predict lapses. All subjects were assessed on withdrawal symptoms,
dispositional optimism, and mastery at baseline. All variables except optimism and mastery were reassessed at
follow-up meetings during weeks 2-8. The prototypical data analysis method will be proportional hazard regression.
As predicted, a stringent abstinence goal predicted abstinence from heroin. Poor mood was reported concurrent with
lapses, but neither mood nor stress predicted abstinence from heroin. Use of cocaine, marijuana, and
benzodiazepines predicted subsequent lapse to heroin. but alcohol use did not.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-09253 and DA-30300 and a VA Research Career
Scientist Award to Dr. Hall.
90
PREDICTION OF 7 MONTH METHADONE MAINTENANCE TREATMENT RESPONSE BY
4 MEASURES OF ANTISOCIALITY
A. I. Alterman, M. J. Rutherford, J. S. Cacciola, and J. R. McKay
Center for Studies of Addiction, University of Center for Studies of Pennsylvania School of
Medicine
Simultaneous regression analyses were performed to ascertain the comparative validity of four measures of
antisociality for predicting the initial seven month treatment response of 193 male methadone maintenance Veterans
Administration patients. The predictor variables were the number of childhood antisocial personality disorder
behaviors (CD), number of adult antisocial personality disorder behaviors (A-ASPD). the total revised Psychopathy
Checklist (PCL-R) score, and the revised California Psychological Inventory- Socialization scale (CPI-So) score.
The outcome measures evaluated were completion/noncompletion of the initial seven months of treatment, percent
positive during-treatment cocaine, opiate, and benzodiazepine urine toxicologies, and relative change from baseline
to seven month follow-up in the seven Addiction Severity Index (ASI) composite scores. Only the PCL-R score
entered into the regression model for completion/noncompletion. No variables significantly predicted opiate use and
only the PCL-R predicted cocaine toxicologies. Although both the PCL-R and CPI-So measures were significantly
correlated with benzodiazepene use, neither variable was significant in the regression model. None of the predictor
variables were significantly correlated with baseline to follow-up composite score change in any of the Seven ASI
areas.
ACKNOWLEDGMENTS:
Supported by NIDA Center Grant # DA05186, NIDA Grant # DA-05858, and the
Department of Veterans Affairs.
NTORS: THE NATIONAL TREATMENT OUTCOME RESEARCH STUDY (UK)
M. Gossop, J. Marsden, D. Stewart, P. Lehmann, C. Edwards, A. Wilson, and G. Segar
National Addiction Center, Maudsley Hospital, London, UK
The National Treatment Outcome Research Study (NTORS) is the largest study of treatment outcome for drug
abusers ever conducted in the UK. and plays an important role in the development and guidance of UK national drug
treatment policy responses. The NTORS cohort of 1075 clients were treated in four modalities: specialist inpatient
units, residential rehabilitation units, methadone maintenance and methadone reduction programs. NTORS
investigates the impact of these treatments on drug-related problems, health and social functioning. The project was
established to advise the Department of Health’s Task Force on the effectiveness of existing national drug treatment
services and preliminary findings from NTORS were given to the British Government in 1996. NTORS results
have also been used by the Department of Health to formulate guidance to treatment purchasers. The early findings
show marked improvements in key problem behaviors after treatment. Some of the main findings obtained six
months after starting treatment, and especially those relating to substance use problems, are reported in this paper.
The extension of NTORS to permit the continuing follow-up of clients over a 5-year period will enable its findings
to provide further assistance to the direction of services within the UK.
ACKNOWLEDGMENT:
Funded by the Department of Health, UK
91
METHADONE TREATMENT REDUCES HOSPITAL UTILIZATION: PRELIMINARY
ANALYSIS OF A CONTROLLED TRIAL
S. L Batki, M. Bradley, T. Jones, J. Moon, M. A. Hauf, R. Narvaez, P. Ralston, J.
Raynovich, M. Schissel, and C. Masson
University of California, San Francisco, Department of Psychiatry, San Francisco General
Hospital, Division of Substance Abuse and Addiction Medicine, San Francisco, CA
Objective: To describe the relationship between methadone maintenance (MM) treatment and medical care
utilization in injection drug users (IDUs). Method: This is a preliminary analysis of medical care utilization by
the first 55 of an eventual 112 opioid dependent tuberculin skin-test positive IDUs. Subjects participated in a 6
month controlled trial of MM vs. routine care. Routine care consisted of referral to TR Clinic and 21-day methadone
detoxification. but no methadone maintenance, (No-MM). MM was either Standard MM with counseling (S-MM)
or Minimal MM with no counseling (M-MM). Nineteen participants were assigned to No-MM, 17 to S-MM and
19 to M-MM. 26 (47%) were women, 19 (35%) were African -American, 10 (18%) were Latino(a), and 26 (47%)
were white. All were HIV seronegative. Mean age was 42 (± 5.8) yrs. Mean years of heroin use was 17.2 (±9.1).
All were patients at San Francisco General Hospital (SFGH). Utilization data was obtained from computerized
SFGH records. Results: In the No-MM group, mean annualized medical charges totaled $9841/pt-yr (± 2661)
prior to entry into the study and $9047/pt-yr (± 3703) after entry. For the two MM groups, the mean annualized
medical charges decreased from $14069/pt-yr (± 2997) prior to entry into the study to $4869/pt-yr (± 1428) after
entry. The two MM groups had a greater reduction in total medical charges compared to the no-MM group (repeated
measures ANOVA. F=3.51, p=.067). Conclusion: MM treatment is associated with major reductions in medical
care utilization.
ACKNOWLEDGMENTS:
Supported by NIDA Grants R01 DA 08526, P50 DA09253, and P50 DA01696.
SUBSTANCE ABUSE TREATMENT NEED AMONG ARRESTEES-ADULTS
R. S. Schottenfeld, J. Pakes, and S. Mody
Yale University and The APT Foundation, New Haven, CT
To evaluate rates of current drug or alcohol use and dependence among adult arrestees and to evaluate the social and
psychiatric comorbidity, criminal history, prior treatment history, and treatment needs of dependent arrestees, we
used structured interviews and urine toxicology testing to assess 278 mates and 200 females, ages 21 or over from
detention centers in two CT cities. Utox was performed on 157 mates and 71 females. Estimated rates of use within
72 hours preceding arrest (based on self-report or positive Utox) for mates and females respectively were 72%, 84%
for any drug; 48% 48% for cocaine; 18.6%. 15.8% for heroin; and 27.3% 18.6% for marijuana. Rates of current
drug or alcohol dependence were 53.2%, 60.8%; 27.4%, 38.2% for cocaine; 16.9%, 18.6% for heroin; 12.5%, 7.4%
for marijuana, and 36.3%, and 25.7% for alcohol. Compared to their counterparts without drug dependence, heroin
dependent arestees had lower rates of arrest for violent offenses and higher rates for property offenses, while cocaine
dependent females had tower rates and cocaine dependent mates had equivalent rates of arrest for violent charges.
Compared to drug free arrestees, drug dependent arrestees had lower rates of employment, more income from illegal
sources, and higher rates of current depression, anxiety, and recent suicide attempts, and engage in more HIV risk
behaviors. While 80-92% of those dependent on heroin or cocaine reported a need for treatment, only 9% of males
and 19.1% of females were enrolled in treatment at the time of arrest. Despite long duration and severity of
dependence and interest of drug dependent arrestees in treatment, few are currently in treatment and most have never
received treatment other than detoxification. Treatment services for drug dependent arrestees need to address their
educational and vocational deficits, HIV risk, and psychiatric comorbidity.
92
ORAL COMMUNICATIONS VIII
SYNTHESIS AND BIOLOGICAL EVALUATION OF ANANDAMIDE ANALOGS
P. R. Fleming, B. Berglund†, A. C. Howlett†, and K. C. Rice
LMC, NIDDK, NIH, Bethesda, MD and †Dept. of Pharm. and Physiol. Sci., St. Louis
Univ. Sch. of Med., St. Louis, MO
The discovery of an endogenous ligand, anandamide, for the cannabinoid neurochemical system by Devane et al. in
1992 introduced a structurally unique cannabinoid agonist: the ethanolamide of arachidonic acid. A number of SAR
studies followed shortly thereafter that primarily involved either changing the alkyl group at the amide nitrogen or
increasing or reducing the degree of unsaturation in the arachidonyl chain. These initial SAR studies left open the
question of which conformations of anandamide were biologically relevant. The flexibility of the arachidonyl chain
makes the determination of the biologically active conformations of anandamide by computational methods a great
challenge. We wished to address the question by preparing a number of conformationally restricted anandamide
analogs. Analogs were prepared that incorporated a phenyl ring in the arachidonyl portion of the molecule as shown
in the structures. We then measured their affinities for the cannahbinoid (CB1) receptor. All analogs had CB1
receptor affmities in the range of low to high µM in rat brain membranes which are three orders of magnitude
smaller than anandamide
EVIDENCE FOR PERIPHERAL-TYPE CANNABINOID RECEPTORS (CB2) ON RAT
MICROGLIAL CELLS
C. S. Kearn and C. J. Hillard
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI
Modulation of immune cell function by cannabinoids is believed to be mediated by the peripheral cannabinoid
receptor (CB2). The CB2 receptor has been shown to decrease adenylyl cyclase, activity through a pertussis toxin
sensitive G-protein. Microglia are immune competent cells of myeloid lineage which reside in the central nervous
system and have been implicated in several pathologies including AIDS dementia complex. We investigated the
hypothesis that microglia express the CB2 receptor. Microglia were isolated in >98% purity from confluent
cultures of 2 day old rat pups using standard techniques. RT-PCR was used to amplify the mRNA for the CB2
receptor from total RNA. Sequencing of the 694 bp amplicon showed 94% identity with the mouse CB2 transcript,
and 82% identity with the human CB2. The CB2 agonist CP55,940 elicited a dose dependent decrease in cAMP
accumulation in IBMX treated microglia stimulated with one micromolar forskolin. The EC50 for CP55,940 was
1.98 nM and 100 nM CP55,940 decreased stimulated adenylyl cyclase activity by 95%. In light of the relationship
between microglia and AIDS dementia complex, further work is needed to elucidate the effects of cannabinoid
agonists on microglial function.
Supported by the Cancer Center of the Medical College of Wisconsin, NIDA grant
ACKNOWLEDGMENTS:
DA-08098, and NIDA-Office on AIDS Travel Award.
93
SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 1,1-DIMETHYLHEPTYL
ANANDAMIDES.
B. F. Thomas, A. F. Gilliam, D. N. Fleming, R. G. Pertwee*, D. R. Compton†, B. R. Martin†, and H. H. Seltzman
Research Triangle Institute, RTP, NC, *Univ. of Aberdeen, Aberdeen, Scotland, UK and †Medical College of
Virginia, Richmond, VA
We have proposed, based on a previously reported pharmacophore alignment between anandamides and classical and
nonclassical cannabinoids, that extension of the pentyl side chain of anandamide to a dimethylheptyl side chain
should result in increased binding affinity and pharmacological potency. In order to test this hypothesis, we have
synthesized and assayed a series of 1,1-dimethylheptyl anandamides for comparison to their pentyl side chain
analogs. We have found that while the binding affinity of each dimethylheptyl analog was improved over that of its
pentyl side chain analog (Table 1), their potency in the isolated mouse vas deferens (EC50's) preparation did not
increase as predicted. In this tissue, the dimethylheptyl compounds exhibited decreased potency and efficacy when
compared to their pentyl side chain analogs.On the other hand, the in vivo potency of the dimethylheptyl compounds
(mouse tetrad) was greater than that seen with their pentyl analogs and paralleled their increased binding affinity.
Therefore, the data supports the relevance of the side chain equivalence postulated in our original pharmacophore
model and suggests that the cannabinoid receptor population in the mouse vas deferens differs from neuronal (CB1)
receptors. Supported by NIDA: DA 10063-01A1, DA03672-09.
9-THC, R-METHANANDAMIDE,
EFFECTS OF
BEFORE & AFTER DAILY 9-THC DOSING
SR 141716,
&
d-AMPHETAMINE
R. J. Lamb, T. U. C. Järbe, A. Makriyannis, S. Lin, and A. Goutopoulos
Department of Psychiatry, Allegheny University of the Health Sciences, Philadelphia, PA,
and Department of Molecular & Cellular Biology University of Connecticut, Storrs, CN
We examined the effects of 9-THC, R-methanandamide, SR 141617, and d -amphetamine on fixed-ratio responding
maintained by food in rats before and after daily dosing with 9-THC. Rats responded under a schedule with 4 fiveminute periods of FR 10 food reinforcement separated by 15-minute time-outs during which responding had no
consequences. Cumulative dose-response curves for the various drugs were determined before and during daily 9 THC administration by giving ascending doses of the drug at the beginning of consecutive time-out periods. All
four drugs dose-relatively deceased responding both before and during daily dosing with 9-THC (18 mg/kg/day).
The dose-response curves for both 9-THC and R-methanandamide were shifted to the right with daily dosing with
9-THC. In other words, there was tolerance to the effects of 9-THC and cross-tolerance to the effects of Rmethananadamide. The doses of d-amphetamine examined produced similar effects both before and during daily
dosing with 9-THC. We determined the effects of SR 141716 twice during daily 9-THC administration. On the
first occasion, the SR 141716 dose-response curve was shifted to the left of the curve determined before daily 9 THC administration began. The second SR 141716 curve. however, approximated the SR 141716 curve determined
before daily 9-THC administration. These two results indicate that if sensitization occurrs to the effects of SR
141716 with daily 9-THC administration, it is labile. This finding is not simply a result of the instability of the
dose-response curves, because we determined the 9-THC curve at two points during daily 9-THC administration
and both of these curves demonstrated similar degrees of tolerance.
Supported by NIDA grants DA 09064, DA 00253, DA09158, & DA 03801.
ACKNOWLEDGMENTS:
94
SR141716A PRECIPITATES SUPPRESSION OF OPERANT RESPONSE RATES IN THC
CHRONICALLY TREATED RATS
P. M. Beardsley and B. R. Martin
Department of Pharmacology/Toxicology, Virginia Commonwealth University, Richmond,
VA
Prior to the availability of cannabinoid antagonists, we had demonstrated that chronic, i.v. infusion of delta-9tetrahydrocannabinol (THC) can induce behavioral dependence in rhesus monkeys as reflected by the suppression of
food-maintained lever pressing rates upon termination of THC infusion. In the present studies, we attempted to
systematically extend this demonstration to rats treated s.c. with THC and in which withdrawal effects were
precipitated with the cannabinoid antagonist, SR141716A. Adult male Long-Evans rats were trained to lever press
according to VI-10 sec schedules during daily experimental sessions composed of six, 3-min food-reinforcement
periods which alternated with six, 10-min time-out (TO) periods. Following training, separate groups of rats were
treated b.i.d. for 6 days with either vehicle or escalating dosage regimens terminating with either 30, 40, or 50
mg/kg of THC. On days 7 and 8, tests with cumulative doses of SR141716A (3 and 9 mg/kg, respectively) were
conducted. SR141716A dose-dependently suppressed response rates only in rats with THC histories and did so as a
positive function of THC dosage regimen. Subsequently, rats were administered an escalating 6-day b.i.d. THC
treatment terminating with 30 mg/kg and then were tested with vehicle or 1, 3, or 6 mg/kg SR141716A. Again,
SR141716A dose-dependently suppressed response rates only in rats with THC histories. These data suggest that
SR141716A can precipitate withdrawal effects in THC-treated rats and are consistent with inferring that THC can
induce behavioral dependence.
ACKNOWLEDGMENT:
EFFECTS OF
RATS
9
Supported by NIDA grant DA03672
-THC AND R-METHANANDAMIDE ON OPEN-FIELD BEHAVIORS IN
T. U. C. Jarbe, R. Sheppard, R. J. Lamb, A. Makriyannis*, S. Lin*, and A. Goutopolos*
Department of Psychiatry, Allegheny University of the Health Sciences, Philadelphia, PA
and *Department of Molecular Cell Biology, University of Connecticut, Storrs, CT
This study compared the effects of R-methanandamine (RM), an analog of the mammalian brain constituent
amandamide, and 9-THC; on the open-field (O-F) behavior of male Sprague-Dawley rats. Before testing. rats were
individually housed with free access to food and water. Groups of rats (n=10; N=80) were tested with 0, 1, 3, and
5.6 mg/kg THC given i.p. 30 min. pre session, and 0, 3, 10, and 18 mg/kg RM, 15 min. pre session. The O-F
arena was a gray painted wooden box (60 x 60 x 50 cm) with an open top and a white floor divided into 16 squares
(15 x 15 cm) and a circle (diameter 19 cm) marked in the center of the field. The squared floor was covered with an
acrylic plate (60 x 60 cm), which was cleaned between trials. The behavioral categories recorded were ambulation
(the number of squares crossed). rearing (the number of times the rat stood erect on its hind-legs), latency (the time
in sec to leave the starting area, the circle in the center of the field), circling (the number of times the animals turned
around its vertical axis, 0.5 point given for each 180 degrees turn), grooming (the number of cleaning bouts).
urination and defecation (the number of urination spots and fecal boli deposited during the 5 min. observation
period). THC was more potent than RM, but otherwise the effects of THC and RM were similar with one
exception. While THC produced dose related increases in circling. RM did not increase circling over the doses
examined. This may indicate that there are qualitative behavioral differences in the effects of THC and RM. In order
to determine if the THC-induced circling was a cannabinoid mediated effect, two doses of the CB1 selective
antagonist SR141716 (1 and 5.6 mg/kg) were examined in combination with 3 mg/kg THC (N=15; n=7 and n=8).
Only the higher dose prevented circling.
ACKNOWLEDGMENTS:
Supported by NIDA grants R01-DA 09064 and KO2-DA 00253.
95
THE CANNABINOID ANTAGONIST SR141716A ENHANCES RADIAL ARM MAZE
PERFORMANCE IN RATS
A. H. Lichtman, S. Neviaser, K. R. Dimen, and B. R. Martin
Department of Pharmacology and Toxicology, Medical College of Virginia-Virginia
Commonwealth University, Richmond, VA
The putative endogenous cannabinoid system has been proposed to be tonically active in a variety of processes
including learning and memory. In the present study, we examined whether blockade of this system with the
specific cannabinoid antagonist SR141716A would enhance spatial memory as assessed in a variation of the 8 arm
radial maze task. Rats were given an i.p. injection of either vehicle or SR141716A (3 mg/kg) and given access to
seven run-way arms, the eighth arm was blocked off (phase 1). After all of the available arms were visited and food
pellets consumed, the subjects were removed from the maze for either a 1, 10, 30, or 60 min delay. After the delay.
the subjects were placed in maze again with all eight arms available (phase 2). The number of entries to obtain the
food reinforcement in the eighth arm was scored. SR141716A signhicantly decreased the number of trials required to
visit the previously unavailable arm. At the 30 min delay, for example, the subjects committed 2 ± 0.5 reentries
when given vehicle, but only 0.6 ± 0.2 reentries after drug administration. In an additional experiment, rats were
9
given an i.p. injection of 9-THC (0, 1, 2, 4, or 6 mg/kg) 20 min prior to phase 1.
-THC significantly impaired
maze accuracy in both phases. Our results are consistent with those from a recent report in which SR141716A
enhanced memory in a social recognition task. These findings suggest that antagonism of a tonically active
cannabinoid system may enhance some forms of memory.
ACKNOWLEDGMENTS:
NIDA grants DA-08387 and DA-03672.
ORAL COMMUNICATIONS IX
REVERSAL OF COCAINE-INDUCED
ISRADIPINE
CHANGES IN BRAIN BLOOD FLOW BY
B. A. Johnson, L. Lamki, D. Simms, R. Chen, B. Fang, B. Barron, L. T. Wells, D.
Abramson, S. Dhother, R. Meisch, and V. Oderinde
University of Texas Health Science Center - Houston
Using a new quantified technique for measuring absolute brain blood flow (BBF) with Single Photon Emission
Computerized Tomography (SPECT), we studied the effects of intravenous (IV) cocaine (0.325 mg/kg and 0.65
mg/kg dissolved in 25 ml of 0.9% NaCl) and IV cocaine and isradipine (10 mg orally) in two recently abstinent
cocaine dependent subjects. We found that cocaine administration was associated with a significant reduction in total
BBF, and in induced perfusion to areas rich in dopaminergic innervation (e.g. putamen, superior temporal lobe,
prefrontal cortex). Importantly; however, these cocaine-induced reductions in BBF were completely reversed by
isradipine. These results show that isradipine, a L-type calcium channel blocker, can antagonize the ischemic effects
of cocaine. We postulate that the effects of isradipine is achieved via the inhibition of dopaminergic activity.
ACKNOWLEDGMENT:
Supported by Advanced Technology Program #011618 Texas.
96
OPEN TRIALS AS A METHOD OF SCREENING POTENTIAL MEDICATIONS FOR THE
TREATMENT OF COCAINE DEPENDENCE
K. Kampman, M. Rukstalis, D. McGinnis, R. Ehrman, H. Dixon, and C. O’Brien
University of Pennsylvania Treatment Research Center, Philadelphia, PA
Objective: This study describes the use of open trials with a historical control group to rapidly identify
promising medications for the treatment of cocaine dependence The following medications were compared:
propranolol, nefazodone, phentermine and fenflutamine (phen/fen), and a multivitamin control. Methods: Each
medication was evaluated sequentially in an open trial. Propranolol (n=15) was given for 8 weeks at a dose of 60100 mg daily. Nefazodone (n=17) was given for 8 weeks at a dose of 100-300 mg daily. Phentermine 30 mg and
fenfluramine 80 mg (N=16) were given for 7 weeks. Finally, a multivitamin (N=17) was given for 7 weeks as a
control. Outcome measures and psychosocial treatment were standardized in all groups. Primary outcome measures
included treatment retention and urine toxicology screens. Secondary outcome measures included the Addiction
Severity Index (ASI). Results: Retention at 7 weeks was significantly better in the propranolol group. Defined
as completion of 7 weeks of treatment with 4 weeks of documented abstinence from cocaine, treatment success was
better in the propranolol group. Forty percent of propranolol group achieved success, whereas only 24% of the
multivitamin group, and less than 20% of the nefazodone and phen/fen group achieved success. Among completers
in all 4 groups, there was a significant decline in ASI Composite Drug Scores. The propranolol anl nefazodone
groups also had significanl declines in ASI Composite Alcohol Scores. Treatment retention of patients with high
ASI Composite Alcohol Scores was significantly better in the propranolol and the nefazodone groups.
Conclusions: Propranolol may be helpful in assisting cocaine dependent outpatients stay in treatment and attain
abstinence. Propranolol and nefazodone may be especially useful in cocaine dependent patients who also abuse
alcohol. Open trials may be useful in rapidly identifying promising medications for the treatment of cocaine
dependence.
MOTIVATIONAL ENHANCEMENT TO INCREASE TREATMENT READINESS AMONG
STIMULANT USERS: A PILOT EVALUATION
E. A. Wells1,2 , D. A. Calsyn1,3 , L. L. Clark 2 , and T. R. Jackson1,2
University of Washington1, Evergreen Treatment Services2, and VA Puget Sound Health Care
System 3 , Seattle, WA
This was a pilot study to assess the effect of Motivational Enhancement (ME) (Miller and Rollnick, 1991) with
cocaine dependent people not actively seeking treatment. It employed a 3-group design with two waiting lit
controls and follow-up interviews at 1 and 2 months. Participants, recruited in street contacts by outreach workers,
were 57% male, and 90% African American. At initial interview, the ME group (n=21) completed a structured
assessment administered by research staff and feedback using ME techniques. Feedback was delivered by outreach
workers trained in ME for this project or by a psychologist with background in ME. The Assessment Only (AO)
(n =14) group received an assessment initially and received feedback after the follow-up assessment at 1 month. The
Assessment at Follow-up Only (AFO) (n =7) group, a control for the effects of assessment, completed only consent
and locator at initial, a follow-up assessment at 1 month, and assessment and feedback at 2 months. There was
differential study attrition at 1 month, with the ME group returning at a greater rate (85%) than the AO (46%) or
AFO (57%) groups. The ME group showed greater reductions than the AO group in self-reported cocaine use at 1
month (Group X Time F = 3.19, df = 1.21, p = .088). The groups differed at 1 month in readiness to change
(University of Rhode Island Change Assessment questionnaire) with the ME group showing the greatest readiness.
There was also some indication, although not significant that ME participants increased the number of days in
which they sought help for their drug problem. Self-efficacy did not seem to be improved by ME.
ACKNOWLEDGMENT: Supported by NIDA grant R01-DA-08625.
97
AN OUTPATIENT COCAINE DETOXIFICATION PROGRAM USING MOTIVATIONAL
ENHANCEMENT THERAPY
A. L. Stotts, J. M. Schmitz, P. S. Bordnick, and A. K. Schwebel
Substance Abuse Research Center, University of Texas - Houston
Achieving initial abstinence from cocaine is considered to be an important prerequisite to the application of Relapse
Prevention (RP) strategies and techniques. Complete abstinence prior to RP treatment may increase motivation and
decrease early dropout rates commonly reported in cocaine treatment outcome studies. In order to inmate abstinence
in cocaine-dependent patients prior to their entrance into an RP maintenance treatment study, the authors developed
and evaluated a brief, outpatient detoxification program. The “detox” program included daily clinic visits (2-6 hrs),
the viewing of educational videotapes, completion of assessment procedures, provision of urine samples, and a
physical examination including EKG, HIV and TB tests. Entrance into the 12-week RP treatment was contingent
on the submission of five consecutive cocaine-free mines within a 10 day period. A brief motivational component
was developed and implemented to promote compliance and abstinence during the detox period. Motivational
Enhancement Therapy (MET) based on the principles and techniques of Miller and Rollnick’s Motivational
Interviewing was provided in a two-session format and included personalized feedback. To evaluate the efficacy of
this component. participants were randomly assigned to MET or a detox-only control group. A detailed description
of the detox program will be presented along with outcome data related to the motivational therapy component.
Stages and Processes of Change data will also be reported. To the authors’ knowledge, this outpatient detoxification
program represents a novel adjunct to traditional outpatient treatment of cocaine dependence and may have important
implications for future treatment research and clinical practice in this area.
ACKNOWLEDGMENT:
Supported by NIDA Grant DA-09262-02.
COCAINE/CRACK USE AND TREATMENT RETENTION IN A NATIONAL TREATMENT
SAMPLE (DATOS)
C. A. Rowan-Szal, G. W. Joe, and D. D. Simpson
Institute of Behavioral Research, Texas Christian University, Fort Worth, TX
Clients who enter treatment with cocaine problems are diffcult to engage and retain in treatment. In the NIDAfunded Drug Abuse. Treatment Outcome Study (DATOS), approximately 25% of the 10,010 clients reported daily
cocaine or crack use before admission to treatment. This study addressed the question of whether crack users have
lower retention rates than noncrack cocaine users. The sample focused on 900 clients enrolled in 13 long-term
residential (LTR) treatment programs. It was limited to cocaine dependent clients as defined by those who met
DSM III-R criteria and also were at least weekly cocaine-crack users. Hierarchical linear model regression analysis
(HLM) was used to examine the relationship between 90-day retention, cocaine use. client attributes, and program
characteristics. Results indicated that 51% of the sample dropped out of treatment within 90 days, and these early
dropouts were more likely to prefer crack (over cocaine), not be dependent on alcohol, have lower motivation, be
adressed, have more lifetime arrests, be married, and have less education. Further research into the characteristics of
these difficult-to-treat cocaine users, especially crack users. is important to the development of new treatment and
engagement strategies.
ACKNOWLEDGMENTS:
Supported by NIDA Grant U01-DA10374 as part of a Cooperative Agreement on
the Drug Abuse Treatment Outcome Study (DATOS).
98
USING FEE REBATES TO REINFORCE ABSTINENCE AND COUNSELING ATTENDANCE
IN COCAINE ABUSERS
L. Amass, E. Ennis, S. K. Mikulich, and J. B. Kamien*
Addiction Research and Treatment Services, Department of Psychiatry, University of
Colorado School of Medicine and *BioPsych Consulting
Voucher-based reinforcement therapies are effective for reducing cocaine use in outpatient cocaine abusers. However,
fmancing voucher programs may be problematic for many community-based treatment providers. Thus, researching
cost-effective and practical techniques for using voucher-based technology in general clinical practice is important.
One solution may be to examine clinic fee structures and rebate portions of client’s fees contingent on their
performance in treatment. This ongoing study investigates the use of fee rebates for treating cocaine abuse. Cocainedependent outpatients were randomly assigned to Rebate (n=5) or Control (n=4) groups for 11 weeks. A matched
Historical Control (HC) group was constructed from records of nine previous patients. Rebate and Control groups
received an individual evaluation, 10 weekly group sessions using modules from the NIDA “Recovery Training”
model and weekly, random urine testing. Treatment fees were based on a sliding scale for low income and averaged
$33/week. Each cocaine-negative urine sample provided and each counseling session attended by the Rebate Group
was reinforced with a fixed weekly rebate averaging $2.99. In addition, bonus rebates averaging $8.37 reinforced
continuous cocaine-abstinence and/or counseling session attendance during weeks 1-3, 4-7 and 8-11. Under this
schedule, clients with perfect performance earned back 25% of their total fee. Data collected from the first 5 weeks of
study participation (and the first 5 weeks of treatment for the HC group) are presented. Missed urine samples were
considered drug-positive. Rebates appear to increase (a) treatment retention (Rebate:100%, Control:50%, HC:44%),
(b) counseling session attendance (Rebate:60±14%, Control:35±22;, HC:42±14%). (c) cocaine-negative urines
(Rebate:53±7%, Control:30±24%, HC:26±11%) and (d) fee payments (Rebate:68±16%, Control:55±21%,
HC:30±10%). Finally, for the Rebate group, the probability of retrieving the rebate increased linearly as the rebate
amount increased, suggesting that rebates functioned as positive reinforcers. Fee rebates appear to be a viable,
practical, cost-effective and easily managed positive reinforcement strategy for improving substance abuse treatment
outcomes.
A COMPARISON OF TWO AFTERCARE TREATMENTS FOR COCAINE DEPENDENCE:
RESULTS AT 6 AND 12 MONTHS
J. R. McKay, A. I. Alterman, J. S. Cacciola, M. J. Rutherford, and C. P. O’Brien
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
As the duration and intensity of primary rehabilitation programs for drug and alcohol abusers are reduced due to
funding constraints. there is likely to be a greater emphasis on the use of aftercare services to prevent relapse. In the
case of cocaine abusers, however, them is a lack of information on both the relative effectiveness of different
approaches to aftercare and on patient by treatment matches that might improve outcomes. In the present study, 98
male cocaine-dependent patients who completed an intensive outpatient program (IOP) were randomly assigned to
either standard group counseling (STND) or individualized relapse prevention (RP) aftercare. Outcome analyses
indicated that the conditions did not differ on percent days of cocaine use in months 1-6. However, fates of complete abstinence during months 1-6 were higher in STND than RP. whereas RP was more effective in limiting the
extent of cocaine use in those who used any cocaine. These treatment group main effects were also observed in
months 7-12. Matching analyses indicated that patients who failed to achieve remission from cocaine dependence
during IOP and those with a commitment to absolute abstinence at entrance to aftercare did better in RP than in
STND in months 1-6, whereas patients with other abstinence goals did better in STND than RP. During months 712, patients who had not achieved remission from cocaine dependence during IOP continued to have much better
outcomes in RP than in STND, whereas the two conditions were equally effective for those who had achieved
cocaine abstinence during IOP.
ACKNOWLEDGMENTS:
Supported by NIDA grants R29 DA08399 and P50 DA05186
99
ENHANCED AND BASIC ADDICTION OUTPATIENT TREATMENT FOR CRACKCOCAINE DEPENDENT MOTHERS
J. R. Volpicelli, J. I. Filing, H. M. Pettinati, I. Markman, G. J. Luck, R. S. Trager, R. H.
Cooke, M. I. Andem, and C. P. O’Brien; Treatment Research Center, University of
Pennsylvania, Philadelphia, PA
The treatment of cocaine dependent women with young children is complicated by special psychosocial factors such
as limited financial resources, histories of physical and sexual abuse, and co-existing emotional disorders, This
special population has historically been difficult to retain in treatment. This study compared two types of
psychosocial treatment in a sample of cocaine dependent females who were pregnant or had a child less than 4 years
old. Subjects were randomly assigned to either basic addiction treatment (BAT) or psychosocial-enhanced treatment
(PET). PET was designed to address some of the special problems of women dependent on cocaine. This
comprehensive program consisted of group addictions counseling as well as outpatient individual psychotherapy,
vocational training, parenting classes, family therapy, and psychiatric monitoring, all available on site. In contrast,
BAT treatment consisted of group addictions treatment and case management in which additional services were
obtained by referrals to community resources. The individual therapy was based on compliance enhancement
techniques (Volpicelli, Pettinati, McLellan and O’Brien, 1997). Results for the first 12 weeks of treatment revealed
that for those who remained in treatment, there was improvement in their drug and alcohol severity scores on the
Addiction Severity Index (ASI), for both PET and BAT conditions. However, treatment attendance was improved by
assignment to the PET condition. Good attendance (attending more than 10 sessions by 12 weeks) was higher in the
PET group (63%) than in the BAT group (37%) (chi square = 4.74, df = 1. p< 0.05). Improved attendance in the
PET condition interacted with initial readiness to change. For those subjects with high levels of readiness to
change, good attendance was high for both the PET and BAT group (61% versus 52%)( chi sq = .33, df = 1, p =
.57). In contrast, for those subjects with low readiness to change, good attendance was only 25% in the BAT gmup
and improved to 65% in the PET group (chi square = 6.46. df = 1, p< 0.05). In sum. treatment attendance in the
first 12 weeks of outpatient addiction treatment was improved for cocaine dependent mothers who scored low on a
“readiness-to-change” measure at treatment entry if they received enhanced psychosocial support.
ACKNOWLEDGMENT:
Supported by NIDA grant #P50 DA09252.
EFFECTIVE TREATMENT FOR HOMELESS COCAINE ABUSERS: ABSTINENCE VS.
REHAB OUTCOMES
J. B. Milby, J. E. Schumacher, C. McNamara, D. Wallace, T. McGill, D. Stange, and M.
Michael
University of Alabama at Birmingham, AL
Day treatment/work therapy with abstinent contingent housing (DT+) was compared to day treatment without
housing or work therapy (DT). In a randomized control outcome study for homeless, dually diagnosed, cocaine
abusers, addiction severity was measured by ASI composite scores at baseline, 2, 6 mo. and bi-weekly urine
toxicologies. Better DT+ outcomes were hypothesized. Independent “blind” interviewers assessed 110 randomly
assigned subjects. DT and DT+ used unique goals established during assessment, random urines 2/wk., individual
and group counseling 6 hr./day for 2 mo., vouchers reinforcing non-drug related social/recreation activities, and
weekly goal reviews reinforcing rehabilitation indicants. Transportation to/from shelters and lunch were provided.
DT+ subjects worked refurbishing housing and had housing available for modest rent, both abstinence contingent.
Results: Baseline ASI’s and toxicologies did not differ. Both groups substantially improved ASI scores baseline
to 6 mo., Med p<.02, Legal p<.01, others p<.0001 (F test Mixed Model df=2, 189) with consistent trends
favoring DT+. Toxicologies show robust, differences favoring DT+. At 2 mo. 75% vs. 31% were abstinent
(p<.001) at 6 mo. 50% vs 17% abstinent (p<.034, Chi Sqs.=15.1, and 4.5, df=1). Similar robust effects favoring
DT+ were found for consecutive weeks abstinent: at 6 mo. DT+ averaged 10.12 vs. 5.45 consecutive wk. abstinent
(p<.0001 Wilcoxon Rank). Results suggest behavioral day treatment is effective, with abstinence contingent
housing and work therapy differentially impacting drug abuse outcomes relative to other rehabilitation outcomes.
ACKNOWLEDGMENT: Supported by NIDA grant RO1 DA08475.
100
ORAL COMMUNICATIONS X
AIDS-RELATED DRUG AND SEXUAL RISK BEHAVIORS: WHAT DRUGS AND WHICH
ROUTES?
R. A. Rawson1,2, W. Ling1,3, S. Shoptaw1,2, A. Huber1,2, and S. Dow
1
Los Angeles Addiction Treatment Research Center1; West Los Angeles VAMC3
Injection drug use (IDU) and unprotected sexual behaviors are the two major determinants of HIV transmission
among drug abusers, though only 7% of AIDS cases in LA County are due to IDU behaviors. Thus, in LA
County, sexual risk behaviors are the primary concern for HIV transmission risks. We describe drug use and
sexual risk behaviors across 3 cohorts of treatment-seeking drug abusers (primary cocaine dependent (PCD), n=74;
primary opiate dependent (POD), n=106; dual dependent (DD), n=58) at baseline and at 13-or 16-week follow-up to
provide an initial evaluation of drug treatment episodes for reducing AIDS-related drug use and sexual behaviors in
these cohorts. Findings (mean (standard deviation) indicated that cocaine abusing subjects rarely used needles in a
30-day reporting period (PCDBaseline=0.2 (0.2) times, PCDFollowUp=0.0 (0.2) times), and opiate abusers significantly
reduced injection behaviors with treatment (PODBaseline=16.4 (27.7) times, PODFollowUp=2.7 (5.0) times;
DDBaseline= 10.5 (14.4) times, DDFollowUp=7.8 (14.4) times; F=16.84, df=2.232, p<.001). Sexual behaviors were
more resistant to change. With treatment, fewer cocaine abusers reported trading xx for money, drugs, or gifts
(PCDBaseline=5.4%, PCDFollowUp=1.4%) compared to opiate abusers (PODBaseline=1.9%, PODFollowUp=0.0%;
DDBaseline=3.4%, DDFollowUp=3.4%). Implications are that drug abusers engage in specific AIDS-related risk
behaviors that are dependent upon drug used and route of administration. Drug and sexual AIDS-risk behaviors
change consequent to drug treatment at statistically and clinically significant levels.
CHANGES IN HIV RISK BEHAVIORS AMONG COCAINE-USING METHADONE
PATIENTS BEFORE AND DURlNG TREATMENT
A. Rosenblum, S. Magura, and E. Rodriguez
National Development and Research Institutes, Inc., New York, NY
Methadone patients who were also dependent on cocaine (N=207) provided information on their current (past 30
days) HIV risk behaviors and their behaviors 30 days prior to entering treatment. DSM-III-R diagnoses for Axis I
disorders and Anti-Social Personality (ASPD) were obtained by the SCID. Significant differences (p < .05) between
the two times were determined with paired t-tests. Multiple regression analyses were conducted to determine
predictors of changes in risk. Subjects were 59% male; 53% Hispanic, 36% African-Am.; mean age = 38; mean
methadone dose = 67 mg; and mean months in methadone treatment = 28. Significant decreases occurred for heroin
frequency (27.9 vs. 3.2 days/mo.), injection frequency (17.6 vs. 4.5 injections/mo.), needle-sharing risk index (7.5
vs. 3.7), multiple partners (3.8 vs. 1.6 partners/mo.), sexual risk partner in&x (0.21 vs. 0.12), unprotected sex
index (3.0 vs. 2.5). However, needle hygiene practices for those continuing to share did not change. Injection
frequency during treatment was independently predicted by heroin frequency pre-tx, current bipolar and current
ASPD. Needle sharing during treatment was predicted by HIV-positive, violent offenses, female gender and cocaine
frequency pre-tx. Overall, these results support the growing recognition of methadone treatment as a harm
reduction modality; even methadone patients who continue to use cocaine and have poor psychosocial functioning
significantly reduced their drug- and sex-related HIV risks when compared with their pre-treatment behaviors.
ACKNOWLEDGMENT:
Supported by NIDA Grant No. 5 R18 DA06959.
101
HIV RISK BEHAVIOR AMONG A COHORT OF OLDER, MALE HEROIN ADDICTS
V. Hoffman, C. E. Grella, Y.-I. Hser, and M. D. Anglin
University of California, Los Angeles, Neuropsychiatric Institute, Drug Abuse Research
Center
This study examined the prevalence of HIV risk behavior among a cohort of male heroin addicts who are currently
being interviewed as part of a longitudinal study of the natural history of heroin addiction. The subjects are part of a
sample of 581 males who participated in the California Civil Addict Program in the 1960s. Of the original sample,
approximately one-half have died, one-third have recently been interviewed, and about 20% have not been located or
are unable to be interviewed. The average age of men in the current sample is 57 years and the ethnic distribution is
36% white, 57% Hispanic, and 7% African American. Of the current sample, 58% reported injection heroin use at
the previous interview ten years ago. and 33% reported current injection heroin use. The subgroup of long-term
heroin injectors (n=51) was more likely than current non-injectors to be Latino, unemployed unmarried, in unstable
housing, under legal supervision; to report symptoms of depression; to have been incarcerated in the last ten years;
and to use cocaine, marijuana amphetamines, tobacco, and alcohol. About one-quarter of the current heroin injectors
reported having two or more female sex partners without always using condoms, 20% reported having a sex partner
who was an injection drug user, and one-third relaxed using others’ injection equipment without always cleaning.
Although the leading causes of mortality among the original sample were accidents, heart disease, and liver disease,
a small subgroup of current injectors was at risk for HIV infection.
ACKNOWLEDGMENTS:
K02-DA00146 (Anglin).
Supported by the NIDA grants R01-DA09169-02, K02-DA00139 (Hser), and
HIV RISK BEHAVIORS OF CRYSTAL METHAMPHETAMINE USERS CONTACTED
THROUGH STREET OUTREACH
C. J. Reback
Van Ness Recovery House, Hollywood, CA
This presentation describes the HIV risk behaviors of 908 gay and bisexual mate drug users contacted through a
street outreach HIV risk reduction program in Hollywood, CA. in 1996. Individuals received a brief drug use and
HIV risk assessment, referrals for needed services, free bleach, condoms and hygiene kits. Over one-third (37%) of
the contacted individuals reported using crystal methamphetamine in the previous 30 days. Compared with the nonmethamphetamine users, methamphetamine users were more likely to be Caucasian/white (p<.001), be younger
(p<.001), engage in sex work (p<.0001), have an IDU sex partner (p<.0001), receive referrals for long-term and
immediate needs (p<.01), and were less likely to always use condoms when having sex with other men (p<0.01), or
with an IDU sex partner (p<.01). Methamphetamine users were also more likely than non-methamphetamine users
to report use of heroin, crack, ecstacy, cocaine, marijuana, and alcohol within the previous 30 days (all differences,
p<.01). Approximately 58% of the crystal users reported injection drug use within the previous 30 days; 29%
reported that they shared injection equipment with others, and the majority (65%) stated that they never used bleach
to clean equipment prior to injection. Methamphetamine use is an emerging drug problem within gay and bisexual
male communities which compounds preexisting HIV risks. HIV interventions to this population should address
both high-risk drug and sexual behaviors.
ACKNOWLEDGMENTS:
Supported by contract #H204213 from the CDC and County of Los Angeles,
Department of Health Services, Office of AIDS Programs and Policy.
102
PSYCHOSOCIAL RISK AND PROTECTIVE FACTORS AND COPING IN FEMALE IDUS
D. W. Brook and J. S. Brook
Department of Community Medicine, Mount Sinai School of Medicine, New York, NY
We studied the psychosocial determinants of coping ability in a cohort of HIV-positive and HIV-negative female
injection drug users (IDUs). We hypothesized that conventionality and family and peer support were related to
greater adaptive coping. Cross-sectional data were collected using a structured questionnaire with 249 female AIDS
clinic or methadone clinic patients in an urban municipal hospital, of whom 43.4% were HIV-positive. Data were
analyzed using Pearson correlation analyses, t-tests, and multiple hierarchical regression analyses. Coping ability
was associated with conventionality, greater control of emotions, and less psychopathology, as well as family
cohesion in both HIV-positive and HIV-negative patients. Different mediational models best depicted the pathways
by which psychosocial factors affected coping in HIV-positive and HIV-negative subjects. The findings supported
the presence of risk/protective interactions in both groups: for the HIV-positive subjects, less significant other
marital harmony was offset by high maternal emotional support, leading to better coping ability. For the HIVnegative group the adverse effects of paternal risk factors were offset by high maternal identification and maternal
attachment. The findings confirm the importance of the interplay between personality factors and external support
on coping ability in female IDUs.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 08323.
A MULTISITE STUDY OF REAL AND PERCEIVED HIV RISK BY COUNTY POPULATION
DENSITY
C. G. Leukefeld 1 , D. Farabee 1 , W. M. Wechsberg 2 , J. A. Inciardi 3 , L. R. Cottler 4 , J. A.
Hoffman5, and D. Desmond 6
1
Center on Drug and Alcohol Research, University of Kentucky, Lexington, KT, 2 Research
Triangle Institute, Research Triangle Park, NC; 3 University of Miami, Miami, FL;
4
Washington University, St. Louis, MO: 5 Neighborhoods in Action, Washington, D.C.; and
6
University of Texas at San Antonio, Health Science Center, San Antonio, TX
The purpose of this study was to contrast real and perceived HIV risk among 2,566 out-of-treatment drug users in a
multisite sample of low-, medium-, and high-population density counties in Kentucky, Maryland, Missouri, North
Carolina, Texas, Virginia, and Washington, DC. It was hypothesized that respondents in lower population density
areas would be less likely to see themselves as being at risk of acquiring HIV/AIDS-despite the high rates of risk
behaviors reported by this sample as a whole. As predicted, the perception of having zero risk of acquiring
HIV/AIDS was indeed more common among respondents in the low- and medium-population density areas than
among those in the high-density areas. Likewise, a logistic regression model predicting the likelihood of perceiving
no HIV risk revealed that population density, in addition to needle use and having multiple sex partners, was
negatively associated with the likelihood of perceiving no risk of HIV. In other words. drug users in the lowerdensity areas were more likely to perceive themselves as having no risk of ever acquiring HIV/AIDS, regardless of
their actual risk levels.
103
HIV SEROPREVALENCE AND RISK BEHAVIOR CHANGES IN HIGH RISK DRUG
USERS: ENCOURAGING TRENDS
S. Deren, S. Tortu, M. Beardsley, and M. F. Goldstein
National Development and Research Institutes, Inc., New York, NY
Introduction: HIV infection was first documented among injection drug users (IDUs) in NYC in 1979;
seroprevalence rates reached 50% by 1990. A variety of prevention efforts were mounted. This study was undertaken
to assess trends in HIV seroprevalence and changes in risk behaviors among IDUs and crack smokers (CSs) in East
Harlem from 1992-1995. Methods: IDUs/CSs participated in baseline interviews, interventions, and six month
follow-up interviews. Analyses conducted: trend analyses of seroprevalence for annual recruitment cohorts of IDUs;
analyses of behavior changes, by serostatus. Results: Trend analyses(450 IDUs):Seroprevalence from 1992 to 1995
was 48%. 38%. 34%. and 21%, respectively (p<.0001). Analyses of behavior change [245 IDUs (33%HIV+) and
338 CSs (15%HIV+). For subjects who had sex at baseline and follow-up, unprotected sex decreased from 50% to
35% among seropositives and 69% to 63% among seronegatives (time effect p<.01; timeXserostatus interaction,
ns). For those who reported injecting drugs at both points, indirect sharing (of cookers/ cotton/ rinse water) reduced
from 41% of seropositives at baseline to 9% at follow-up, and from 24% of seronegatives to 16% (time effect,
p<.0001; timeXserostatus, p<.01). Conclusions: HIV among IDUs declined from 1992-1995. Both HIV positive
and negative subjects reported reductions in risk behaviors over time, with HIV+ subjects reporting greater risk
reductions for selected behaviors. Community-wide prevention efforts contributed to these declines, and are needed to
maintain declines. Further research, particularly among those who continue to engage in risk behaviors, is
indicated.
ACKNOWLEDGMENT:
Research funded by NIDA grant #U01 DA07286.
ORAL COMMUNICATIONS XI
IMPACT OF ILLICIT AMPHETAMINE USE ON NEUROPSYCHOLOGICAL FUNCTIONING
R. Mcketin and R. P. Mattick
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW,
Australia
The purpose of this study was to assess the impact of illicit amphetamine use on cognitive functioning. A
neuropsychological test battery (Wechsler Memory Scale-Revised and the Digit Symbol. Block Design and
Vocabulary subtests of the Wechsler Adult Intelligence Scale-Revised) was admired to 78 amphetamine users
(mean age = 22.5 years, 45 males. 33 females). Regression analysis was used to adjust for premorbid intelligence,
other drug use. drug positive urinalysis and other potentially confounding variables. Severity of amphetamine
dependence was found to be associated with worse performance on the WMS-R indices of Attention/Concentration
(p < .05) and Delayed Recall (p < .01). while the Visual Memory index was negatively correlated with both
severity of amphetamine dependence and extent of amphetamine use (p <.05). A secondary analysis was carried out
on data from 26 subjects with drug free urine. Subjects were divided into two groups (n = 13) based on severity of
dependence (low vs high). Groups did not differ significantly in terms of age, other drug use, or premorbid
intelligence. The high severity of dependence group performed significantly worse than the low group on the WMSR indices of Verbal Memory (p < .01). Attention/Concentration (p <.05) and Delayed Recall (p <.05). The high
severity of dependence group also showed a non-significant decrement on the Visual Memory Index (p < .10). These
results suggest that heavy illicit amphetamine use, particularly severe dependence on amphetamine, is associated
with cognitive impairment. It is not clear whether this impairment is due to amphetamine neurotoxicity or other
factors associated with amphetamine use.
ACKNOWLEDGMENTS:
Funded by a New South Wales Department of Health, Drug and Alcohol
Directorate Post Graduate Scholarship. Neil Donnelly assisted with the statistical analysis.
104
EVOKED POTENTlAL EVIDENCE OF ABNORMAL CORTICAL SUBCORTICAL
INTERACTION IN COCAINE WITHDRAWAL
K. R. Alper, L. S. Prichep, S. Kowalik, E. R. John, and M. S. Rosenthal
Brain Research Laboratories, Department of Psychiatry, New York University Medical
Center, NY, NY; Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY; and
Phoenix House Foundation, New York, NY
Somatosensory EP (SEPs) were measured on 40 male and 16 female subjects in locked residential treatment for
cocaine dependence. Peak latencies were normal for brainstem and cortical components of the SEP, however
significant relative reductions in cortically generated SEP peak amplitudes were observed which correlated with
length of exposure to cocaine and persisted into 6 months of continuous drug abstinence. SEP amplitudes in the
central cortical region contralateral to the side of stimulus delivery correlated with length of exposure (R=-0.36,
p<=.01) and also with subjects length of slay in treatment (R=-0.28, p<=0.04). In view of reasonably reliable data
regarding the anatomical localization of SEP components, these results suggest that the pathophysiology of cocaine
withdrawal involves a disturbance at the level of the cortex. The possible clinical significance of these findings with
respect to the compulsive self administration of cocaine is considered in the context of the “incentive sensitization”
model of T.E. Robinson and others, and the role of descending cortical regulation of striatal activity as a determinant
of behavioral output.
ACKNOWLEDGMENT:
Supported by NIDA grant RO1-DA 07707
ABNORMAL METYRAPONE TESTS DURING COCAINE ABSTINENCE
J. H. Schluger, G. Bodner, M. Gunduz, A. Ho, and M. J. Kreek
The Laboratory on the Biology of the Addictive Disease, The Rockefeller University, New
York, NY
Metyrapone testing was performed in chronic cocaine addicts admitted to the GCRC at the inpatient unit of the
Rockefeller University Hospital, to assess the response of the hypothalamic-pituitary-adrenal axis to an acute cut-off
of glucocorticoid negative feedback, in the setting of abstinence from cocaine. Nineteen subjects were studied (15
males, 4 females, age: mean 34.1 yrs. range 22.8 - 42.1 yrs), 10 were in methadone maintenance treatment, and 9
were not opiate dependent Subjects were free of active major active medical problems on admission other than
substance abuse. and were HIV-1 antibody negative. Patients were administered 2.25 g of melyrapone in a single
oral dose al 9:00 A.M. Blood was drawn 30 to 120 minutes prior to, and immediately prior to metyrapone
administration, and 1.2.4 and 8 hours afterwards. Plasma levels of -endorphin were determined by RIA. Subjects
were tested after a period of abstinence from cocaine ranging from 1 to 155 days, and 7 subjects had a repeal test
after sustained abstinence, totaling 26 tests. Results of individual tests were expressed as the ratio of the highest
post-metyrapone level of -endorphin to the lowest pre-metyrapone level, this ratio having previously been
determined to range from 2 to 4 (“normal”) in normal volunteers. Seventeen out of 26 tests yielded “highest-post”/
“lowest-pre” ratios that were abnormal: 15/26 (57%) were “high, (> 4) 2/26 (8%) were “low” (< 2). Upon
examining levels of -endorphin at individual the points, it appeared that “high” responders had lower than normal
pre-metyrapone, and higher than normal post-metyrapone levels. There was not a significant difference in the rates
of abnormal tests in methadone treated vs. non-opiate dependent patients The results of this study suggest that
during abstinence from cocaine following chronic addiction, there is a hyper-responsivily to an acute cut-off of the
usual negative feedback exerted by endogenous glucocorticoids, which persists long into abstinence.
ACKNOWLEDGMENTS:
Supported in part by grants: DA-P50-05130, DA00049 and M01-RR00102
105
COCAINE-INDUCED CEREBRAL VASOSPASM IN HUMANS: DETECTION WITH
MAGNETIC RESONANCE ANGIOGRAPHY
M. J. Kaufman, J. M. Levin, M. H. Ross, N. Lange, S. L. Rose, T. J. Kukes, J. H.
Mendelson, S. E. Lukas, B. M. Cohen, and P. F. Renshaw
Brain Imaging Center and Alcohol and Drug Abuse Research Center, McLean Hospital,
Harvard Medical School, Belmont, MA
Cocaine has been suggested to induce cerebral vasospasm based on clinical case reports in cocaine abusers. However,
no study has determined whether acute cocaine administration, in the absence of other factors (e.g. polydrug abuse,
underlying disease), induces cerebral vasospasm. This study used magnetic resonance angiography (MRA) to detect
the effects of acute cocaine on cerebral arterial blood flow. Subjects were 24 males aged 29±5 years (mean±SD)
reporting casual cocaine use (10±12 lifetime exposures). MRA was conducted on a 1.5 Tesla scanner with a 3D
Time-of-Flight sequence. Axial MRAs were obtained at baseline and 17 minutes following intravenous double-blind
placebo or cocaine (0.4 or 0.2 mg/kg) administration. Two raters, interpreting MRAs independently and blindly,
concerdantly determined that 5 of 8 and 3 of 9 subjects administered 0.4 or 0.2 mg/kg cocaine, respectively,
experienced MRA changes indicative of cerebral vasospasm, compared to 1 of 7 subjects administered placebo. This
suggests that cocaine induces cerebral vasospasm in a dose-related manner(p =0.041). Stratification of the data by
self-reported lifetime cocaine use strengthened the statistical significance of this relationship (p <0.001). These
results, that low dose cocaine promotes acute cerebrovascular abnormalities, particularly in persons with other risk
factors, may help explain the complication of vasospasm associated with chronic cocaine abuse.
ACKNOWLEDGMENTS:
DA00329.
Supported by NIDA grants DA09448, DAC-4059, DA00064, DA00115, and
BRAIN IMAGING DURING CUE-INDUCED OPIATE AND COCAINE CRAVING
A. R. Childress, W. McElgin, P. D. Mozley, M. Reivich, and C. P. O’Brien
Addiction Treatment Research Center, University of Pennsylvania School of Medicine, and
VA Medical Center, Philadelphia, PA
Powerful drug incentive (“craving”) states are cardinal features of addictive disorders, and can fuel the relapse
tendency which charactetirizes addictions. We recently studied the brain substrates of cocaine craving by monitoring
brain activity (indexed by regional cerebral blood flow, rCBF) during video cues which reliably induce the state.
Based on preclinical data showing limbic activation both to cocaine and to cocaine cues, and on the salient
emotional and motivational properties of cocaine craving, we hypothesized and subsequently confirmed increases in
limbic activity (amygdala, anterior cingulate and temporal pole) during cue-induced cocaine craving. Comparison
regions (cerebellum, dorsolateral prefrontal cortex, basal ganglia, occipital cortices, and thalamus) did not show
differential activation. Cocaine-naive controls neither craved nor showed differential limbic activation during the
cocaine videos. We are now testing the generalizability of these llmbic findings to a sample of opiate patients (n=3
thusfar) imaged during cue-induced opiate craving. As in the prior study, imaging of rCBF is accomplished with
PET (Positron Emission Tomography) scans, using radioactively-labeled (0-15) water as the flow tracer. PET scans
for each subject are co-registered with an MRI (magnetic resonance image) to permit anatomical localization of
radioactivity. Findings from the opiate sample will test the hypothesis that limbic activation is a shared feature of
drug incentive states.
ACKNOWLEDGMENTS:
Supported by NIDA Center 5-P50-DA05186-08 (Project 1/Dr. Childress) and by
NIDA RO1 10241 to Dr. Childress.
106
BRAIN MU-OPIOID RECEPTOR BINDING BY PET SCANNING DURING EARLY AND
PROLONGED COCAINE ABSTINENCE
B. Bencherif*, D. Gorelick#, R. Nelson#, R. Stouffer#, N. Ilgin*, H. T. Ravert*, W. B.
Mathews*, J. L. Musachio*, R. F. Dannals*, and J. J. Frost*
*Johns Hopkins Medical Institutions and #NIH-NIDA, Div. of Intramural Res., Baltimore,
MD
Upregulation of brain mu-opioid receptors (mOR) has been reported in animals and humans shortly after cessation
of chronic cocaine administration. We evaluated the time course of this change using positron emission
tomography (PET) scanning with 11C-carfentanil (GE 4096 scanner, FWHM resolution 7 mm) in 12 chronic (mean
6.6 years of use) heavy cocaine users (10 male, mean age 32 years) with no other recent drug use and 25 nondrug
using healthy controls (12 male, mean age 30 years). Regions of interest were localized by MRI. Cocaine users
had 90 days of monitored abstinence on the DIR closed research ward. during which they had 5 PET scans: #1
within 48 hours of last cocaine use (1 day after admission), #2 and #3 (on the same day) about 7 days later, and #4
and #5 (on the same day) about 90 days after admission. Cocaine (80 mg intranasal) was given during scans #3 and
#5 5 minutes after IV carfentanil to achieve plateau plasma cocaine concentrations (100-300 ng/ml) during the
period of scan acquisition. Compared to controls, cocaine users bad significant (> 20%) increases in mOR binding
in putamen, cingulate, temporal, and frontal cortex at scan #1, which persisted through scan #4 except in temporal
cortex. Thalamus, caudate, amygdala and parietal cortex showed increased binding only at scan #2. There was a
significanl positive correlation between plasma cocaine concentration and the change in regional mOR binding
between the pairs of scans without and with cocaine challenge. There was also a significant correlation between the
decrease in mOR binding between scans #2 and #4 and the time to relapse to cocaine use after ward discharge. These
findings suggest that increased regional mOR binding persists during prolonged cocaine abstinence (possibly
mediated by cocaine-induced decreases in endogenous opioid neurotransmission) and may influence relapse to cocaine
use.
ACKNOWLEDGMENT: Supported by NIDA intramural funds and grant RO1-DA 09479.
ORAL COMMUNICATIONS XII
THE ROLE OF CORTICOTROPIN-RELEASING FACTOR IN RELAPSE TO HEROINSEEKING
Y. Shaham 1 and J. Stewart2
1
Biobehavioral Research Department, ARF and Department of Psychology, U of Toronto,
Toronto, ONT and 2CSBN, Department of Psychology, Concordia University, Montreal, PQ
Background: We have shown previously that brief footshock stress and priming injections of heroin reinstate
heroin-seeking after prolonged drug-free periods. Recently we have found that adrenalectomy appears to potentiate
the reinstatement effect of footshock, and that acute administration of a synthesis inhibitor of corticosterone.
metyrapone, potently reinstated heroin-seeking. Based on these observations, we have examined whether
corticotropin-releasing factor (CRF) is involved in reinstatement of heroin-seeking. Methods: Three groups of
rats (n=10-14) were trained to self-administer heroin (100 g/kg/infusion, IV) for 12-14 days. Extinction sessions
with saline were given for 4-8 days. We then compared the effect on reinstatement of heroin-seeking of acute
intracerebroventricular (ICV) injections of CRF (0.3 and 1.0 µg) to those of intermittent footshock stress (15 and
30 min, 0.5 mA) and priming injections of heroin (0.25 mg/kg, SC). We also tested the effect of ICV injections
of the CRF antagonist, alpha-helical CRF (3 and 10 µg) on reinstatement induced by saline priming, heroin
priming and footshock. Results: Acute exposure to CRF reinstated heroin-seeking compared with a vehicle ICV
injection (p<0.05). This effect of CRF; however, was somewhat weaker than the reinstatement effects of stress and
heroin priming. In addition, the CRF antagonist, alpha-helical CRF, significantly attenuated stress-induced
reinstatement (p<0.05). The effect of the CRF antagonist on reinstatement by heroin was less consistent,
Conclusions: These results suggest that CRF, a major brain neuropeptide involved in the stress response,
contributes to relapse to heroin-seeking induced by stressors.
107
ACKNOWLEDGMENTS: Supported by NIDA and MRC of Canada.
A METHOD FOR TESTING THE SPECIFICITY OF MANIPULATIONS ON DRUG SELFADMINISTRATION
A. R. Morral, R. J. Lamb, T. V. C. Jarbe, R. Fidler-Sheppard, K. Mosher, and M. Y. Iguchi
Allegheny University of the Health Sciences, MCP-Hahnemann School of Medicine,
Philadelphia, PA
Drug self-administration may be modified with pharmacologic (e.g., methadone) and environmental (e.g., footshock)
interventions. whether such interventions modify behaviors other than drug use is less well characterized. We
describe a model of choice behavior that provides a sensitive and realistic assay of the specificity of pharmacologic
and environmental manipulations on drug self-administration. Twelve male Sprague-Dawley rats were trained to
orally self-administer fentanyl HCL (56 µg/ml) dissolved in tapwater on an FR schedule using a sucrose fading
procedure. After eliminating sucrose, a second lever reinforced with 45 mg food pellets was activated, with rein
forcement for responding on each lever controlled by separate but concurrent VI schedules. After responding on the
levers stabilized. a series of within-subject ABA design studies were used to evaluate the sensitivity of dipper
responding (as a percentage of all responding) to changes in available contingencies. When the feeder was placed
under extinction, responding shifted to the dipper lever, F(1,11)=50, p<.001. When the dipper was placed under
extinction, and when the dipper was empty, responding shifted to the feeder lever, F(1,11)=28 and F(1, 10)=64, both
p<.001. Effect sixes were large accounting for 72% to 86% of variance in responding. Despite this sensitivity, no
changes were noted in dipper responding when water was substituted for fentanyl for 2 weeks. Therefore, we cannot
conclude that responding was maintained by fentanyl more than for the water vehicle alone. The concurrent VI
paradigm appears useful for assessing the specificity of interventions designed to modulate drug self-administration.
In particular, by using Matching Law principles to adjust base rates of responding for drug vs an alternative
reinforcer, this paradigm offers the promise of greater control over pre-intervention response ratios, a factor that
might decisively influence post-intervention response ratios. Furthermore, choice paradigms provide a good model
of human drug use. since drug abusers typically have nondrug-reinforced responses available to them.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA 06096 and DA 08395.
DEPRENYL PREVENTS LONG-TERM BEHAVIORAL AND NEUROCHEMICAL CHANGES
THAT FOLLOW OPIATE WITHDRAWAL
K. Grasing and S. Ghosh
Department of Medicine, Division of Clinical Pharmacology, UMDNJ-Robert Wood Johnson
Medical School, New Brunswick, New Jersey
Because of evidence for decreased dopaminergic function during the withdrawal syndromes associated with opiates
and other medications with potential for abuse, we investigated the effects of treatment with deprenyl on in vitro
measures of dopamine release during opiate withdrawal. Forty-eight male Wistar rats received injections of either
saline or morphine, 3 times per day, with the dose of morphine gradually increased to 120 mg/kg-injection. During
withdrawal, morphine treated animals received daily subcutaneous injections of either saline (WS) or 2.0 mg/kg-day
of deprenyl (WD). Control subjects initially received an identical pattern of saline injections to morphine treated
subjects, which was then followed by a daily injection of deprenyl (SD) or saline (SS). Behavioral and
neurochemical measures were obtained 17 to 24 days after the onset of withdrawal. Deprenyl treatment prevented
increases in stress immobility that occurred in saline treated withdrawn subjects (values of 6.59 ± 0.60 minutes for
group SS, 5.40 ± 0.69** for SD, 7.50 ± 1.06* for WS, and 5.64 ± 0.78** for WD [group means and standard
deviation, *P<0.05 and **P<0.01 relative to group SS]). In addition, effects of morphine withdrawal on in vitro
dopamine release by brain slices obtained from the nucleus accumbens were not observed in deprenyl treated animals
(percent decline in fractional dopamine release between an initial and subsequent 4-aminopyridine exposure was 40.5
± 11.5 for group SS, 31.5 ± 18.5 for SD, 52.5 ± 7.00 ** for WS, and 39.9 ± 10.8 for WD [**P<0.01]). Similar
effects were observed for in vitro release for brain slices obtained from the striatum. In conclusion, opiate
withdrawal is followed by long-term effects on both the behavioral response to stress and the functional reserve for
dopamine release. Both behavioral changes and deficits in dopaminergic function can be prevented through depenyl
treatment
108
DISCRIMINATIVE STIMULUS EFFECTS OF DEPRIVATION-INDUCED AND
PRECIPITATED WITHDRAWAL IN LAAM-TREATED RHESUS MONKEYS
M. R. Brandt and C. P. France
Department of Pharmacology, Louisiana State University Medical Center, New Orleans, LA
The purpose of the current study was to characterize the behavioral effects of withdrawal in monkeys (n=4) treated
with 1.0 mg/kg/12 hr s.c. of 1-alpha-acetylmethadol (LAAM). Monkeys discriminated between 0.0178 mg/kg of
naltrexone and saline while responding under a fixed-ratio schedule of stimulus-shock termination. Monkeys
responded on the saline lever after injections of LAAM; 0.1 mg/kg of naltrexone increased drug-lever responding to
more than 90% and elicited signs of opioid withdrawal (e.g., emesis). Naloxone and quadozocine substituted,
whereas, morphine, nalbuphine and ketamine did not substitute, for the naltrexone discriminative stimulus. Acute
injections of morphine or nalbuphine, and not ketamine, dose-dependently shifted the naltrexone dose-effect curve to
the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever
responding and fewer withdrawal signs. Maximal naltrexone-lever responding occurred between 24 and 48 hr after
the discontinuation of LAAM treatment. Similarly, the magnitude and frequency of withdrawal signs peaked
between 24 and 48 hr after the discontinuation of LAAM treatment. Partial naltrexone-lever responding occuned for
up to 10 days following the discontinuation of LAAM treatment; during this time, naltrexone did not further
increase either naltrexone-lever responding or signs of withdrawal. Although the partial naltrexone-lever responding
that occurred following the discontinuation of LAAM might suggest that LAAM, or one of its metabolites, has a
very long duration of action, the inability of naltrexone to increase drug-lever responding or elicit signs of
withdrawal indicate that the discriminative stimuli associated with deprivation-induced withdrawal are qualitatively
different from the stimuli associated with precipitated withdrawal.
ACKNOWLEDGMENT:
Supported by USPHS DA05018.
THE EFFECTS OF NALOXONE ON RESPONSES REINFORCED BY ORALLY
DELIVERED METHADONE
N. S. Wang, R. B. Stewart, and R. A. Meisch
Department of Psychiatry and Behavioral Sciences, University of Texas-Houston, TX
The relationship between methadone reinforced behavior and naloxone dose was studied with three monkeys and
under three schedules (Not all monkeys were studied under each schedule). Unlike most other studies, the
methadone was taken orally; however, like other studies methadone did serve as a positive reinforcer. The three
schedules wae all concurrent schedules with waler and methadone available. The schedules were a fixed-interval
15”. a mutually exclusive fixed-interval 15”, and a fixed-ratio (FR) 16. Under the mutually exclusive FI schedule,
the monkey could obtain one liquid delivery from either of the two spouts. In general, naloxone doses from 0.0125
to 0.2 mg/kg were presented in an ascending and then descending order. Blocks of sessions with daily naloxone
injections alternated with blocks of daily saline session. Naloxone and saline were administered by IM injection 10
min prior to the session. In the ascending series, low naloxone doses produced slight increases in responding,
except for M-JS under the mutually exclusive FI 15” schedule. At higher doses, naloxone decreased responding
under all three schedules, except for M-ED under the FI 15” schedule. During the ascending series, responding was
usually greater than during the descending series, suggesting an order effect. Analysis of the time course showed
that the duration of naloxone’s effects were a direct function of dose and occurred within the first hour of the
session. In the third hour of the session responding rebounded In the second part of experiment, the dose of
naloxone (0.1 mg/kg) was held constant and the methadone concentration was varied (0.05, 0.2, 0.4 and 0.8
mg/ml). The responding maintained by the methadone concentrations was differentially affected by the 0.1 mg/kg
naloxone dose. Naloxone’s effects also varied among monkeys. Theses experiments confirm and extend earlier
results by demonstration that methadone reinforced responding is sensitive to naloxone pretreatment and that the
effects of naloxone are as a direct function of dose.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA 08398, DA 04972 and DA 00159.
109
DISCRIMINATIVE STIMULUS EFFECTS OF NALTREXONE FOLLOWING ACUTE
MORPHINE PRETREATMENT
K. W. Easterling and S. G. Holtzman
Emory University School of Medicine, Atlanta, GA
Opioid antagonists such as naltrexone (NTX) have few documented behavioral effects in otherwise drug-free
subjects, but have prominent effects in subjects receiving morphine (MOR) chronically or acutely. The present
experiments characterized the discriminative stimulus effects of an acute MOR NTX combination. Adult male
Sprague-Dawley rats (N=6) were trained to discriminate between two drug treatments in a discrete-trial
avoidance/escape procedure -- MOR (10 mg./kg. s.c., 4 hr) NTX (0.3 mg/kg, s.c., 15 min.) vs. SAL (1 m/kg,
s.c., 4 hr) NTX (0.3 mg/kg, s.c., 15 min.). Subjects acquired the discrimination within 69 (± 9.1) sessions and
responded almost exclusively only on the SAL NTX-appropriate lever when SAL was given 3.75 hr after MOR
or 3.75 hr before any dose of NTX (0.3 - 100 mg/kg). In contrast, responding occurred on the MOR NIXappropriate lever dose-dependently when small doses of NTX (0.01 - 0.1 mg/kg) followed MOR, with complete
substitution occurring at the training dose of 0.3 mg/kg (ED50 = 0.03 mg/kg). Holding other parameters constant,
full MOR =) NTX-appropriate responding was also dependent on the pretreatment dose of MOR (ED50 = 2.19).
Further, at the training doses of MOR and NTX, stimulus effects were dependent on the duration of the MOR
pretreatment, with full effects seen only at 34 hr. At MOR pretreatment times less than 3 hr (1 hr), NTX ( < 30
mg/kg) did not engender full stimulus effects, although it did result in partial responding on the MOR NTXappropriate lever (ED50 = 7.72). Therefore, a qualitatively unique “withdrawal” stimulus that is dose- and timedependent appears to be the basis of this discrimination.
ACKNOWLEDGMENTS:
Supported in part by NIH &ants DA00541 and K05DA00008.
NMDA RECEPTOR ANTAGONISTS ATTENUATE TOLERANCE TO MORPHINE’S
DISCRIMINATIVE STIMULUS EFFECTS
A. Y. Bespalov, R. L. Bolster*, and P. M. Beardsley*
Pavlov Medical University, St. Petersburg, Russia, and *Department of Pharmacology and
Toxicology, Virginia Commonwealth University, Richmond, VA
Adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water under a standard twolever fixed ratio 10 schedule of food reinforcement. Cumulative dose-effect functions for morphine were determined
before and after repeated treatment with water or morphine. Treatment with morphine (10 mg/kg; 14 days, b.i.d.) had
little effect on morphine’s discriminative stimulus properties but induced tolerance to its response rate effects.
Increasing the treatment dose of morphine to 20 mg/kg resulted in more than a 4-fold rightward shift in the dose-effect
curve for morphine’s discriminative stimulus effects and tolerance to its response rate effects. Sensitivity to both
stimulus and response rate-altering effects returned to initial levels when rats were tested 2 weeks after morphine’s
repeated treatment. Separate groups of rats were treated with a combination of 20 mg/kg morphine or its vehicle and the
non-competitive NMDA receptor antagonist dizocilpine (MK-801; 0.1 mg/kg, i.p.), the competitive antagonist dCPPene (3 and 5.6 mg/kg; i.p.), the polyamine site antagonist eliprodil (17.3 mg/kg; i.p.), or the partial agonist at the
strychnine-insensitive glycine site (+)-HA-966 (10 mg/kg; i.p.). The development of tolerance to morphine was
attenuated only by eliprodl and d-CPPene. Because earlier reports have described inhibition of the development of
tolerance to morphine analgesia by dizocilpine, these results suggest different mechanisms underlying the development
of tolerance to analgesic and discriminative stimulus effects of morphine.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA01442 and the INVEST program.
110
BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF BUPRENORPHINE AND MORPHINE
IN NON-DRUG ABUSING VOLUNTEERS
J. P. Zacny, K. M. Conley, J. Galinkin, J. M. Klafta, P. A. Klock, C. J. Young. and D. W.
Coalson
Department of Anesthesia and Critical Care, The Pritzker School of Medicine, The
University of Chicago, Chicago, IL
Buprenorphine is an opioid with putative partial mu agonist and kappa, agonist effects, and kappa, antagonist
effects. In the present investigation, we characterized, in non-drug abusing volunteers, the subjective, psychomotor,
and physiological effects of a range of intravenous doses of buprenorphine [B], up to and including doses that would
be used for post-operative pain. We also compared me effects of one of the doses of B to that of morphine [M]; our
hypothesis was that the two drugs at equianalgesic doses would have a similar profile of effects given the similarity
of their actions at the mu receptor. An IRB-approved, crossover, Latin-square, double-blind, placebo-controlled trial
was conducted; sixteen nondrug abusing volunleers (mean age: 26 yrs, 5 females) were injected in an upperextremity vein with 0, 0.075, 0.15, and 0.3 mg/70 kg B, and 10 mg/70 kg M, and saline, 0.3 mg B is considered
clinically to be equianalgesic to that of 10 mg M. Results indicated that 0.3 mg B and 10 mg M produced a similar
spectrum of subjective and physiological effects, but that the intensity of effects (including VAS ratings of dizzy,
sleepy, high, difficulty concentrating, and me physiological measure of miosis) was significantly greater with 0.3
mg B. Psychomotor performance [e.g., Digit Symbol Substitution Test] was impaired and the VAS rating of
nauseous was increased by 0.3 mg B, but not by 10 mg M. Seven subjects vomited during 0.3 mg B sessions, but
none did so during the 10 mg M sessions. In general, B effects were dose-related, and, consistent with the
pharmacokinetic profile of this drug, were long-lasting (> 5 h). We conclude that a clinically-relevant dose of B
produces a greater intensity of behavioral and physiological effects. overall, than does an equianalgesic dose of M.
ACKNOWLEDGMENT: Supported by NIDA grant DA-08573.
SUBJECTIVE RESPONSES TO DYNORPHIN A(1-13) IN NORMAL CONTROLS AND
METHADONE MAINTENANCE PATIENTS
A. King, A, Ho. L. Borg, J. Schluger, and M. J. Kreek
Rockefeller University, Laboratory on the Biology of Addictive Diseases, New York, NY
Twelve normal healthy controls, 5 stabilized methadone maintenance patients (MMPs), and 5 MMP’s with ongoing
cocaine abuse participated in a placebo-controlled single-blind study of the subjective response to acute i.v.
administration of dynorphin A(1-13),# a synthetic kappa opioid agonist. Subjects were tested on three separate days
for the response to low (120 µg/kg) and high (500 µg/kg) dynorphin compared to placebo (saline) injection. Each
subject completed 100 mm visual analog scales (VAS) for “Drug Effect” (0 for “sick/cold turkey” to 10
“euphoric/high”) and general “Mood Effect” (0 for “terrible” to 10 “terrific”). The patient groups also completed a
drug craving VAS. The results for the controls showed that postinjection (10 min), mere were significantly higher
ratings of “Drug Effect” (euphoria) for both me high and low dose of dynorphin compared to placebo ( ps<.05), with
no significant dose-dependent differences. For general “Mood Effect,” the MMP’s with ongoing cocaine use showed
greater “terrific” mood (p <.05) after low dynorphin compared to controls. Preliminary results on drug craving in the
cocaine-abusing MMP’s show a directional dose-dependent increase in craving (placebo craving=4.8/10, low
dynorphin=6.4/10, high dynorphin=7.7/10). In contrast to cocaine-abusing MMP’s, stabilized MMP’s did not
significantly differ from the controls in mood response to either dose of dynorphin, although craving was augmented
after high dynorphin (placebo craving=2.2/10, high dynorphin=5.5/10). The results show that dynorphin was welltolerated and that normal subjects can discern the effects in a euphoric direction of both low and high dynorphin
compared to placebo. Cocaine-abusing MMP’s, in contrast to well-stabilized MMP’s, have a variable subjective
response to dynorphin with potential dose-dependent increased craving.
ACKNOWLEDGMENTS:
Supported in part by NIDA grant K05-DA00049 and NIAAA grant AA11001.
111
EFFECTS OF ANTISOCIAL PERSONALITY DISORDER (APD) AND PROVOCATION ON
AGGRESSIVE RESPONDING
M. K. Greenwald, R. K. Brooner*, C. R. Schuster, and C.-E. Johnnson
Dept. of Psychiatry and Behavioral Neurosciences, Wayne State Univ. School of Medicine,
Detroit, MI; * Dept. of Psychiatry and Behavioral Sciences, Johns Hopkins Univ. School of
Medicine, Baltimore, MD
Recent research suggests that drug abusers with APD may exhibit greater aggressive behavior in a laboratory model
(Point Subtraction Aggression Procedure) than those without APD. This study validates and extends this model in
relation to clinical state. Methadone-stabilized clients (50-80 mg/day) diagnosed with APD and matched non-APD
Controls participate in this inpatient study (target n= 18/group). On three consecutive days, subjects are tested
before and after receiving their fixed methadone dose. Across sessions, three widely varying provocation levels are
presented. Eleven APDs and 6 Controls have completed testing. Initial results show trends for a Group effect
(APD > Control) and Group x Provocation interaction on mean aggressive responding, which increases with
provocation level more for APDs than Controls. Number of aggressive behavioral responses at the high
provocation level is significantly correlated with Buss-Perry Physical Aggression scores for APDs ( r =0.56) but not
Controls. APDs also exhibit greater negative mood shifts with increasing provocation (decreases in Profile of
Mood States Positive Mood scale). As their aggressive responding increases, APDs decrease responding for money;
money-reinforced responding (and money earned) significantly increases with less provocation, more so for APDs
than Controls. Escape responding (from money loss) tends to be greater overall for APDs and unrelated to
provocation level. At present, no clear effects of time since methadone dose (possibly related to early withdrawal
signs) on aggressiveness have emerged. These results suggest that APDs are more aggressive generally and more
sensitive to repeated provocation than their non-APD counterparts, and suggest important new avenues for
investigating parameters and treatment of aggressiveness in this high-risk population.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 05569.
ORAL COMMUNICATIONS XIII
IMMUNE ALTERATIONS IN MICE LACKING THE MU-OPIOID RECEPTOR GENE
C. Gave’riaux-Ruff, J. Peluso, H. W. D. Matthes, and B. L. Kieffer
UPR9050 CNRS, ESBS Universit
Louis Pasteur, Illkirch, France
It has been well established that opiates alter immune functions. In order to study µ-opioid receptor (MOR)
implication in modulation of immune responses by endogenous opioid peptides and opiates alkaloids. we used mice
where the MOR gene has been disrupted by homologous recombination. We determined the weight and cellularities
of thymus and spleen. as well as splenic macrophage content and Natural Killer activity. To assess T cell activity,
we analyzed the percent of CD4 and CD8 cells in thymus and spleen, 4s well as in vitro Concanavalin A-induced
proliferation. In order to evaluate B cell activity, we measured serum immunoglobulin (Ig) levels, in vitro
lipopolysaccharide-induced proliferation and Ig production. Our results show that disruption of the MOR gene does
not produce any overt immune abnormalites in mice. We also assessed the contribution of MOR in morphineinduced immunosuppression by comparing alterations of immune responses after chronic morphine treatment in
vivo. Spleen and thymus cellularities as well as NK activity were altered by morphine in wild type but not in MOR
knock-out mice.
112
CHANGES IN KAPPA OPIOID RECEPTOR EXPRESSION DURING MATURATION OF
MOUSE IMMUNE CELLS
T. A. Ignatowski and J. M. Bidlack
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY
Recent initiatives combining flow cytometric analysis with indirect immunofluorescent labeling have been
successful in demonstrating opioid receptor expression on mouse immune cells. This sensitive method employs
amplification of labeling by a -selective opioid, fluorescein-conjugated arylacetamide, with the addition of
biotinylated anti-fluorescein IgG and extravidin-R-phycoerythrin, along with double-labeling by various fluorophoreconjugated monoclonal antibodies for phenolypic analysis of immune cells. Immature (>80% CD4+/CD8+) T-cells
isolated from thymi of 6-8 week old C57BL/6ByJ mice demonstrated greater than 50% specific opioid recetor
labeling. as assessed in the presence of the K-selective antagonist nor-binaltorphimine. Likewise, mature splenic Tcells (CD8+/CD3+ or CD4+/CD3+) and B-cells (CD45R+), as well as resident, peritoneal macrophages demonstrated
specific opioid receptor labeling. Interestingly, the relative percentage of T-lymphocytes expressing the opioid
receptor appears to change upon phenotypic maturation. decreasing from approximately 60% of the immature,
double-positive thymocytes to less than 25% of the mature, single-positive splenic T-cells showing labeling for the
receptor. Likewise, only 15% of splenic B-cells show labeling for the opioid receptor. Taken together, these
findings demonslrate the diversity in the expression of the opioid receptor on immune cells at varying stages of
differentiation.
ACKNOWLEDGMENTS:
Supported by USPHS grants DA04355 and DA09676.
POTENTIATION OF T CELL PROLIFERATION WITH NOVEL NON-PEPTIDIC OPIOID
LIGANDS
M. E. Riley*, S. Ananthan , and R. J. Weber*
*Dept. of Biomedical and Therapeutic Sci., Univ. of IL College of Medicine at Peoria,
Peoria, IL and Organic Chemistry Dept., Southern Research Institute, Birmingham, AL
Although the central nervous system mediated indirect effect of opioids has been shown to suppress immune
function (see Suo and Weber, Gomez-Flores and Weber; Weber, et. al., abstracts this meeting), the direct effect of
certain novel opioid derivatives on cells of the immune system has been shown to induce immunopotentiation in
vitro. Naltrindole (NTI), selective for the opioid receptor, and benzylidenenaltrexone (BNTX), selective for the
opioid receptor, have been shown to act as antagonists in classical neuronal opioid receptor systems. We have
identified a class of novel NTI derived non-peptidic opioid receptor ligands with direct immunopotentiating effects
on mitogen stimulated lymphocytes. In vitro, the NTI analogues SoRI 9331 and 9340 consistently produced a dose
dependent (10-7 to 10-6 M) potentiation of lymphocytes following mitogen stimulation. BNTX related compounds
SoRI 9334 and 9336 produced no significant effect on T-cell proliferation. Future studies will address
structure/activity relationships of these and other compounds and investigate the cellular mechanisms of
immunopotentiation. This series of novel non-peptidic opioid ligands could serve as immunotherapeutic agents with
potential use in the treatment of infectious diseases including AIDS, and cancer.
ACKNOWLEDGMENT:
This work was supported by NIDA Grant DA/AI 08988.
113
MORPHINE ENHANCES MACROPHAGE (M ) APOPTOSIS
P. Sharma, V. Sanwal, A. Kapasi, N. Franki, K. Reddi, N. Gibbons, and P. C. Singhal
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, N.Y. and The
Long Island Campus for Albert Einstein College of Medicine, New York
Clinical reports suggest that heroin addicts are prone to infections. We studied the occurrence of apoptosis in
peritoneal (P) M (harvested from control and morphine treated rats), murine (M) M (J774.16) and human
monocytes (HM, isolated from healthy volunteers). Subconfluent M were incubated in media containing either
buffer alone (control) or variable concentrations of morphine (10-10 to 10-4M) for variable periods (12 to 48
hours; n= 4 to 6). Subsequently, M were either stained with H-33342 and propidium iodide or underwent DNA
isolation, 32PdCTP labeling and gel electrophoresis. To determine whether this effect of morphine is opiate receptor
mediated, M were treated with morphine with or without naloxone. We also evaluated the effect of L-NAME (a
nitric oxide synthase inhibitor) with or without morphine on macrophage apoptosis, nitric (NO) production, and
accumulation of inducible NO synthase, (iNOS). We also examined the dose response and time course effect of
morphine on macrophage p53 accumulation. Morphine enhanced M apoptosis in a dose and time dependent
manner. Morphine treated M showed integer multiples of 180 base pair (ladder pattern). Naloxone, an opiate
receptor inhibitor, attenuated morphine-induced M apoptosis. Morphine also stimulated M NO production in a
dose dependent manner. Morphine promoted the accumulation of iNOS and p53. Since L-NAME attenuated
morphine-induced M apoptosis, iNOS expression, and NO production it appears that morphine may be causing
M apoptosis through the activation of M iNOS and the generation of NO. We conclude that morphine-induced
M apoptosis is mediated through opiate receptors and nitric oxide and associated with the accumulation of iNOS
and p53.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-06753
CHRONIC EXPOSURE TO MORPHINE, NOT ETHANOL, ATTENUATES THE
EXPRESSION OF INTERLEUKIN-1 CONVERTING ENZYME IN RAT SPLEEN
J. A. Craf, J. A. Patel, and S. L Chang
Department of Biology, Seton Hall University, South Orange, NJ
Interleukin-1 (IL-1 b) is generated from an inactive precursor by IL-1 converting enzyme (ICE). IL-1 exerts its
effects directly by acting on immune cells and indirectly through the neuro-endocrine regulatory system. Exposure
to ethanol has been shown to decrease the plasma level of IL-1 in human subjects (Muzes et al. 1989). IL-1
reverses the suppression of antibody response in the rats given chronic morphine (Bussiere et al. 1993). Recently,
we reported that chronic exposure to morphine attenuates IL-1 immunoreactivity in the rat hippocampus (Pate1 et
al. 1995). and preliminary data show that chronic exposure to morphine attenuates the expression of ICE in the rat
brain (Chang et al. 1995). In this study, we examined the expression of ICE in the rat spleen after chronic
exposure to morphine or ethanol. Twelve adult male Harlan Sprague-Dawley rats were implanted subcutaneously
with 2 pellets of morphine sulfate (75 mg/pellet) with or without 1 pellet of naltrexone or 2 pellets of placebo
with or without 1 pellet of naltrexone on Day 1 and 4 pellets of morphine sulfate (75 mg/pellet) with or without 1
pellet of naltrexone or 4 pellets of placebo with or without 1 pellet of naltrexone of on Day 2. On Day 5, the rats
were sacrificed, the spleens were collected, frozen on dry ice and stored at -80° until RNA isolation. Four male rats
were randomly assigned to receive a liquid Lieber-DeCarli diet or a control diet with an isocaloric amount of dextran
for 16 weeks. At the end of the treatment, the spleens were collected as above. Total RNA was isolated from each
spleen and subjected to RT-PCR procedures. Following chronic ethanol treatment, the expression of ICE in the
spleen of rats was equivalent to those given placebo. The expression of ICE in the spleen of rats given chronic
morphine was less than that of the animals given placebo. This attenuation was reversed by cotreatment with
naltrexone. These data suggest that chronic use of morphine, but not ethanol, attenuates the expression of ICE in
the spleen. Naltrexone reversibitity suggests specificity for the mu opioid receptor. Although both morphine and
ethanol alter the actions of IL-1 morphine may act through an ICE cascade mechanism, while ethanol does not.
ACKNOWLEDGMENT: Supported by NIDA 07058 to SL.
114
THE EFFECTS OF PRENATAL COCAINE EXPOSURE ON IMMUNE FUNCTIONING
B. M. Bayer*, E. M. McIntosh, T. C. Pellegrino*, K. L. Dunn*, and A. L. Riley
American University and *Georgetown University, Washington, DC
We have recently reported that pups born of dams exposed to cocaine prior to and during pregnancy displayed
decreased mitogen-induced lymphocyte proliferation in whole blood relative to pups born of pair-fed or vehicletreated dams or darns exposed to cocaine only during pregnancy (Pellegrino et al., Soc. Neurosci. Abstr. 22:1886;
1996). The presenl study extended this analysis by examining such exposure on a functional immune response,
specifically, delayed-type hypersensitivity. Adult female rats were exposed to cocaine (40 mg/kg. daily; sc) 30 days
prior to pregnancy, during Gestation Days 7 - 19 or both prior to and during pregnancy. Vehicle-injected controls
were pair-fed to the cocaine-exposed subjects. All pups were reared by untreated lactating dams. On Day 60, subjects
were injected with Primary Bovine Serum Albumin (BSA). One week later, subjects were injected with BSA into
the left or right hind paw and equivolume saline into the other paw. On the next day, the left and right paws were
measured for swelling induced by BSA (relative to saline). There was a significant reduction in swelling in female
pups born of dams receiving cocaine both prior to and during pregnancy, indicating a reduced immune reaction.
Male pups born of dams receiving cocaine (independent of when cocaine was given) displayed significantly reduced
swelling in response to BSA. These results are consistent with our prior work reporting reduced lymphocyte
proliferation and suggest that prenatal cocaine exposure compromises immune functioning.
ACKNOWLEDGMENTS:
(DAO 7293) to BMB.
Supported by grants from the MacArthur Foundation to ALR and from NIDA
ELEVATED SPLENIC CATECHOLAMINES AND IMMUNOSUPPRESSION FOLLOWING
MICROINJECTION OF MORPHINE INTO THE PAG
R. J. Weber, P. K. Mishra, J.-L. Suo, and D. Hall
Section of Medical Sciences, Department of Biomedical and Therapeutic Sciences, University
of Illinois College of Medicine at Peoria, Peoria, IL
Central nervous system mediated morphine-induced immunosuppression has been hypothesized to be due to
activation of either the hypothalamic-pituitary-adrenal (HPA) axis or the sympathetic nervous system (Weber and
Pert; Science 245:188-190, 1989). Studies in our lab, (see Sue and Weber, abstract this meeting), demonstrate that
bilateral injection of morphine into the ventral-caudal periaqueductal gray (PAG) matter of the mesencephalon
results in elevated plasma levels of adrenocorticotrophic hormone (ACTH) and corticosterone, as well as suppression
of natural killer (NK) cell activity, T cell proliferation and macrophage phagocytic activity (see Gomez-Flores and
Weber, abstract this meeting). However, the glucocorticoid antagonist, RU486, is ineffective in blocking either the
suppression of NK ceil activity or T cell proliferation. Consequently, we examined the role of the sympathetic
nervous system in the observed immunosuppression. Catecholamine levels were measured kinetically and
continuously in splenic microdialysates in freely moving Fischer 344N rats, both before and after bilateral
administration of morphine into the PAG. Our results indicate that morphine induces an increase in norepinephrine
(NE), dopamine (DA) and serotonin (5-HT) levels but does not alter 5-hydroxyindolacetic acid (5-HIAA) levels
within the spleen. The elevated levels of NE, DA and 5-HT reach a maximum level between 15 to 30 minutes after
injection of morphine, and then gradually decline. Both NE and 5-HT levels return to a basal level approximately
150 minutes after morphine injection, while DA and levels remain elevated for more than 15 hours post injection.
Our findings indicate that morphine injection into the ventral-caudal PAG, leads to a subsequent increase in
catecholamine levels within the spleen, and is correlated with changes in splenic lymphocyte function.
ACKNOWLEDGMENT:
Supposed by NIDA Grant DA/AI 08988
115
EFFECTS OF ENDOGENOUS CORTISOL LEVELS ON NATURAL KILLER CELL
ACTIVITY IN HEALTHY HUMANS
G. Bodner, A. Ho, and M. J. Kreek
Biology of Addictive Diseases Laboratory, Rockefeller University, New York, NY
Natural killer (NK) cells are large, unprimed lymphocytes which have a direct, immediate cytolytic activity against
tumor and virus infected cells. NK activity can be modulated by a variety of humoral substances including
endogenous opioids, lymphokines and hormones. Cortisol is a potent inhibitor of NK activity in vitro. However,
there are conflicting results in human studies after either exogenous cortisol administration or during physiologic
conditions in which endogenous plasma cortisol is elevated, such as in physical or emotional stress. There are no
data on the effects on NK activity in vivo of cortisol levels in a lower than normal physiologic range. The present
work examined the effects of manipulating endogenous cortisol level on NK activity in vivo. Normal healthy
volunteers were studied on separate days: baseline (n=27), metyrapone test (n=10), dexamethasone suppression test
(n=10) and ACTH stimulation test (n=8). Each subject served as his own control. NK activity and plasma cortisol
levels were measured at 9 a.m., just before the challenge drug administration. and at 10a.m, except for the
dexamethasone study in which only the 9 a.m. blood was drawn, 10h after dexamethasone administration. On the
baseline study day. a significant decrease in plasma cortisol levels was found from 9 to 10 a.m. (p<0.02) along with
a significant increase in NK activity (p<0.001). In the metyrapone test, plasma cortisol levels were significantly
reduced at 10 a.m. (p<0.005) as expected, while NK activity at the same time point was not affected and was
increased to an extent equivalenl to me baseline study day. In the dexamethasone test, plasma cortisol concentrations
were significantly decreased (p<0.0001), without any significant change in the NK activity. In the ACTH test,
plasma cortisol rose significantly at 10a.m. (p<0.02). with no change in NK activity. We conclude that plasma
cortisol alone has no significant effects on NK activity in vivo.
ACKNOWLEDGMENTS:
Supported by NIH-P50-DA05130; DA0049
NITRIC OXIDE LIBERATED BY ISOBUTYL NITRITE IS NOT RESPONSIBLE FOR THE
INHALANT’S IMMUNOTOXICITY
L. S. F. Soderberg
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences,
Little Rock, AR
Isobutyl nitrite is an inhalant abused by male homosexuals and adolescents. We have shown that inhaled isobutyl
nitrite severely depressed immunity, including macrophage function and decreased blood and spleen cellularity.
Immunosuppression by nitrite inhalants could explain epidemiological correlations of inhalant abuse with HIV
seropositivity and with Kaposi’s sarcoma. To determine if the inhalants produced their immunotoxicity by
liberating nitric oxide (NO•), we first measured NO• release from isobutyl nitrite. An immunotoxic dose of isobutyl
nitrite (900 ppm) liberated 115 ppm NO•. To determine whether NO• was responsible for the immunotoxicity, mice
were exposed to 115 ppm authentic NO• using the same exposure regimen used for isobutyl nitrite exposures (45
min/day, 14 days). At this dose, NO• did not affect peripheral blood cell counts, peritoneal macrophage tumoricidal
activity, or spleen cell mitogen responses. Inhalation exposure to authentic NO• did reduce spleen cellularity by
35% and increased spleen cell reactivity in mixed lymphocyte cultures and macrophage induction of NO• by LPS +
interferonIt is, thus, likely that immunotoxicity is mediated by direct nitration of critical mediators or by other
radicals, such as peroxynitrite.
ACKNOWLEDGMENT:
Supported by NIDA grant DA06662.
116
COCAINE AND TUMOR NECROSIS FACTORINCREASE INULIN AND HIV-1
PERMEABILITY ACROSS THE BLOOD-BRAIN BARRIER
M. Fiala, L. Zhang, S. L. Chang*, X. Gan, M. C. Graves, and T. Newton+
UCLA Medical School, Los Angeles, CA; *Seton Hall University, South Orange, NJ; + WLA
VA Hospital, Los Angeles, CA
The blood-brain barrier does not fully protect the brain from some viruses, in particular HIV-l which penetrates into
the brain early after the infection. We constructed a model of the blood-brain barrier with human brain microvascular
endothelial cells (BMVEC) and fetal astrocytes on a matrix-coated porous membrane to evaluate the effects of abused
drugs on molecular permeability and HIV-l penetration. In basal state, the permeability was modulated by the
matrix. Collagen I/fibronectin was optimal for construction of a tight model with the permeability coefficient for
14
C-inulin as low as 0.0014 (BMVEC passage 2). Cocaine (10-5M) treatment (1 hr) increased the coefficient for
14
C-inulin 1.31 to 2.17 fold and, in comparison, TNF- treatment (100 ng/ml for 4 h) increased the coefficient
two-fold. Infectious HIV-1 was placed in the upper chamber and its penetration into the lower chamber was
measured by p24 antigen assay after amplification in CEM cells. Using this assay, the unmanipulated model leaked
less than measurable amount of HIV-1 (<7 pg/ml ) for a variable interval ranging from 1 to 6 days post-infection.
Cocaine (10-6 M for 24 h) treatment of the model enhanced penetration of infectious HIV-1 an average of five-fold
(range 1.5 to 8 fold in 4 experiments) and TNF- (100 ng/ml) up to 12.8 fold (range 4 to 12.8 fold in 3
experiments). Cocaine (10-4 M to 10-8 M for 24 hr, max 10-5 M) also increased migration of monocytes across the
BBB model by 136 to 202%. In rats chronic exposure to cocaine (20 mg/kg twice a day for 19 days) significantly
increased rolling WBC flux and leukocytcendothelium adhesion (LEA). We postulate that cocaine’s effects on
increased cell migration are due to upregulation of cell adhesion molecules (CAM’s), intercellular adhesion molecule
1 (ICAM-1). vascular cell adhesion molecule 1 (VCAM-1), and platelet/endothelial cell adhesion molecule 1
(PECAM-1), on endothelial cells. CAM upregulation was shown by cell ELISA, and in the case of ICAM-1 in
vivo, by RT PCR. In cocaine-addicted subjects enrolled in a therapeutic study, i.v. cocaine administration increased
cytokine responses associated with strong Th1 responses (IFN- IL-12, and TN- ) by peripheral blood
mononuclear cells. Since in vitro secretion of inflammatory cytokines, IL-6, IL-12 and TN by monocytes was
greatly increased by their coculture with endothelial cells, the upregulation of adhesion molecules could potentiate
further the vicious circle of cocaineinduced adhesion and inflammation These results show that cocaine abuse
increases immune cell migration. which could cause vasculitis and increase the BBB permeability for cell-free HIV1.
ACKNOWLEDGMENT:
Supported by NIDA grant DA10442.
117
ORAL COMMUNICATIONS XIV
SEROTONERGIC AGENTS IN RATS TRAINED TO DISCRIMINATE ETHANOL FROM
SALINE
T. F Meert, P. De Haes, N. Aerts, and G. Clincke
Janssen Research Foundation, Belgium
Different serotonergic agents - including 5-HT-uptake inhibitors, 5-HT1A-agonists and 5-HT2- and 5-HT3-antagonists
-have been described to reduce the consumption of alcohol in a variety of animal models. In the present study, it
was evaluated whether the alcohol reducing properties of these serotonergic agents may be related to an interference
of these compounds with the discriminative stimulus properties of ethanol. Rats were trained to discriminate 1000
mg/kg ethanol from saline (IP, at 15 min prior to testing) in a two-lever food reinforced drug discrimination test
procedure. After training, generalization and antagonism trials were performed. The test compounds were given SC.
at 1 h prior to testing. The ED50 (95% confidence limits) of ethanol for stimutus generalization in the ethanol
trained rats was 933.5 (680.5-1280.6) mg/kg. Partial generalization to the ethanol cue was obtained with buspirone
and fluoxetine (80%), 8-OHDPAT, DOM, ipsapirone and TFMPP (60%), mCPP (40%) and mianserin and
fluvoxamine (20%). No generalization was measured with citalopram, paroxetine, ritanserin and ondansetron. In
terms of antagonism of the ethanol cue, a limited antagonism was only observed with fluoxetine and TFMPP (40%)
and ipsapirone (20%). These results indicate that stimulation of the 5-HT system with 5-HT1 or 5-HT2 agonists and
with some 5-HT-uptake inhibitors produces in some rats cueing properties analogous to 1000 mg/kg ethanol.
THE EFFECTS OF NALTREXONE AND OTHER OPIOID ANTAGONISTS ON ORAL
ETHANOL-REINFORCED RESPONDING IN RHESUS MONKEYS
K. L. Williams and J. H. Woods
University of Michigan, Ann Arbor, MI
These experiments examined the effects of naltrexone (NTX) and µ-, , and selective antagonists on the oralreinforced responding for ethanol. The effects of NTX were also examined in the presence of specific µ- and
antagonists. Six rhesus monkeys were given daily 3 hr opportunities to respond for ethanol (1% or 2%) or water on
independent, concurrent FR4 schedules of reinforcement. On some test days, the monkeys were pretreated with an
i.m. injection of saline or NTX at 0.032 - 0.32 mg/kg. On other test days, they received injections of the
antagonist, naltrindole at 1 - 3.2 mg/kg. the µ-irreversible antagonist, clocinnamox (CCAM) at 0.1 mg/kg, or the
-antagonist, nor-binaltorphimine (nBNI) at 3 mg/kg. CCAM and nBN1 were administered atone and in conjunction
with NTX (0.32 mg/kg). When NTX alone was tested, only 0.32 mg/kg significantly reduced ethanol, but not
water, fluid deliveries when compared to saline (SNK, p<.05). There was no effect of any NTI dose. CCAM when
tested alone, had no effect. When NTX was given in the presence of CCAM, ethanol fluid deliveries were
significantly less that that when given saline (SNK, p<0.05). When nBNI was tested alone, and when NTX was
tested in the presence of nBNI, them were significant reductions of ethanol fluid deliveries (SNK, p<0.05). The
reduction by nBNI was observed only on the day of injection. In other behavioral situations nBNI exerts kantagonist effects for more than 2 weeks in rhesus monkeys. Thus. in these experiments. NTX exerted similar
behavioral effects under circumstances where µ- and receptors were significantly altered.
ACKNOWLEDGMENT:
Supported by USPHS Grant DA-08568.
118
EXTINCTION AND REINSTATEMENT OF ORAL ETHANOL SELF-ADMINISTRATION IN
RATS
C. J. Heyser, A. Konstanturos, and G. F. Koob
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
Extinction is a useful procedure for assessing drug seeking behavior and is an important aspect for treatments of
drug abuse. However, time is known about the processes and patterns of extinction in rats trained to self-administer
ethanol. The present study was conducted to characterize the behavioral response to the removal of ethanol
(extinction) and its subsequent reinstatement (availability of ethanol restored). Male Wistar rats were trained in a
limited access paradigm (30 min/day) to respond for ethanol (10% w/v) in a two-lever free-choice condition using a
saccharin fading procedure. Responding to one lever resulted in delivery of an ethanol solution, while responding to
the other lever resulted in either delivery of water or nothing (i.e., a blank lever). Extinction was conducted for 3
days using operational extinction (responding to either lever resulted in nothing) or water substitution procedures.
Operational extinction procedures resulted in a rapid decrease in responding that was influenced by the training
condition. Water substitution significantly prolonged extinction, with a greater resistance to extinction observed in
animals trained with water when compared to those trained with a blank lever. The reinstatement of ethanol resulted
in a return to baseline levels of ethanol intake for the operational extinction groups, whereas an increase in ethanol
consumption above previous baseline levels was observed in animals receiving water substitution. These results
suggest that ethanol acts as a classic reinforcer and that partial substitution of cues associated with ethanol selfadministration (e.g., oral fluids) prolong or prevent extinction.
ACKNOWLEDGMENTS:
Supported by NIDA Grants AA08459, AA06420 and AA05403
EFFECTS OF ACUTE ETHANOL AND COCAINE ADMINISTRATION ON MOTOR
COORDINATION AND BALANCE
R. C. Taylor, S. J. Heishman, and D. J. Crouch*
Clinical Pharmacology Branch, IRP, NIDA, Baltimore,
Toxicology, University of Utah, Salt Lake City, UT
MD and *Center for Human
We investigated the effects of ethanol and cocaine on four standardized field sobriety tests (FST) that are used to
determine whether a person can safely operate a motor vehicle. Subjective and physiological effects and drug plasma
concentrations were also measured to correlate with behavioral effects. In a nonresidential study, 20 community
volunteers participated in 6 experimental sessions on separate days. At each session, subjects were administered a
single dose of either oral ethanol (0, 0.28, 0.52 g/kg) or intranasal cocaine (4, 48, 96 mg/70 kg). Ethanol increased
body sway in the Romberg Balance lest and number of misses in the Finger to Nose test. In contrast, cocaine
produced a trend toward improved performance. Cocaine decreased number of arm raises needed to maintain balance
in the One Leg Stand test (p=.08) and decreased number of misses in the Finger to Nose test compared with placebo
(p=.09). Ethanol and cocaine produced orderly dose-related increases in subjective ratings of drug strength and drug
liking. Cocaine increased blood pressure and produced a more robust heart rate increase than ethanol. Peek ethanol
plasma concentrations for low and high doses were 24 and 54 mg/dl, respectively, and occurred at time of FST
testing (15 min postdosing). Peak cocaine plasma concentrations for low and high doses were 81 and 201 ng/ml,
respectively, and occurred at 45 minpostdosing, which was at the end of FST testing. These data indicate that
ethanol impaired balance and motor coordination at doses that produced ethanol plasma concentrations below legal
intoxication limits. Cocaine did not impair FST performance at doses that significantly increased subjective and
physiological measures.
119
CHARACTERIZATION OF SIGNS OF ALCOHOL WITHDRAWAL DURING ACUTE AND
PROTRACTED PHASES
R. E. Humeniuk and J. M. White
Dept. Pharmacology, University of Adelaide, South Australia
Alcohol withdrawal in humans is most severe in the first live days, but symptoms have been reported to persist for
weeks following cessation of drinking. Most reports on the intensity and duration of alcohol withdrawal are
primarily cross-sectional, and often employ non-standardized subjective measures of withdrawal severity. This
study used an ambulatory monitor to provide objective, 24 hour recording of skin temperature, sweating and sleep
restlessness, all of which vary during alcohol withdrawal. Monitors were worn for 24 hours on days 2, 3 and 4
(acute withdrawal phase) and days 14, 42 and 70 (protracted withdrawal phase) following cessation of drinking.
Subjects were 30 patients presenting to an m-patient unit for treatment of alcohol withdrawal and were matched with
30 controls who also wore the monitor for 24 hours. Withdrawal subjects received standard clinical treatment
including monitoring of withdrawaI severity using the CIWA-Ar, with diazepam dosing when scores were greater
than 10. Data were analysed using a mixed model analysis of variance. Results showed that alcohol withdrawal
subjects experienced disruption to temperature rhythms in the acute phase, which persisted into the protracted phase.
Sweating was prominent at night during acute withdrawal, and during the day in the protracted phase, lasting for at
least 70 days. Sleep disturbance was a significant feature of withdrawal in both the acute and protracted phases, also
persisting for at least 70 days. Results from this study show that the withdrawal syndrome was most severe during
the acute phase. but that most symptoms persisted for at least 70 days following me last drink. In contrast with
many studies, the ambulatory monitor allowed alcohol withdrawal symptomatology to be measured objectively, and
also generated data on night withdrawal severity. These results provide a baseline of alcohol withdrawal severity,
which has the potential to be useful in evaluation of novel therapies.
THE USE OF CUE EXPOSURE TO OBTAIN A GOAL OF CONTROLLED DRINKING
S. Dawe, V. Rees, T. Sitharthan, R. Mattick, and N. Heather
Department of Applied Psychology, QLD, Australia and NDARC, Sydney, Australia
Mild-to-moderately dependent out patient problem drinkers (n=100 were randomly allocated to receive a standard
behavioral self management treatment (BSMT) or moderation oriented cue exposure treatment (MOCE) with a goal
of learning to drink in a controlled manner. Following assessment and, if necessary, an outpatient detoxification,
subjects received a mean of 7 (+ 3) sessions. The MOCE Involved administration of a priming dose of the subject’s
preferred alcoholic beverage (PAB; typically 1-2 standard drinks), followed by exposure to the PAB. Thus, each
session consisted of exposure to alcohol effects, the interoceptive cue, and to the visual, tactile and olfactory cues
associated with the PAB. During the MOCE sessions, subjects rated their desire to drink for its pleasant effect, their
desire to drink to take away an unpleasant feeling or mood and intoxication on a ten point scale at four minute
intervals. The BSMT consisted of self monitoring of alcohol consumption, training in drink refusal skills,
alternatives to drinking and relaxation training. Seventy eight per cent of the sample were followed up at
approximately 8 months. Preliminary analyses indicate that, irrespective of treatment condition, there were
significant decreases in total alcohol consumption, mean number of stardard drinks per day, severity of dependence
and alcohol-related problems. Further analyses will determine whether them was an additional beneficial effect of
moderation oriented cue exposure.
120
THE EFFECT OF DEPRESSION ON RETURN TO DRINKING: A PROSPECTIVE STUDY
S. F. Greenfield, R. D. Weiss, L. R. Muenz, L. M. Vagge, J. F. Kelly, and L. R. Bello
McLean Hospital, Belmont, MA and the Consolidated Department of Psychiatry, Harvard
Medical School, Boston, MA
Background: The effect of depression on return-to-drinking among individuals with alcohol depndence is
controversial. Between 1993 and 1996, we recruited 40 women and 61 men hospitalized for alcohol dependence, and
followed them monthly for one year to assess the effect of depression on subsequent drinking behavior, and to
determine whether such an effect would differ by gender. Methods: We conducted structured interviews during
hospitalization and then monthly following discharge for one year to determine whether depressive symptoms or a
current diagnosis of major depression al treatment entry affected the likelihood of return to drinking, and whether
this effect differed by gender. Using survival analysis, we examined the effect of both depressive symptoms and a
diagnosis of current major depression at treatment entry on men’s and women’s time-to-first drink and time-torelapse during the 12 months of follow-up. Results: A diagnosis of current major depression at the time of entry
into alcohol treatment was associated with shorter time-to--first drink [hazard ratio 2.03, (95% CI 1.28-3.21),
P =.003] and shorter time-to-relapse [hazard ratio 2.12, (95% CI 1.32-3.39), P =.002]. There was no significant
difference between women and men in this effect. Depressive symptoms as measured by the BDI did not predict
time-to-first drink or time-to-relapse in either women or men. Conclusions: A diagnosis of current major
depression at entry into inpatient treatment for alcohol dependence predicted shorter time-to-first drink and time-torelapse in both women and men. These results differ from earlier reports that men and women differ in the effect of
depression on return-to-drinking.
GENETIC AND ENVIRONMENTAL FACTORS SHARED BY ALCOHOL DEPENDENCE
AND ANTISOCIAL PERSONALITY
M. van den Bree, E. Johnson2, and R. Pickens1
1
Division of Intramural Research, NIDA, Baltimore,
Henry Ford Health Sciences Center, Detroit, Ml
MD and
2
Department of Psychiatry,
The twin method was used to examine whether alcohol dependence (AD) and antisocial personality disorder (ASP)
share underlying genetic and environmental factors. The sample consisted of 56 MZ and 66 DZ male twin pairs,
recruited through alcohol and drug dependence programs (Pickens et al. 1991). To increase power, quantitative
measures (symptom counts of DIS-III diagnoses of AD and ASP) rather than diagnoses were used. Because of
reports on differences in magnitudes of genetic and environmenlal influences on juvenile and adult ASP, relations
with AD were analyzed separately for the two types of ASP. Structural equation modeling approaches were used to
estimate shared genetic and shared environmental variation in alcohol dependence with juvenile and adult antisocial
behavior. While the majority of variation in AD (83%) was found to be independent of juvenile ASP, 17% was
estimated to be shared with juvenile ASP (7% additive genetic, 6% common environmental, and 4% specific
environmental). Shared variation was somewhat higher between AD and adult ASP (30%, of which 5% was of
additive genetic, 15% of common environmental, and 10% of specific environmental origin). Conclusion: juvenile
ASP and AD, and to a greater extent adult ASP and AD share genetic, but also environmental influences. These
influences are mostly smaller than genetic and environmental influences contributing to AD and ASP separately.
REFERENCES:
Pickens, R.W.; Svikis, D.S.; McGue, M.; Lykken, D.T.; Heston, L.L.; and Clayton, P.J. Heterogeneity in the
inheritance of alcoholism: A study of male and female twins. Arch Gen Psychiatry 1991 48:19-28.
121
ALCOHOL, DRUGS AND RISK OF DYING IN THE BALTIMORE ECA COHORT, 19811995
Y. D. Neumark, M. L. Van Etten, and J. C. Anthony
Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins
University, Baltimore, MD
We tend to assume that alcohol and drug dependence shorten human life and harm our chances for survival.
Nonetheless, there is surprisingly little evidence on this matter, except for cases of alcohol and heroin dependence
severe enough to have been treated. To add new evidence, we have conducted a 14-year follow-up of adult
community residents with and without these disorders - the vast majority of our cases had never sought treatment.
This community sample consisted of 3481 adult participants in the Baltimore Epidemiologic Catchment Area
study. At baseline in 1981, psychiatric diagnoses, levels of drug use and smoking, and other characteristics were
assessed via an interview that included the Diagnostic Interview Schedule (DIS). After tracing age at death from
1981-95, we used survival analyses to estimate median age at death and the relative risk of dying for persons with
and without these disorders. When compared to non-cases, DIS/DSM-III alcohol dependence cases were 40% more
likely to have died within 14 years (relative risk estimate, RR = 1.4. p=.01), and DIS cases of the other drug
disorders were 220% more likely to have died (RR=2.2, p<0.05), after statistical adjustment for age, sex, race, and
tobacco smoking. Median age at death was substantially lower for cases with DIS alcohol and drug diagnoses, as
compared to non-cases (p<0.0001). This epidemiologic study provides important quantitative estimates on the
excess risk and life-shortening effects of alcohol dependence and other drug disorders. The evidence also indicates
that information captured by the DIS diagnoses for alcohol and drug disorders help to account for 148-year mortality,
over and above information captured by assessments about level of drinking or drug use. Limitations of this study
and its implications for future research are discussed.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA07292 and DA08199, and NIMH grant MH47447.
ORAL COMMUNICATIONS XV
EFFECTS OF CHRONIC COCAINE TREATMENT ON PREPRODYNORPHIN mRNA
LEVELS AND NEST BUILDING BEHAVIORS IN PREGNANT FISCHER RATS
V. Quiñones-Jenab, R. Spangler, S. D. Schlussman, A. Ho, and M. J. Kreek
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY
Previous studies showed that preprodynorphin mRNA levels are induced persistently in the caudate putamen by
“binge” cocaine administration in male Fischer rats (Spangler et. al. 1993, 1996). To determine if similar changes
occur in pregnant females, we administrated cocaine from gestation days 8 to 17 in pregnant Fischer rats. Similarly
to male rats, preprodynorphin mRNA levels were significantly (p<0.05) increased in the caudate putamen of
pregnant rats following 10 days of “binge” cocaine administration (15mg/kg/injection/3 times/day). No changes in
the levels of preprodynorphin mRNA were observed in the thalamus, frontal cortex, and hypothalamus of cocaine
treated animals when compared to saline treatment. The alteration of preprodynorphin mRNA levels by cocaine
during pregnancy may have significant implication for the regulation of different aspects of pregnancy. Cocaine
exposed animals incorporated less material into their nests and built fewer fully completed nest than control
animals. The overall quality of the nest was significantly lower than that of control. Thus, cocaine exposure
impairs maternal nest-building behaviors in pregnant animals. Furthermore, cocaine exposed dams gained less
weight than contro1 dams. No differences in the number of pups, weight or lengths of pups was observed between
groups. The effect of cocaine in the nest building behavior could be mediated by changes in the hormonal and
neurochemical factors that regulate. the stimulation and/or maintenance of the maternal behaviors. The interaction
between the alteration of preprodynorphin mRNA levels by cocaine, other cocaine induced neurochemicand
hormonal alferations, and maternal behaviors remain to be elucidated.
Supported by NIDA grant P50-DA05130 (MJK), NIDA K05-DA0049 (MJK)
ACKNOWLEDGMENTS:
and an Altman Foundation Fellowship (VQJ).
122
FETAL COCAINE EXPOSURE AND NEUROBEHAVIORAL BIRTH OUTCOMES:
BIOLOGIC AND SELF-REPORT MEASURES
L. Singer, R. Arendt, S. Minnes, K. Farkas, M. Collin, and T. Yamashita
Case Western Reserve University School of Medicine, Cleveland, OH
In 404 infants (211 cocaine-exposed and 193 non-exposed) recruited into a longitudinal study at birth, standardized
clinical interviews, urine screens, and meconium assays were used to assess the relationship of cocaine and polydrug
exposure to infant birth and neonatal neurobehavioral outcomes using the Gardner Neurobehavioral Assessment.
Meconium assays measured cocaine and its metabolites; cocaine (COC), benzoylecgonine (BEN), M-O-H
benzoylecgonine (MOH), and cocaethylene (COCETH); and marijuana (THC). In regressions controlling for
alcohol. marijuana, and tobacco use, and GA if warranted, maternal self report of cocaine use predicted lower infant
GA, head circumference, and birth length. An interaction effect of cocaine and tobacco was found for GA. Ng THC
was related to higher GA. Higher levels of BEN were related to lower birthweight and length. Heavily exposed
infants had more attentional, movement and tone abnormalities and jitteriness than lightly or non-exposed infants.
Maternal report of tobacco use was the only self report measure to correlate with ND total score. Higher levels of
COCETH were related to more attentional abnormalities and sensory asymmetries on the NB assessment; higher
levels of BEN and MOH, to poorer head control, and higher COC and BEN to total abnormality score. These data
support a dose-response effect of in utero cocaine exposure on birth outcomes and neurobehavioral functioning.
ACKNOWLEDGMENT:
Supported by NIDA grant 07957.
SENSORY MOTOR DEVELOPMENT IN COCAINE EXPOSED INFANTS
R. Arendt, J. Angelopoulos, O. Busdiecker, J. Mascia, and L. Singer
Department of Pediatrics, Case Western Reserve University
Childrens Hospital, Cleveland, OH
and Rainbow Babies and
This longitudinal study investigated effects of prenatal cocaine exposure on infant sensory-motor development
through 12 months of age. One hundred and sixty-seven infants (74 cocaine exposed and 93 non-exposed) were
assessed using the Bayley Scales of Infant Development (BSID). Ninety-seven of the 12-month-olds had previously
been evaluated on the Movement Assessment of Infants (MAI) and the Test of Sensory Functioning of Infants
(TSFI)) at age 4 months. On the BSID, the cocaine exposed group performed significantly less well on both Mental
(103.8 vs. 107.9, p.<.05) and Psychomotor Development (100.6 vs. 105.0, p <.05) Indices. The mean scores of
both groups; however, were within the average range. Cocaine exposed infants were also more frequently rated as
behaviorally suspect. Separate MANOVA’s found significant group differences for the four-month-old subset of
infants, with cocaine exposed group performing significantly less well on both motor (MAI risk scores 8.9 vs 6.3,
p<.05) and sensory (TSFI 36.2 vs 38.6, p<.01) measures. When the groups were combined, early motor
performance, but not sensory performance, predicted 12 month MDI and PDI scores. Correlations between maternal
drug use and child outcomes showed significant relationships between prenatal cocaine exposure and 12 month
Mental (r=.21) and Psychomotor (r=.18) and Behavioral Suspect (r=.22) scores, and a relationship between cigarette
use and Mental (r=23) scores. Findings suggest that it is possible to detect early delays in sensory motor
development related to prenatal cocaine exposure.
ACKNOWLEDGMENTS:
Supported by NIDA grant R29-073 58 and R01 -07957.
123
COMPARISONS OF THE BAYLEY SCALES (BSID-I and-II) ACROSS NORMAL,
COCAINE-EXPOSED AND CNS-INJURED INFANTS
B. Z. Karmel, J. M. Gardner, and R. L. Freedland
Department of Infant Development, NYS Institute for Basic Research in Developmental
Disabilities, Staten Island, NY
The Bayley Scales of Infant Development (BSID) are widely used for research and clinical purposes in the evaluation
of both normal and risk infants. We present comparisons between initial (BSID-I) and revised (BSID-II) versions
involving 3334 tests on 1032 infants. The BSID-II was administered with additional items given from the BSID-I,
when necessary, so that both BSID-I and -II mental and motor scores could be calculated. NormaI nursery and NICU
Infants were recruited as part of research protocols for infant follow-up in which testing was scheduled every 3
months between 4 and 25 months (corrected ages). Normal term nursery infants were divided into 2 groups cocaine-exposed (CE) or not (no-CE). NICU infants were divided into 3 groups according to varying degrees of CNS
pathology as diagnosed by brainstem auditory evoked responses and cranial ultrasonography. Results indicate
inflated scores for younger infants on the BSID-I, but depressed scores for infants over a year of age on the BSID-II.
For term no-CE infants, the standard deviation of me BSID-II showed a restricted range compared to the BSID-I (12
vs 15). The BSID-I showed better differentiation across groups (Fmax 1.5-3.0) and better inter-age correlations.
especially at younger ages. The BSID-II tended to designate more normal infants as abnormal. After correction for
non-linear age trends, no prenatal care, and minority status, normal CE infants showed declining BSID-I and II
mental scores after 10 months comparable to mild/moderate CNS-injured infants, but higher than strong/severe
CNS-injured infants. We would advise caution in changing from the BSID-I to BSID-II, since both age at test and
estimates with respect to CNS pathology or neurotoxicity might differ and not be as differential.
ACKNOWLEDGMENTS:
grant R-01-HD-21784.
Supported by NIDA grants R-01-DA-06644 and K-2I-DA-00236, and NICHD
AROUSAL AND MODULATION IN E-WEEK-OLD INFANTS AS A FUNCTION OF
GESTATIONAL AGE AND PRENATAL DRUG EXPOSURE
C. D. Coles, K. A. Bard, K. A. Platzman, and M. E. Lynch
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine
We investigated homeostasis in a sample of 155 8-week-old infants as part of a longitudinal study of the differential
effects of prenatal drug exposure on full term and preterm healthy infants. Developmental outcome was assessed on
the mental (MDI) and motor (PDI) scales of the Bayley Scales of Infant Development -II. Concurrently,
physiological measures of arousal and arousal modulation were collected. (behavioral state, heart rate [HR], HR
variability, respiratory ram [RR], and RR variability). No significant differences were found on either PDI or MDI
between infants prenatally exposed to cocaine and/or alcohol and controls, nor between preterms and full terms. The
ability of infants to regulate their physiological state differed based on both gestational age and prenatal drug
exposure. The findings that prenatal exposure to drugs and gestational age at birth interact suggest that preterm
delivery may modulate me effects of prenatal drug exposure, perhaps as a protective mechanism. Neither variable,
however, directly infIuences developmental outcome suggesting that me ability to modulate arousal may be a
significant factor later in develpment.
ACKNOWLEDGMENT:
Supported by NIDA grant R-01 DA-07362.
124
SUBSTANCE MISUSE DURING VERY EARLY PREGNANCY: RELATIONSHIP TO
MATERNAL PROGNOSIS AND FETAL OUTCOME
R. A. Sherwood, J. Keating, V. Kavadia, A. Greenough, and T. J. Peters
Departments of Clinical Biochemistry and Child Health, King’s College School of Medicine
and Dentistry, Denmark Hill, London, UK
Previous studies of the prevalence of substance, including nicotine misuse during pregnancy, have screened subjects
at ante-nalal clinic attendance, and thus are likely to underestimate the prevalence of misuse around the time of
conception and implantation when much of the potential foelal damage is likely to have occurred. In the present
study, the frequency of substance misuse was determined by urine analysis in positive pregnancy test samples in a
multi-ethnic socially deprived community in South East London. Eight hundred and seven consecutive positive
pregnancy tests were analysed for substance misuse by immuno assay (positives confirmed by GC), enzymatic and
HPLC analysis, as appropriate. Positive tests for cotinine were present in 34.3%, for cannabinoids in 14.5%,
opiates in 1.3%, with multiple drug misuser in 1.1%. Pregnancy outcome was traced in 288 subjects, 36 of whom
were drug (predominantly cannabinoid) positive. There was no significant difference in the frequency of ante-partum
haemorrhage, pre-eclampsia or still birth in the drug positive and negative sub-groups. In terms of foetal outcome.
no infant in the drug positive group had congenital abnormalities and 5 minute Apgar scores were similar in both
subgroups. There was, however, a highly significant risk of prematurity (p=0.02), reduced birth weight (p=0.002)
and lower gestational age (p=0.005) in the new-born of cannabis using mothers. Maternal cigarette use was
associated with reduced birth weight (p=0.05) but not gestational age (p>0.5). This study indicates that one in six
women in South London are using drugs around the time of conception and suggests that cannabinoids, as well as
cigarette use, is associated with impaired foetal outcome.
ASSESSMENT OF DIETARY PRACTICES IN A POPULATION OF COCAINEDEPENDENT PREGNANT WOMEN
S. M. Bahl, R. Elk, S. E. Williams, J. Grabowski, and S. Graham
School of Allied Health Sciences, Department of Psychiatry and Behavioral Sciences, UTHouston Health Science Center, Houston, TX
This continuing investigation is aimed at assessing the nutritional status of cocaine-dependent pregnant women
who are participating in a comprehensive treatment program designed to decrease cocaine use and increase
compliance with the treatment regimen. Subjects are pregnant women who are 28 weeks gestation or less, with a
primary diagnosis of cocaine dependence, or opiate dependent with secondary cocaine dependence. They are
randomly assigned to one of 3 treatment groups. Patients in all 3 groups receive baseline treatment which includes:
behaviorally-based individual counseling twice a week, group therapy/ parenting skills class, HIV pre- and post-test
counseling and testing. and prenatal care once a week. Patients are required to attend the Substance Abuse parental
Clinic once a week and the Treatment Research Clinic (TRC) twice a week, providing a urine sample at each of
these visits. All subjects are also required to complete a nutrition questionnaire which includes a 24-hour dietary
recall and a food frequency at beginning and end of the study. Results indicate that a significant proportion (over 70
percent) derive their caloric needs from fast food and processed foods including hamburgers, pizza, tacos, fried
chicken, etc. Consumption of vegetables was often limited to small amounts of lettuce and tomato on sandwiches.
preliminary results reveal that a significant number of patients (greater than 25 percent) have less than adequate
levels of serum albumin, hematocrit and hemoglobin. Analysis of 24-hour dietary recalls shows deficiencies of
several essential nutrients. The need for nutritional intervention in this population cannot be overemphasized.
125
EFFECTIVENESS OF INTENSIVE SERVICES FOR SUBSTANCE-USING WOMEN WITH
COCAINE-EXPOSED INFANTS
A. Laudet, S. Magura, and * S. Whitney
National Development and Research Institutes, NYC, USA; *Administration For Children’s
Services, NY
The increase in substance abuse is making new and growing demands on the child welfare system. One initiative
aimed at addressing substance abuse in the context of clients’ family needs is New York City’s Family
Rehabilitation Program (FRP), a multi-site, comprehensive services program for families with cocaine-exposed
infants. Preliminary outcome data from an ongoing evaluation study based on 73% of the baseline sample of 253
clients indicate that at 12-month post-admission follow-up, 40% of clients are still enrolled in the program; median
length of enrollment is 10 months. Seventy-eight percent of clients report no crack/cocaine use in the past month
and 36% test negative for cocaine by hair analysis (estimated time window = 1 month). Overall, retention time in
FRP (mean= 9 months and counting) appears excellent compared with traditional outpatient drug treatmentcor
special treatment/intervention programs for pregnant or parenting women using cocaine crack. Cocaine/crack
abstinence- between 3640% of all clients- at one year follow-up is encouraging. Clients completing or still
enrolled in FRP displayed significantly lower levels of cocaine/crack use than dropouts at one year follow-up, as
measured by quantitative hair levels in a multivariate analysis. Employment and participation in school/training
increased and probation/parole status decreased between baseline and follow-up for the sample as a whole (although
there is no significant difference among FRP enrollment status categories). Thus the FRP, which offers an
integrated mix of treatment and social services where parental recovery is addressed in the context of the family’s
total needs, appears to be beneficial to substance-abusing parenting women.
ACKNOWLEDGMENT:
Supported by NIDA grant R01-DA08636.
ORAL COMMUNICATIONS XVI
DEVELOPMENTAL COMPARISON OF G-PROTEIN COUPLING TO MU-OPIATE
RECEPTORS IN THE RAT BRAIN
P. J. Little, J. Trauth, S. L. Davis, and C. M. Kuhn
Department of Pharmacology, Duke University Medical Center, Durham, NC
Changes in the ability of µ-receptors to couple with G-proteins may play an integral role in the development of
tolerance to opiates. Studies from our laboratory demonstrated that neonatal rats were relatively refractory to the
development of tolerance to morphine (Windh et al., 1995; Little et al., 1995). The purpose of the present study
was to determine the degree of G-protein coupling to µ-receptors in neonatal (10 day old) and adult rats. First, the
ability of GppNHp to regulate n-opiate binding was tested. Second, the ability of the u-selective agonist, DAMGO
to stimulate GTP S binding was determined. In thalamic membranes from adult tats, GppNHp shifted 19% of the
µ-receptors from a high to low affinity state. In contrast, GppNHp failed to shift the affinity of µ-receptors in
membranes from neonatal rats. DAMGO (0.01-10 µM) stimulated GTP- S binding in a concentration-dependent
manner in membranes from adult rats. A maximal stimulation of 55-60% was observed. In neonatal rats,
DAMGO also stimulated GTP- S binding in thalamic membranes. However, the maximal degree of stimulation
of GTP -S binding was only 26%. Using two different indices of µ-receptor coupling to G-proteins, it appears
that the coupling of µ-receptors to G-proteins is not fully functional in the neonatal thalamus. Therefore, it is
possible that adaptations which reflect changes in u-receptor coupling to G-proteins (i.e. desensitization) would
differ between neonatal and adult rats.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-02739.
126
MU AND KAPPA OPIOID-STIMULATED [ 35 S]CTP S AUTORADIOGRAPHY IN MONKEY
BRAIN
J. B. Daunais*, L. J. Sim, M. A. Nader, S. R. Childers, and L. J. Porrino
Physiology and Pharmacology, Bowman Gray Sch. Of Med., Wake Forest Univ., WinstonSalem, NC
Receptor-stimulated guanylyl 5’[ [35S]thio]triphosphate([35S]GTP S) binding was recently applied as an in vitro
autoradiographic tool to identify anatomically receptor-activated G proteins in tissue sections from a control
cynomolgus monkey. In this study, mu and kappa, opioid-stimulated [35S]GTP S binding was examined with
[3H]DAMGO and [3H]U50,488H, respectively. Receptor specificity was verified by blocking agonist-stimulated
binding with CTOP or nor-BNI. Autoradiograms indicated that mu binding was highest in the amygdala, cingulate
cortex, caudate, putamen and nucleus accumbens. Kappa1-stimulated binding was dense in the deep layers of
neocortex and periamygdaloid cortex, amygdala, nucleus accumbens, caudate, putamen and claustrum. [35S]GTP S
binding was also assessed in tissue from two rhesus monkeys: one food control and one that had self-administered
cocaine for 5 days. Both of these monkeys were part of a metabolic mapping study to determine the effects of
cocaine on cerebral metabolism using the 2[14C]deoxyglucose method. It was determined that the [14C] from this
study did not interfere with the [35S]GTP S binding study. Preliminary findings indicated that kappa1-slimulated
[ 35 S]GTP S binding appeared to be increased in cingulate cortex, caudate, putamen and nucleus accumbens
following cocaine as compared to a food control. Further studies are underway to expand on these results. These
findings demonstrate that opioid-stimulated [35S]GTP S autoradiography can be successfully applied to non-human
primate tissue. This technique is useful for identifying receptor populations that are functionally activated.
ACKNOWLEDGMENTS:
06634.
Supported by DA 07246 (JBD), DA 09085 (IJP), DA 02904 (SRC) and DA
RESOLUTION OF TWO [ 35 S]GTP- -S BINDING SITES AND THEIR RESPONSE TO
CHRONIC MORPHINE TREATMENT
S. O. Heyliger, Q. Ni, and R. B. Rothman
CPS, DIR, NIDA, NIH, Baltimore, MD
The mechanisms by which prolonged exposure to morphine leads to tolerance are not fully understood. We
investigated the effects of etorphine (ET) on [35S]GTP- -S binding in brains of rats made tolerant to morphine via
the implantation of morphine (or placebo) pellets. Binding surface analysis was used to characterize the interactions
of ET, Gpp(Np)H and GTP- -S with sites labeled by [35S]GTP- -S. Data sets were fi to one- and two-site binding
models using the nonlinear least squares curve fitting program MLAB-PC. Two binding sites were readily
resolved:
Morphine+ET
Placebo-ET
Morphine-ET
Placebo+ET
BH
2920±360
6800±540*
5000±764#
3020±290*
BL
39000±4800
46000±11400
31000±8500
6800±540*
KDH
11.4±1.2
16.7±2.2 #
8.0±0.6
5.2±0.5*
605±232#
545±213
KDL
275±50
281±58
Chronic morphine significantly increased the Bmax and Kd of high affinity binding site. ET increased [35S]GTPS binding in PLACEBO membranes via an increase in the Bmax. In contrast, ET produced a net stimulation of
[ 35 S]GTP -S in chronic MORPHINE membranes via a large decrease in the Bmax of the high affinity site. These
results suggest that G-proteins coupled to opioid receptors respond differently to etorphine-stimulation in chronic
MORPHINE membranes than PLACEBO membranes. Since proper G-protein/receptor coupling would be expected
to stimulate [35S]GTP- -S binding via an increase in Bmax values, these results suggest that opioid receptors in
chronic MORPHINE membranes are not normally coupled to G-proteins. These findings corroborate earlier studies
that reported changes in G-protein function in morphine tolerant animals.
127
THE CELLULAR MECHANISMS UNDERLYING THE PREVENTION OF MORPHINE
ANTINOCICEPTIVE TOLERANCE BY NITRIC OXIDE SYNTHASE INHIBITORS
J. Y. Xu, K. P. Hill, and J. M. Bidlack
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY
A single i.c.v. pretreatment of mice with morphine (3 nmol, -140 min) produced an acute antinociceptive tolerance
to subsequent i.c.v. morphine. When co-administered with morphine the nitric oxide synthase inhibitors, LNAME, 3-bromo-7-nitroindazole, 7-nitroindazole, and L-NMMA, blocked the development of morphine
antinociceptive tolerance. Also, the guanylyl cyclase inhibitors, LY-83,583 and methylene blue, blocked the
development of morphine tolerance. The cellular mechanisms of this prevention of tolerance development were
investigated using the human neuroblastoma SH-SY5Y cell line, differentiated with retinoic acid. Culturing cells
with 1 µM morphine for 18 hr. followed by extensive washing, produced a down regulation of µ opioid receptors,
as measured by a significant reduction in the Bmax value for the binding of the p-selective peptide [3H]DAMGO.
L-NAME (100µM) did not affect this down regulation when included along with the chronic morphine treatment.
Culturing of cells with 10 µM morphine for 18 hr, followed by extensive washing, produced a desensitization
DAMGO-induced inhibition of forskolin-stimulated adenylyl cyclase activity. This desensitization was prevented
when 100 µM L-NAME was included along with the chronic morphine treatment. D-NAME at the same
concentration did not produce this effect. These results suggest that inhibition of nitric oxide synthesis prevents the
desensitization of µ opioid inhibition of adenylyl cyclase activity, but not down regulation of µ opioid receptors
following chronic exposure of SH-SY5Y cells to morphine. Blocking desensitization of the µ opioid receptors may
be the mechanism by which L-NAME blocks the development of antinociceptive tolerance in mice.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA03742 and DA07232.
EFFECTS OF OPIOIDS ON PROTEIN KINASE C (PKC) TRANSLOCATION: EVIDENCE
FOR PKC INVOLVEMENT IN OPIOID RECEPTOR DOWNREGULATION
H. K. Kramer, J. M. Hiller, and E. J. Simon
Department of Psychiatry, New York University Medical Center, New York, NY
Prolonged exposure to opioid agonists leads to loss of opioid receptor function. Desensitization is a rapid loss of
agonist affinity and function produced by an uncoupling of the receptor from its effector system. Longer periods of
exposure produce a physical loss (downregulation) of receptor binding sites. Despite their differences, both
desensitization and downregulation appear dependent on pbosphorylation of some portion of the receptor-G-proteineffector system. The specific kinases that promote opioid receptor phosphorylation, and initiate the loss of receptor
function, have not been identified. Protein kinase C (PKC) has been shown to be involved in the phosphorylation
and desensitization of several GPCRs, suggesting that PKC activation could play a similar role in opioid receptor
regulation, and previous reports have provided some evidence for opioid receptor phosphorylation by PKC. Using
cultured SH-SY5Y neuroblastoma cells. we observed that µ-opioid agonists have a dual effect on cellular PKC
activity. PKC translocation and opioid receptor density were quantified by 3H-phorbolester and 3H-diprenorphine
binding, respectively. to washed cell membrane homogenates. Short-term exposure (3-12 hours) to morphine or
DAMGO promotes the translocation of PKC from the cytosol to the plasma membrane. Longer periods of exposure
(>12 hr.) decrease membrane-bound PKC density. During both periods, there is a decrease in membrane opioid
binding sites, the opioid antagonist, naloxone, the PKC inhibitor, chelerythrine chloride, and the L-type calcium
channel antagonist, nimodipine, all reversed agonist-mediated opioid receptor downregulation and PKC
translocation. Conversely, a 60 minute pre-exposure of cells to the phorbol ester, 12-myristrate 13-acetate (PMA),
accelerated the loss of 3H-diprenorphine binding sites by DAMGO. Interestingly, downregulation of total
diacylglycerol-sensitive PKC, by 24-hr. exposure to PMA, does not modulate DAMGO’s ability to decrease the
number of opioid binding sites. This raises the possibility that non-conventional PKC isozymes are involved in
this regulatory process.
128
ORAL COMMUNICATIONS XVII
DOES ADHD IMPACT ON THE DEVELOPMENTAL COURSE OF DRUG AND ALCOHOL
ABUSE AND DEPENDENCE?
T. E. Wilens, J. Biederman, E. Mick, S. V. Faraone, and T. Spencer
Pediatric Psychopharmacology Unit, Massachusetts General Hospital; Department of
Psychiatry, Harvard Medical School, Boston, MA
Objective: The co-occurrence of ADHD and substance use disorders (SUD) in adults has been the focus of much
clinical and scientific inquiry. In this study, we examine the effects of ADHD on the transitions from substance
abuse to dependence and between different classes of agents of abuse. Methods: An ADHD sample of 239
consecutively referred adults of both genders with a clinical diagnosis of childhood-onset and persistent DSM-III R
ADHD confirmed by structured interview were compared with 268 non-ADHD healthy adults. Cox proportional
hazard models evaluated the association between age at onset of a PSUD subtype following the earlier onset of
another. Results: ADHD was associated with a two-fold increased risk for PSUD. ADHD subjects were
significantly more likely than comparisons to transition from an alcohol use disorder to a drug use disorder
(HR=3.8) and were significantly more likely to continue to abuse substances following a period of dependence
(HR=4.9). Conclusions: ADHD is associated with a sequence of PSUD in which early alcohol use disorder
increases the risk for subsequent drug use disorder and early substance dependence increases the risk for subsequent
substance abuse. If confirmed, such developmental pathways might lead to preventive and early intervention
strategies aimed at reducing the risk for PSUD in ADHD subjects.
PSYCHIATRIC COMORBIDITY AND SUBSTANCE ABUSE TREATMENT OUTCOME IN
METHADONE MAINTENANCE PATIENTS WITH A HlSTORY OF ADHD
V. L. King, A. F. Mirsky, M. S. Kidorf, and R. K. Brooner
The Johns Hopkins University School of Medicine, Baltimore, MD
Objective: The relationship between the diagnosis of attention-deficit/hyperactivity disorder (ADHD) and drug
abuse treatment outcome was assessed over nine months in 100 new admissions to a community-based methadone
substitution treatment clinic. Method: Opioid dependent patients stabilized on methadone were evaluated for
ADHD using a modified structured interview (the ADHD module of the Diagnostic Interview Schedule: DIS).
Patients received an extensive assessment battery including the SCID I and II to assess for other psychiatric disorder.
Urine toxicology and treatment retention data were also collected. Results: Twenty one percent (21/100) met
childhood criteria for ADHD, 52% (11/21) of these had clinically meaningful current symptoms, and 19% (4/21)
met criteria for a current diagnosis. Patients with a lifetime diagnosis of ADHD were compared to patients who did
not have the diagnosis (Non-ADHD). There were significantly higher rates of current psychiatric comorbidity in the
ADHD vs. Non-ADHD groups (76% vs. 45%; p=.01) including antisocial disorder (62% vs. 25%; p<.001), and
Axis I disorders (52% vs. 19%; p=.01). Rates of anxiety disorders (29% vs. 8%; p=.06) and mood disorders (29%
vs. 13%; p=NS) were higher in the ADHD group. but did not reach significance. Fifty-two percent of those
diagnosed with ADHD were female, which is two to four times the expected rate in the community. No differences
between ADHD and Non-ADHD patients were observed for substance abuse diagnoses or urine toxicology positivity
rates for abused drugs. There was a trend for ADHD patients to be better retained in treatment over the 9 month
assessment period (90% vs. 72%; p=.08). Conclusion: Twenty-one percent of patients entering methadone
treatment had a history of ADHD, and comorbidity with antisocial personality, mood, and anxiety disorders was
common. Substance abuse diagnoses and urine toxicology results did not differentiate the groups. The high
percentage of women with a history of ADHD was unexpected. Surprisingly, patients with a history of ADHD
were retained as well or better than Non-ADHD patients over the first nine months of treatment.
129
ADHD : PARENT REPORTS AND STIMULANT TREATMENT
C. Hopfer, S. Mikulich, I. Guillemet, and T. Crowley
Addn. Res. and Trmnt. Serv. Univ. of CO Sch. of Med., Denver, CO
ADHD may contribute to substance problems in conduct-disordered (CD) adolescents. However, such
adolescents may underreport ADHD symptoms and prior stimulant treatment. Hypotheses: Parent and
child reports may differ with regard to: (1) ADHD symptoms and diagnoses and (2) stimulant treatment.
Youths with a history of stimulant treatment will have (3) more ADHD symptoms and (4) may differ in rates
of DSM-III-R cocaine, amphetamine, or methylphenidate abuse or dependence. Methods: During
treatment adolescents received the Diagnostic Interview Schedule for Children version 2.1 (DISC) and CIDISAM to assess their psychiatric and substance use. Parents of 26 boys and 4 girls (ages 13-17) were
subsequently interviewed with the ADHD section of parent DISC 2.1 and additional lifetime questions.
Results: (1) Parents report in their children significantly more ADHD symptoms (10.3 vs. 6.1; p<.0005)
and diagnoses (60% vs. 6.7%; p<.0005) and (2) significantly more stimulant treatment (p<.03) than their
children. Youths with a history of stimulant treatment did not have more (3) ADHD symptoms or (4) differ
in their rate of cocaine, amphetamine, or methylphenidate abuse or dependence. Conclusions: In
CD/SUD adolescents, parent reports indicate that adolescents may underreport ADHD symptoms and
treatment. History of stimulant treatment was unrelated to current ADHD symptom count or stimulant
abuse or dependence.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA06941 and DA09842.
SUBSTANCE ABUSE TREATMENT NEEDS AMONG ARRESTEES-JUVENILES
J. Pakes, S. Mody, and R. S. Schottenfeld
Yale University and The APT Foundation
To evaluate rates of illicit drug and alcohol use and dependence and treatment needs among juvenile arrestees, we
interviewed 127 males and 103 females 13 to 21 years, sampled at random from detention centers in 3 CT cities.
The interview included DUF questions, SCID substance use disorders sections, and questions regarding AIDS risk
behaviors, social and vocational functioning, and history of drug treatment. Utox was performed on 82/127 males
and 51/103 females. Reported use within 72 hours preceding arrest for males and females, respectively, were 67.5%,
49% for any illicit drug or alcohol; 54.8%, 27.5% for marijuana; 6.4%. 2.0% for cocaine; 1.6%, 1.0% for heroin.
Cocaine positive Utox for 18.6% of males and 7.4% of females led to estimated rates of current cocaine use of 22%
for males and 9.3% for females. THC-positive Utox was found in 82.9% of males and 40.7% of females. Based on
SCID, 35.2% of juveniles are currently dependent on alcohol or an illicit drug; 30% on marijuana, 3% on cocaine,
and 2% on heroin. Only 37% of drug dependent juveniles reported a current need for treatment, compared to 80-92%
of drug dependent adult arrestees; 7% were in treatment at the time of arrest, and 72% had no prior treatment. Drug
dependent juveniles also reported high rates of persistent depressive symptoms (55.7%). suicide attempts (20%).
school dropout (35%). and high risk sexual activity (90% are currently active; 63% had multiple partners in the past
3 months, and 54% engaged in unprotected sex). Rates of drug use are higher among juveniles 18-21 compared to
those 13 to 17, but sexual behaviors did not differ. Drug dependent juveniles report higher rates of drug or alcohol
problems in a parent compared to juveniles not dependent (OR=2.24, p<.01). High rates of psychiatric, educational,
vocational and family comorbidity and increased risk for HIV point to the need for interventions targeting these
areas. Despite the presence of family pathology, 98% of parents contacted gave permission for their children to be
interviewed, suggesting their interest in finding treatment for their children.
130
GENDER DIFFERENCES IN SUBSTANCE USE AND PSYCHIATRIC SYMPTOMS IN
SCHIZOPHRENICS WITH COCAINE ARUSE/ DEPENDENCE
D. E. Johnson, K. J. Trudeau, T. R. Kosten, and D. M. Ziedonis
Yale University School of Medicine, Substance Abuse Center, New Haven, CT
Gender differences in substance use patterns and psychiatric symptomatology in adults dually-diagnosed with
schizophrenia/schizoaffective disorder and cocaine abuse/dependence are underreported. Participants were 59 (20
females) adults who met DSM-III-R criteria for Schizophrenia or Schizoaffective Disorder and Cocaine Abuse or
Dependence who were being assessed prior to entry into an outpatient treatment study of cocaine dependence.
Results revealed no statistically significant gender differences in age (M =32.9), years of education (M=11.5), or race
(73% AA, 19% Caucasian. 3% Hispanic). With regard to psychiatric symptoms, there were no group differences on
the Hamilton Rating Scales for Depression (M=6.4) and Anxiety (M=4.3), Global Assessment of Functioning
(M=44.0), and the Brief Psychiatric Rating Scale (BPRS) total score (M =26.6). However, males scored statistically
significantly higher than females on two items of the BPRS that assess negative symptoms of schizophrenia
(Emotional Withdrawal: Males=1.5 vs. Females=1.1; Motor Retardation: Males= 1.5 vs. Females=1.1). With
regard to cocaine use patterns, there were no gender differences with regard to age of onset of use ( M =24.3 yrs), age
of onset of problem use (M =28.1 yrs), years of lifetime use (M=5.6). and recent use (M=5.5 days/month). Females
did report more intense cocaine cravings at time of assessment as measured on the 0-10 point Cocaine Craving Scale
compared to males (M=4.2 vs. 2.6, respectively). There were no group differences on the Addiction Severity Index
Severity Scores (Psychiatric M=6.5, Drug M=6.9, and Alcohol M=3.1). Results indicate the need for further
assessment of gender differences in this dually-diagnosed population, with treatment implications.
ACKNOWLEDGMENTS:
Supported by NIDA grants P50-DA09250 (TK) and K20-DA00193 (DZ)
RELATIONSHIP BETWEEN PSYCHIATRIC COMORBIDITY AND FAMILIAL INFLUENCE
FOR DRUG DEPENDENCE
R. W. Pickens, K. L. Preston, E. O. Johnson,* M. B. M. van den Bree, D. S. Svikis,** J.
Soriano, and A. DeJesus
National Institute on Drug Abuse, Baltimore, MD; *Henry Ford Health Sciences Center,
Detroit, MI; and **Johns Hopkins Medical School, Baltimore, MD
A family history interview (FHI) was conduced on 142 adults with DSM-IIIR opioid dependence (85 males, 57
females; mean age 37.5 yr). Excluded were probands with current diagnosis of alcohol dependence, major depression,
bipolar disorder, or schizophrenia. FHI reliability was estimated from reports on 39 common relatives by 7 pairs of
probands. Internal consistency was K = .84 for alcohol dependence and K = .62 for other drug dependence (excluding
nicotine). FHI validity was estimated by comparing proband FHI reports to DIS diagnoses of relatives also
participating in the study (N=33). FHI sensitivity for detecting alcohol and /or drug dependence in relatives was
96.4% (K=.89). Agreement between FHI and DIS drug diagnoses in probands was 97.8%. After exclusion, 37.2%
of probands were comorbid for an Axis I mental disorder or ASP. Opioid dependent probands with comorbid mental
disorder (N=51) were over twice as likely to have a parent with substance dependence disorders (OR=2.5, 1.2-5.1) as
was opioid dependent probands without a comorbid mental disorder (N=86). The effect was significant only for
female probands (OR=3.8, 1.0-13.6), and only for the mother being substance dependent (OR=3.9, 1.4-10.5). In
addition, probands with comorbid mental disorder were over three times more likely to have any sibling with
substance dependence (OR=3.2, 1.5-6.9), which was also significant only in female probands (OR=5.2, 1.5-18.2).
Mean density of substance dependence in siblings (for probands who had siblings) was greater for opioid dependent
probands with comorbid mental disorder (.44) than opioid dependent probands without comorbid mental disorder
(.20) (p<.001). The results suggest a relationship between psychiatric comorbidity and familial influence of
substance dependence.
131
PSYCHIATRIC COMORBIDITY IN COCAINE ABUSERS IN OUTPATIENT SETTINGS OR
A THERAPEUTIC COMMUNITY
F. R. Levin, S. M. Evans, M. Rosenthal, and H. D. Kleber
Columbia University and NY State Psychiatric Institute, New York, NY
Although researchers have noted high prevalence rates of psychiatric comorbidity among cocaine abusers seeking
treatment, there is litlle information comparing the rates of psychiatric disorders in cocaine abusers entering
therapeutic communities (TC’s) to those entering outpatient settings. Treatment-seeking cocaine abusers in both
types of treatment settings were given multiple assessments including: the SCID for DSM-IV, a SCID-like module
for adult attention-deficit hyperactivity disorder and pattern of drug use questionnaires. One-hundred and eighty-one
patients were interviewed: 158 within a TC and 123 within three outpatient settings, Individuals interviewed in the
TC were more likely to be younger (p<.001) and male (p<.001). Compared to males in outpatient settings, males
treated within the TC were mom likely to have antisocial personality disorder (ASP; 39% versus 27%). Females in
outpatient treatment were more likely to have a major depression than females in the TC (33% versus 6%). Within
the TC, 35% had substance-induced depression, 16% had adult attention-deficit hyperactivity disorder (ADHD) or
subthreshold ADHD, 15% had specific phobia and 12% had social phobia. These rates were not significantly
different than those found in the outpatient settings. Regardless of gender, cocaine abusers in the TC began using
cocaine regularly at a younger age and had more frequent days of current cocaine use. Although abuse of multiple
substances was common for both settings and for both genders, this was more so among individuals with adult
ADHD; 67% of individuals with adult ADHD had at least two substance use disorders compared to 47% of
individuals without ADHD (p<.05). These findings suggest that individuals within TC’s, as well as outpatient
settings, have a range of psychiatric disorders that may require targeted interventions.
ACKNOWLEDGMENTS:
Supposed by NIDA Grants DA-08650 and K20 DA-0021 14-01A1.
ATTENTION AND MEMORY IMPAIRMENT IN COCAINE ABUSING SCHIZOPHRENIC
PATIENTS
M. R. Serper1,2, A. Bergman3, G. Dacpano 2, and M. L. Copersino 1
1
Hofstra University, Hempstead, NY; 2 New York University School of Medicine, New York,
NY; and 3St. John’s University, Jamaica, NY
Two possible results concerning the effects of cocaine on schizophrenic (SZ) patients’ neurocognitive functioning
exist. The first is that psychostimulants may enhance prefrontal cortical D1 receptor activity and thereby improve
SZ executive functioning, memory, and altentional performance. An alternative outcome is that the cerebral
vascular constricting action of cocaine on frontal-subconical circuit functions will significantly women SZ
cognitive functioning. Numerous reports have found rCBF brain abnormalities and cognitive deficits in cocaine
abusing non-SZ individuals. In me present report. we examine executive, memory, and attentional functioning in a
group of DSM-IV cocaine abusing SZ patients (n=15), cocaine nonSZ patients (n=15) and a comparison group of
non-cocaine abusing SZ patients (n=15). We hypothesized that recent cocaine use by SZ patients would reduce SZ
hypofrontality and improve cognitive performance. Attention and concentration was measured using the CPT.
Memory was assessed using the CVLT and executive functioning was measured using the WCST and the
Trailmaking Test. Contrary to expectations, results revealed cocaine abusing SZ and cocaine-only patients
manifested significant long-term memory and attentional dysfunction. No differences were found on any
demographic variable for SZ subjects including age, years of education or chronicity of illness or executive
function tasks. These results suggest that cocaine abusing SZ patients, similar to their nonSZ cocaine abusing
counterparts manifest striking cognitive impairment on tasks requiring sustained attention, concentration and
verbal memory following acute cocaine use. Follow-up studies are needed to determine if these cognitive deficits
persist after periods of prolonged abstinence.
ACKNOWLEDGMENT: Supported by NARSAD grant - Young Investigator Award.
132
ORAL COMMUNICATIONS XVIII
METHADONE MAINTENANCE DURING PREGNANCY: DOES METHADONE DOSE
RELATE TO INFANT OUTCOME?
W. B. Kisson, D. S. Svikis, R. E. Johnson, L. M. Jansson, C. M. McCormick, and D. R.
Jasinski
The Johns Hopkins University School of Medicine, Baltimore, MD
Methadone maintenance is recommended by NIDA and CSAT as the treatment of choice for opiate dependent
pregnant women. The use of methadone during pregnancy; however, has been controversial, and the empirical
literature regarding the relationship between dose and neonatal outcomes has yielded mixed results. The present study
was a retrospective review of neonatal outcomes for 102 pregnant women maintained on methadone (15-70 mg) for
at least eight weeks prior to delivery. AU infants’ urine toxicology screens at birth were negative except for
methadone. A 2 X 2 factorial design (Newborn Nursery (NN) vs. Neonatal intensive Care Unit (NICU) and
treatment of neonates with opium drops vs. no treatment (-)) was utilized to minimize the effects of possible
confounds. The groups were not significantly different in age, race, or education. The Neonatal Abstinence Scores
(adapted) were obtained every 12 hours by nursing staff, and the NN- group received the lowest Neonatal Abstinence
Scores over the first 96 hours. Time course analyses of withdrawal scores for the first 96 hours revealed linear effect
curves for the untreated groups, with a increasing and no slope for the NN- and NICU-groups, respectively. Treated
groups displayed increasing curvilinear functions over time. Mean maternal methadone doses were significantly
higher for the NICU+ than for the NN- group. Some symptoms, especially vomiting and hyperactive more reflex,
were dose related. Division of neonates into these four patient subgroups and me assessment of individual signs of
withdrawal may be useful for interpreting methadone neonatal dose effects.
ACKNOWLEDGMENT:
Supported by NIDA grant 5T32 DA07209.
METHADONE WITHDRAWAL DURING PREGNANCY, MATERNAL AND FETAL EFFECTS
M. Jarvis*, J. Knisley**, M. Dinsmoor**, and S. Schnoll**
* Fairfield Psychiatric Clinic, Fairfield, IA and **Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA
At the end of this project, 26 pregnant opioid-dependent women have undergone supervised withdrawals using
methadone. The withdrawals were 10 days long. Fetal well-being and maternal welt-being were monitored. Three
patients left against medical advise before the taper ended, two patients were referred to methadone maintenance
because of fetal distress and one patient was delivered because of fetal distress. Twenty-three of the 26 patients
showed no fetal distress on non-stress test and biophysical profile. While the study focused primarily on the
immediate consequences of withdrawal, information about 13 of the offspring was available. One baby was delivered
preterm; the average gestational length was 39 weeks, 3 days, which is well within the normal range. One baby was
admitted to the NICU. The average weight at birth was 2797 grams, which is within the normal range. Four of the
babies were treated for withdrawal. We conclude that withdrawal during pregnancy is not an inherently unsafe
procedure, and that it can safely be used in judiciously-chosen circumstances.
133
BUPRENORPHINE MAINTENANCE IN PREGNANT OPIATE ADDICTS
F. Gabriele, S.-M. Kathrin, E. Petra, E. Harald, J. Reinhold, and G. Wolfgang
Clinical Department of General Psychiatry, University Clinic of Psychiatry, Vienna, Austria
The use and effects of methadone during pregnancy have been well investigated. Alternative substances like
morphine have been applied during pregnancies in opiate addicts and showed safety for the unborn child. Both,
methadone and morphine improved the situation for mother and child in comparison to heroin exposure but yielded
to art enhanced neonatal withdrawal syndrome. Reisinger reported, at the CPDD 1995, regarding low dose
buprenorphine maintenance in pregnant opiate addicts that withdrawal syndrome did not occur in the newborn. At
the drug addiction out-patient clinic in Vienna, seven opiate addicts with a mean duration of pregnancy of 28 weeks
were maintained on sublingual buprenorphine during pregnancy. The subjects were switched from a mean daily
dosage of 430mg slow-release morphine to a mean daily dosage of buprenorphine of 9 mg. The subjects were
inregrated in an already established program with obstetricians and pediatricians and until delivery followed on an
out-patients basis, observed 3 times a week. Supervised urine samples were examined weekly for toxicology to
exclude illegal drug consumption. Buprenorphine was well tolerated in the females. Our preliminary results
demonstrate that the newborns showed a decreazed opiate withdrawal syndrome in comparison to morphine or
methadone exposure during pregnancies.
PREGNANCY OUTCOME AND SERUM NUTRIENT LEVELS IN WOMEN CONSUMING
DRUGS AND VITAMIN AND MINERAL SUPPLEMENTS
E. M. Knight, C. H. Edwards, A. A. Johnson, U. J. Oyemade, O. J. Cole, W. L. West, O.
Westney, H. Laryea, H. James, S. Jones, L. Westney, G. Narula, and L. Kesee
Department
of Nutritional Sciences and
CDAR, Howard University, Washington, D.C.
The lack of adequate prenatal care has been associated with negative pregnancy outcomes. Substance abusing
subjects who receive little or no prenatal care have a greater risk for delivering infants weighing <2500g compared
with those who do not consume drugs and receive prenatal care. However, women receiving no prenatal care and
who abuse substances, are at a greater risk for delivering low birth weight infants. The data presented are from a
subset of African American subjects (16-35 years old) who reported drug usage before and during pregnancy. In
addition, the effects of vitamin and mineral supplement consumption on biochemical and pregnancy outcome
variables were compared among the groups who respended “yes” (YDYS) or “no” (NDNS) to drug use and to
vitamin and mineral consumption. In the YDYS and NDNS subjects, gestational age, birth length, head
circumference, and birth weight were similar among those who reported drug use before or during pregnancy. Infant
birth weights were <2500g for the YDYS women who consumed vitamin and mineral supplements before or during
pregnancy. Among the women who received prenatal care, infant birth weight was 3242.5+27.7g which reflects the
consumption of vitamin and mineral supplements. It appears that the consumption of vitamin and mineral
supplements modulated the negative effects of birth weight.
ACKNOWLEDGMENTS:
0041) NIH.
Supported by NICHD Chant P01 3 HD17104-05, ENG. and NIDA (N01DA-4-
134
PREDICTORS OF DEVELOPMENT IN PRENATALLY DRUG-EXPOSED TODDLERS
J. Howard, L. Beckwith, M. Espinosa, and R. Tyler
Department of Pediatrics, University of California, Los Angeles (UCLA), CA
Because early play skills have been associated with children’s later social development and because early cognitive
development is associated with later learning, this study examined potential predictors of play and cognitive
development in a sample of 86 children whose mothers used cocaine and other drugs during pregnancy. The sample
was studied from pregnancy through 18 months of age. The hypothesis was thal both toddler’s play behavior and
cognitive development would be predicted by maternal pre- and post-natal drug use, maternal prenatal psychological
status, birth weight, and caregiver behavior. A videotaped play assessment at 18 months was rated on the maturity
and directedness of the toddlers’ play. The Bayley Scales of Infant Development, Mental Development Index, was
also administered at 18 months. Maternal drug use was measured prenatally by the ASI, a urine toxicology screen
at delivery, and by the ASI at 6 months post-delivery. Prenatal maternal psychological status was assessed using
the Million Clinical Multiaxial Inventory. Caregiver behaviors were rated by an observer in the home using a
caregiver behavior rating scale at 6 months post-delivery. The results indicate that the prenatal ASI and the 6-month
ASI did not predict either the play or the developmental outcome at 18 months. For the other predictors, no single
measure, with the exception of the urine toxicology screen at delivery, predicted both play and developmental
outcomes. However, a cumulative risk score, combining four individual predictors--prenatal psychological status,
urine toxicology screen at delivery, birth weight, and care giving behaviors--more strongly predicted both play and
cognitive outcomes at 18 months. Thus. both biological and environmental factors predict 18 month toddler
developmental outcomes. Abstinence or decreased drug use by mothers who use drugs prenatally is not, by itself,
sufficient to promote their children’s developmental outcome.
DISTINCTIVE QUANTITATIVE EEG (QEEG) ABNORMALITIES IN CHILDREN EXPOSED
TO COCAINE IN UTERO
L. S. Prichep, S. Kowalik, K. Alper, and R. Chabot
Brain Research Laboratories, Dept. Psychiatry, New York University, Medical Center NY,
NY and Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY
In a pilot study, six male children with histories of in utero exposure to crack cocaine were evaluated using QEEG.
The QEEG obtained in these children were strikingly similar to those reported in adult cocaine dependence.
However, while the adults show an anterior predominance of abnormalities, the children show a more posterior
predominance, possibly reflecting Interactions between time of insult and specific developmenlal features. The
significant overall similarities in QEEG profiles suggest that brain dysfunction reflected in the QEEG is not a result
of transient changes in neurotransmission, but a more profound alteration persisting in the children at school age. In
an extension to this study, QFEGs in children with attention deficit hyperactivity disorder (ADHD), specific
learning disabilities (SLD), and normals (NL), [all without history of any in utero drug exposure] were compared to
the crack cocaine exposed children (CCE), matched for age, sex and IQ. Significant differences from normative
values were common in the CCE and ADHD children, less common in SLDs and rare in NLs. Several features
distinguished the CCE children from the other groups. These QEEG inrergroup distinctions suggest differences in
underlying pathophysiological etiology.
ACKNOWLEDGMENT:
Supported by NIDA grant R01-DA-07707.
135
SUBSTANCE USE RISK FACTORS: A BIRTH COHORT OF PREADOLESCENTS
M. D. Cornelius, S. L. Leech, Y. Zuo, and N. L. Day
Departments of Psychiatry, Epidemiology, and Pediatrics, University of Pittsburgh School of
Medicine, Pittsburgh, PA
This study uses a birth cohort of 577 ten-year-olds who have been followed since their second trimester in utero.
Mothers were interviewed about their drug use during pregnancy and ten years postpartum. Child variables in this
analysis were: IQ, temperament, age, race, gender, attention, activity, delinquent behavior, anxiety, depression, selfesteem, and in utero exposure to substances. Current maternal tobacco, marijuana, and alcohol use was also
included. Most of the children came from single parent homes of low socioeconomic status, and many of their
mothers used substances prenatally and postpartum. Their mean age was 10.5 years; 53% were African-American.
Regular substance use was rare among these children. However, 41% had experimented with alcohol and 6.2%
with tobacco. Also, 23% had friends who smoked tobacco, drank alcohol (14%), and used marijuana (4%). The
outcome variable was dichotomized as, use and no-use. The use group (5.5%) was made up of children who used
and/or whose friends used any substances. The no-use group (45%) was those who did not use and whose friends
did not use any substances. Bivariate analyses between outcome and each exploratory variable determined which
variables were to be considered in the logistic regression model. The final model showed that children who were
male, had a history of theft, were prenatally exposed to tobacco, were Caucasian race. and had lower self-esteem were
significantly more likely to be in the use group. This is the first study to show that prenatal exposure to a
substance, in this case. tobacco, is a significant risk factor for early substance experimentation among
preadolescents.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-03874 and NIAAA grant AA-06666
136
POSTER SESSION I
AMLODIPINE TREATMENT OF COCAINE DEPENDENCE
R. Malcolm, K. T. Brady, and J. Moore
Medical University of South Carolina, Charleston, SC
Preclinical animal studies support the hypothesis that the reinforcing effects of cocaine are reduced by isradipine and
nifedipine. In one human laboratory study, pretreating subjects with nifedipine decreased the subjective euphoric
properties of IV administered cocaine. Amlodipine, a dihydropyridine type calcium channel antagonist and an
analogue of isadipine and nifedipine, was administered in an open label trial to 16 mate and 3 female cocainedependent individuals aged 21-47 in doses of 5r mg/day of amlodipine for subjects <70 kg and 10 mg/day in subjects
>70 kg. All subjects repotted having used over $1000 of crack in the past three months. Seventy Percent of
subjects had positive urine drug screens for cocaine at the time of enrollment in the study. Flushing, headache,
fatigue, nocturia, and lightheadedness were reported by four subjects. At 3-4 weeks on medication the proportion of
positive urine drug screens had dropped to 50%. Subjects reported reduced cocaine craving, improved concentration,
and clearer thinking. Calcium channel antagonists may act to improve the cardiovascular blood flow in cocaine
addicts or act by some yet-undelineated neural mechanism.
ACKNOWLEDGMENTS:
Labs, Inc.
Supported by NIDA Grant DA-08355 and Pharmaceuticals Supplied by Pfizer
EFFECTS OF COCAINE PRIOR TO AND DURING BUPROPION MAINTENANCE IN
COCAINE ABUSERS
A. K. Singha, A. Oliveto, E. McCance, I. Petrakis*, S. Stine*, and T. R. Kosten
Yale University and *VA Connecticut Healthcare System, West Haven, CT
This pilot study examined the self-reported effects of cocaine prior to and during bupropion (BPP) maintenance in
nonopioid-dependent cocaine abusers. Prior to BPP maintenance, subjects (n=6) underwent an experimental session
during which each of the following was adminstered intranasally 90 minutes apart in ascending order cocaine
placebo, cocaine at 50 mg/70 kg. and cocaine at 100 mg/70 kg. Subjects were then inducted onto BPP over a two
week period. At both an intermediate (150 mg) and maximal (300 mg) BPP maintenance dose, participants
underwent an experimental session during which the effects of cocaine (0, 50, 100 mg/70 kg) were reassessed.
Assessments prior to and after each drug administration included the addiction research center inventory (ARCI),
adjective ratings (ADJ), visual analog scales (VAS), and profile of mood states (PCMS). Results were that cocaineinduced “desire for cocaine” and “rush” ratings on the VAS appeared to be lower during BPP maintenance relative to
no BPP. Also, cocaine-induced increases in POMS ratings of “friendliness”, “arousal”, and “vigor” appeared to be
lower during BPP maintenance compared to no BPP. These preliminary findings suggest that chronic administration
of BPP may reduce several positive subjective effects of cocaine in human subjects.
ACKNOWLEDGMENTS:
Supported by National Institute on Drug Abuse Grants # DAO4060, DA07238,
DA09250, and K20DA00216.
137
EFFECT OF PHENYTOIN ON COCAINE SELF-ADMINISTRATION IN HUMANS
M. Sofuoglu1 , R. L. Bliss, P. R. Pentel2 , and D. K. Hatsukami
Departments of Psychiatry, Pharmacology 1 and Medicine 2 , University of Minnesota,
Minneapolis, MN
In a recent double-blind, placebo-controlleded study, phenytoin treatment has been shown to decrease cocaine use in
outpatient settings. The goal of this pilot study was to determine the effects of phenytoin on smoked cocaine-base
self-administration, using our laboratory self-administration model. Self-administration session consists of work and
cocaine-option periods. During the work period, subjects had the option to earn up to five tokens, worth $5 each,
by doing simple arithmetic problems. In the cocaine option period, subjects were given the opportunity to exchange
the tokens that they had earned earlier for doses of 0.4 mg/kg cocaine. A total of 12 patients were randomized, 6 to
phenytoin and 6 to placebo treatment group. There were two phases in this 10-day inpatient study. During Phase 1,
subjects underwent a cocaine self-administration session and those who administer all doses of cocaine while
medication free were moved on to Phase 2. Subjects were randomized at the start of Phase 2, Day 4. Those assigned
to phenytoin treatment received an oral loading dose (20 mg/kg) aimed at achieving plasma phenytoin
concentrations of 10-20 mg/L. During Phase 2, subjects had self-administration sessions on Days 5, 7 and 9.
Eighteen subjects enrolled in the study, 12 subjects were randomized, 6 to placebo and 6 to phenytoin treatment.
Oral phenytoin loading was generally well tolerated, most of the side effects were short-lived. There were no
differences between the two treatment groups in the number of tokens exchanged for cocaine. The subjective and
the cardiovascular response to the sample dose of cocaine on Day 5 were comparable in the two treatment groups.
This preliminary analysis of our study does not support efficacy of phenytoin in reducing cocaine self
administration in a laboratory setting.
ACKNOWLEDGMENT:
Supported by NIH grants P-50 DA09259 and MO1-RR00400.
BENZTROPINE PRETREATMENT MODIFIES THE PROFILE OF COCAINE’S EFFECTS IN
MALE VOLUNTEERS
S. E. Lukas, M. Erös-Sarnyai, S. L. Daniels, V. Rogers, and J. Wines
Clinical Neuropsychopharmacology Laboratory, McLean Hospital/Harvard Medical School,
Belmont, MA
In the search for new and improved pharmacotherapies for cocaine abuse, we studied a relatively non-toxic drug that
inhibits the dopamine transporter with the aim of finding a “substitute” for cocaine that is not abused. Six healthy,
male occasional cocaine users provided informed consent and volunteered to participate in this study. Each subject
served as his own control and was tested under double-blind conditions on four separate experimental sessions during
which they received either placebo, 1.0 or 2.0 mg of benztropine two hours before an intranasal dose of lactose
(placebo) or cocaine (0.9 mg/kg). Studies were separated by at least one week. Dependent variables were measured
for two hours after cocaine and included: heart rate; the Addiction Research Center Inventory; visual analog scales;
subjective reports of drug detection, euphoria and dysphoria; and plasma cocaine and metabolite levels. Other than
slight tachycardia benztropine produced few effects of its own. Compared to placebo pretreatment, benztropine
slightly increased the intensity of the cocaine-induced “high”, attenuated the “crash”, increased the number of
euphoric events, and prolonged the duration of cocaine’s effects on heart rate in the absence of any changes in the
kinetics of either cocaine or its metabolites. These data suggest that although it is unlikely that benztropine alone
will be a useful medication to treat cocaine abuse, the strategy of using a drug that enhances some of cocaine’s
effects may he appealing because it could actually reduce the number of times cocaine is used during a binge.
ACKNOWLEDGMENTS:
NIDA Grants DA03994 and DA00115.
138
DEVELOPMENT OF A SUBJECTIVE RATING SCALE SENSITIVE TO ACUTE COCAINE
ADMINISTRATION
M. E. Di Marino, K. A. Haberny, L. J. Felch, S. L. Walsh, K. L. Preston, and G. E.
Bigelow
Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine,
Baltimore, MD
The epidemic of cocaine abuse has generated much research with the goal of understanding cocaine effects and
finding effective treatments for cocaine addiction. Various instruments have been used to measure subjective effects
produced by cocaine administration in the laboratory. This study evaluated responses to a list of subject-rated
descriptors presented to inpatient volunteers (N=76) following intravenous cocaine (0 vs 40-50 mg) injections.
Intravenous cocaine significantly altered scores of 21 adjectives, which were combined to form the Subjective
Adjective Rating Scale. Sensitivity and specificity of this scale were assessed by examining the effects of
psychoactive drugs administered concurrently with cocaine injections. Scale scores were not significantly altered by
pretreatment with methadone, bromocriptine, fluoxetine, mazindol, buprenorphine, selegiline, or naltrexone.
Compared to placebo, oral cocaine significantly lowered Subjective Adjective Rating Scale scores during i.v.
cocaine administration. The adjective checklist described in this study is a sensitive and specific measure of
subjective intravenous cocaine effects in humans under laboratory conditions.
ACKNOWLEDGMENTS:
K05DA 00050.
Supported by USPHS/NIH/NIDA grants R01DA 05196, T32DA 07209, and
COCAINE-SEEKING BEHAVIOR AND DOPAMINE OVERFLOW IN THE AMYCDALA
DURING COCAINE WITHDRAWAL
L. E. O’Dell, L. T. L. Tran-Nguyen, R. A. Fuchs, G. P. Coffey, D. A. Baker, and J. L.
Neisewander
Department of Psychology, Arizona State University, Tempe, AZ
Cocaine and cocaine-paired cues elicit craving in humans and reinstate cocaine-seeking behavior (CSB; i.e., lever
pressing in the absence of cocaine) in rats. It has been suggested that craving and CSB may be. mediated by changes
in dopamine (DA) neurotransmission that occur during the course of withdrawal. To examine this hypothesis,
experimental rats received 14 3-hr daily sessions of cocaine self-administration training and control rats received
yoked administration of saline. DA overflow in the amygdala was assessed following a 1-day (1D), 1-week (1W) or
1-month (1M) withdrawal period during 1) baseline (BL), 2) extinction of CSB and 3) cocaine reinstatement of
CSB. BL measures revealed enhanced DA overflow in the amygdala in the 1M group relative to the control and 1W
groups. During extinction, the pattern of changes in CSB did not correspond to changes in DA overflow. CSB was
exhibited by the 1W and 1M groups, but DA overflow was only enhanced above BL in the 1M group. In contrast,
during cocaine reinstatement, the pattern of changes across these variables was similar. CSB and DA overflow were
enhanced in all cocaine groups and both effects were greater in the 1M group relative to the 1D and 1W groups.
These findings indicate that CSB and DA overflow in the amygdala are enhanced following longer withdrawal
periods.
ACKNOWLEDGMENTS:
Supported by DA07730, DA11064, MH19547, and HHMI.
139
PREDICTIVE VALIDITY OF THE EXTINCTION/REINSTATEMENT MODEL OF DRUG
CRAVING
R. A. Fuchs, Ly T. L. Tran-Nguyen, S. E. Specio, R. S. GrofJ and J. L. Neisewander
Department of Psychology, Arizona State University, Tempe, AZ
The effects of chronic desmethylimipramine (DMI) treatment on measures of incentive motivation for cocaine were
assessed in order to investigate the predictive validity of the extinction/reinstatement model of drug craving. Rats
were trained to respond for cocaine infusions (0.75 mg/kg/0.1 ml) or received saline infusions during daily 3-hr
sessions. A light and tone were presented with the infusions. Following self-administration training, each group
received daily injections of either saline or DMI (10 mg/kg, IP) for 21 days of withdrawal from the selfadministration regimen. On days 12-21 of withdrawal, rats were allowed to respond in the absence of cocaine
reinforcement (extinction phase). After reaching an extinction criterion of no responses for one hr, the cocainepaired stimuli were presented rcpeatedly to reinstate responding (reinstatement phase). In controls, DMI treatment
did not alter the responding during either test phase but increased the response latency during the extinction phase.
In contrast, DMI treatment in the cocaine group decreased responding and increased the response latency during both
test phases, and decreased the extinction latency during the extinction phase. Overall the effects of DMI were
consistent with a reduction of incentive motivation for cocaine, lending support for the predictive validity of the
extinction/reinstatement model of drug craving.
ACKNOWLEDGMENTS:
Supported by DA07730, DA11064, and HHMI.
EFFECTS OF PHENTERMINE AND FENFLURAMINE ON REACQUISITION OF COCAINE
SELF-ADMINISTRATION IN RATS
P. Munzar, S. R. Goldberg, C. W. Schindler, R. B. Rothman, and M. Shoaib
Addiction Research Center, Division of Intramural Research, National Institute on Drug
Abuse, NIH, Baltimore, MD
Clinical studies indicate that the administration of the dopaminergic agent phentermine (PHEN) together with the
serotonergic agent fenfluramine (FEN) may be useful in the treatment of cocaine addiction. The aim of this study
was to examine the effects of PHEN and FEN pretreatment on cocaine-seeking behaviour. Under 12-hr unlimited
access conditions, four groups of male Sprague-Dawley rats (n = 5-6 per group) were trained to self-administer i.v.
cocaine (0.66 mg/kg/infusion) under an FR-5 schedule of reinforcement. Once cocaine self-administration was
stable, the behaviour was extinguished by replacing cocaine with saline. Following five days of extinction, cocaine
was re-introduced until complete reinstatement of responding was achieved. Since the first day of extinction, four
groups of rats received two injections a day of either PHEN (2.0 mg/kg IP), FEN (2.0 mg/kg IP), a mixture of
both drugs (PHEN + FEN, 2.0 mg/kg of each IP) or saline (SAL, 1 ml/kg IP). administered 3 hours before and 3
hours after each session, until the end of the experiment. No significant changes of cocaine self-admtinistration
responding were observed in the SAL or PHEN groups. However, rats pretreated with FEN or the mixture (PHEN
+ FEN) showed delayed rates of requisition; the changes were statistically significant (p<0.05) only for the FEN
group. The present findings suggest that FEN is probably an effective substance in the PHEN-FEN mixture and
support the hypothesis that serotonin dysfunction may contribute to craving elicited during withdrawal from
cocaine.
ACKNOWLEDGMENT:
Supported by NIDA/DIR.
140
EFFECTS OF PHENTERMINE IN RHESUS MONKEYS PERFORMING UNDER
PROGRESSIVE-RATIO SCHEDULES OF COCAINE AND FOOD DELIVERY
M. G. LeSage, D. Stafford, and J. R. Glowa
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center in
Shreveport, Shreveport, LA
Recent experiments employing multiple fixed-ratio (FR) schedules of cocaine and food delivery have shown that
phentermine can selectively reduce cocaine-maintained responding in rhesus monkeys at doses that have no effect on
food-maintained responding. The purpose of the present experiment was to examine further phentermine’s effects
on cocaine- and food-maintained behavior. Phentermine (0.1 to 5.6 mg/kg) was administered (i.m.) to groups of
rhesus monkeys performing under progressive-ratio (PR) schedules of cocaine and food delivery that arranged a unit
dose of cocaine and a magnitude of food delivery that were comparable in terms of their relative reinforcing efficacy
(i.e., maintained similar breaking points). Two variants of the PR schedule, one that arranged one trial per ratio
and another that arranged five trials per ratio, were used. Phentermine produced dose-dependent decreases in the
number of reinforces earned under both variants of the cocaine and food PR schedules. In contrast to phentermine’s
dramatic and selective disruption of cocaine self-administration in prior studies using multiple FR schedules of
cocaine and food delivery, only a slight behaviorally-selective reduction in cocaine self-administration was observed
under the 1-trial PR, and no selective reduction in cocaine self-administration was observed under the 5-trial PR.
This finding suggests that phentermine may produce less behaviorally-selective effects when the reinforcing efficacy
of cocaine and food are comparable. Thus, taken together with findings from prior studies, the present results
suggest that the relative reinforcing efficacy of cocaine and food may be a determinant of phentermine’s
behaviorally-selective effects on cocaine self-administration.
ACKNOWLEDGMENT:
Investigator).
Supported by NIDA grant RO1 DA09820-01 (J. R. Glowa, Principal
STRESS RESPONSE AND STRESS-INDUCED CRAVING IN COCAINE ABUSERS
R. Sinha, D. Catapano, and S. O’Malley
Department of Psychiatry, Yale University School of Medicine, New Haven, CT
Stressful situations and negative emotional states are commonly cited as reasons for drug use and relapse among
substance abusers. Two pilot studies were conducted to examine the association between stressful situations and
craving for cocaine among cocaine abusers. In the first study, we examined the effects of a speech stressor task and a
personalized stressful imagery task on self-reported craving and emotional arousal in 10 cocaine abusers. Both
stressors led to significant decreases in neutral and joyful feelings as compared to baseline ratings. The stressful
imagery condition led 10 significant increases in sadness and anger ratings and led to significant increases in cocaine
craving (p<.01). Thus, a personal stressful imagery task provides a useful method for examining the relationship
between stress and cocaine craving. In a second ongoing study, we are examining the effects of stressful imagery as
compared to neutral imagery on cocaine craving, emotional arousal, subjective anxiety and physiological responses.
The stressful imagery task produced significant increases in heart rate. pulse transit time along with increases in
cocaine craving and subjective anxiety ratings. These findings are consistent with preclinical data showing a
significant association between acute behavioral stress and cocaine use.
ACKNOWLEDGMENTS:
Supported in part by P50-DA09241 and K02-AA00171
141
COCAINE CUE-REACTIVITY/CUE-INDUCED CRAVING IN A TRIAL OF FLUOXETINE
FOR COCAINE DEPENDENCE
D. S. Harris, S. L. Batki, and S. P. Berger
UCSF and San Francisco General Hospital
Preclinical data suggest a link between stress reactivity, as measured by corticosteroid response, and cocaine self
administration in rats. Serotonergic systems appear to modulate cue-reactivity for cocaine, a factor implicated in
relapse to cocaine use. Twenty-two subjects in a double-blind, placebo-controlled trial of fluoxetine (flx) treatment
for cocaine dependence participated in 2 cue reactivity sessions, 1 in the placebo run-in week and the other after
approximately 5 weeks of flx or placebo treatment. The aim was to explore whether treatment with flx, a serotonin
reuptake inhibitor, is associated with a decrease in rise in subjective cue reactivity and cortisol response to cocaine
cues. Results: The effects of chronic fix pretreatment on cocaine cue reactivity were complex. Comparing cue
reactivity sessions before and after medication, flx significantly increased a subjective measure of cocaine cue
reactivity (likely to use). This finding is consistent with an earlier study (Satel et al. Am J. Psychiatry 152:778-83,
1995) in which a serotonin depletion diet attenuated cocaine cue reactivity. Other subjective responses were not
significantly different between groups. In contrast, fix significantly attenuated cue induced activation of the
adrenocortical (HPA) axis. These findings suggest that cue induced craving is not dependent on HPA activation.
Any beneficial effects flx may have in the treatment of cocaine dependence are probably not attributable to
suppression of cue-induced craving. Further study is needed to determine whether fluoxetine attenuates activation of
the adrenocortical axis under other conditions (e.g., stress). However, given the literature linking the HPA axis
with addiction and such mood states as anxiety and depression, flx’s ability to attenuate HPA activation could have
therapeutic implications.
ACKNOWLEDGMENTS:
Supported by NIDA Grants No. P50-DA09253-01 and T32-DA07250.
A NICOTINE ANTAGONIST, MECAMYLAMINE, REDUCES CONDITIONED COCAINE
CRAVING IN COCAINE-DEPENDENT SUBJECTS
M. S. Reid, J. Mickalian, K. Delucchi, and S. P. Berger
Psychiatry Services, SFVAMC, San Francisco, CA
Epidemiological studies have documented that cigarette smoking is significantly greater in cocaine dependent
individuals. In a recent study, we demonstrated that nicotine (two 22 mg/day Nicoderm patches) enhanced cueinduced cocaine craving in cocaine dependent subjects suggesting that nicotine may have a direct
psychopharmacological effect on conditioned cocaine craving. In the present study, cocaine-dependent, cigarette
smoker patients were tested in a counterbalanced, double blind, placebo controlled design for the effects of a nicotine
antagonist, mecamylamine (2.5 mg, p.o.). on cue-induced cocaine craving. Measures of cue-reactivity included self
reported visual analog scales for cocaine craving, nicotine withdrawal and mood as well as physiological measures
of skin conductance, skin temperature and heart rate. Subject were also asked to rate which test day they had the
most craving. Cocaine conditioned cues included a 5 min video and the handling of crack cocaine paraphernalia
Neutral cue controls were also performed. Cue-induced cocaine craving was significantly reduced by mecamylamine.
In addition, more patients reported higher levels of craving during the placebo (16) versus mecamylamine (5) test
day. Mecamylamine treatment also produced a mild reduction in cue-induced increases in skin conductance, while
the skin temperature and heart rate responses were not affected. Analyses of the medication effects prior to cue
testing indicated that the desire to smoke was also reduced by mecamylamine. These findings show that
mecamylamine can reduce conditioned cocaine craving and suggest that this medication may be of therapeutic value
in cocaine abuse treatment.
ACKNOWLEDGMENTS:
Supported by NIDA: 1R18DA06097 and NIDA/VA: YOIDA50038-00
142
EFFECTS OF BUTORPHANOL ON CUE-ELICITED COCAINE CRAVING
C. Hart, J. D. Mickalian, K. Delucchi, S. M. Hall, and S. P. Berger
University or California, San Francisco and San Francisco VA Medical Center
There is considerable human laboratory evidence which has demonstrated that cocaine-dependent subjects, when reexposed to environmental cues previously associated with cocaine use. exhibit a conditioned response (i.e., increased
autonomic arousal and cocaine craving). An increase in CNS dopaminergic activity in response to cocaine cues is
thought to underlie this phenomenon. Consistent with this hypothesis, our group recently demonstrated that the
dopamine (DA) antagonist haloperidol blocked increases in plasma homovanillic acid, anxiety, and craving resulting
from cocaine-cue exposure. However, haloperidol can produce a number of side effects, including drowsiness.
parkinsonism, tardive dyskinesia and Neuroleptic Malignant Syndrome. Consequently, patient non-compliance is
likely to be high with long-term use. This fact has been the impetus to search for DA modulating agents with fewer
side effects. Presumably, drugs that indirectly interfere with DA release should blunt cue-induced DA elevations and
craving without the side effects associated with complete antagonism of postsynaptic receptors. The opiate kappa
agonist butorphanol seems well-suited in this regard. Data from several experiments indicate that opiate kappa
agonists effectively attenuate CNS dopamine activity. We examined the effects of acute butorphanol (1 mg)
administration on cue-induced cocaine craving in cocaine-dependent individuals. Our findings suggest that the
conditioned cocaine response is dissociable and complex. Notably, butorphanol attenuated cue-induced euphoria.
anxiety, and nervousness. without affecting craving or the desire to use now. Even though butorphanol was without
affect on craving, the fact that are-induced euphoria was decreased suggests it may still be clinically useful. The
effects of butorphanol on cocaine euphoria warrants further study.
ACKNOWLEDGMENTS:
Supported by NIDA T32 DA07250 and NIDA/VA contract YOIDA 50038-00
RELATIVE SENSITIVITY OF A LABORATORY CUE REACTIVITY PARADIGM
A. Shafer, P. S. Bordnick, D. Simms, R. Chen, V. Oderinde, B. Johnson, and J. Schmitz
Clinical Laboratory and Experimental Research, University of Texas - Houston
Cue-reactivity has been studied in the laboratory with various substances including: cocaine, opiates, alcohol, and
nicotine. The most studied cue modalities include: manual, visual, and audio. Thirty cocaine dependent subjects
received the following cue types in a randomized fashion: 1) cocaine related, 2) neutral, and 3) arousal. Within
each of the cue them were three cue-modalities which were presented in the following order: 1) audio, 2) visual, and
3) manual. Physiological measures consisting of skin conductance, temperature, and pulse was assessed
continuously during the laboratory sessions. A repeated measures ANOVA was used to compare mean change
response on physiological measures to cue-modality. We found that for cue-response, manual cues produced greater
changes in all of the measures compared to audio and visual cues (p=0.001). Pulse was found to be relatively
insensitive compared to skin conductance and temperature for the assessment of physiological responses. Our
results demonstrate that the manual cue modality is the most sensitive measure for assessing craving in the cuereactivity paradigm.
ACKNOWLEDGMENT:
Supported by NIAAA Grant RO1 AA1052201.
143
CUE REACTIVITY AND SPECIFICITY
R. Chen, P. S. Bordnick, D. Simms, B. Johnson, and J. Schmitz
Clinical Laboratory and Experimental Research, University of Texas - Houston, TX
Cue reactivity has been studied extensively in cocaine dependent subjects. The relationship between cocaine craving
and cocaine stimuli remains unclear. The objective of this investigation was to examine the specificity of a cuereactivity paradigm as a measure of cocaine craving. Thirty treatment seeking cocaine dependent subjects were
(
exposed to three types of cues cocaine-related,
arousal, and neutral) in a randomized order. Change in subjective
measures during the study and mood assessments were conducted. Physiological responses were measured
cotinuously during the laboratory session. We found significant differences in craving responses between cocaine
and neutral cues, and the cocaine and arousal cues; with the cocaine cues always producing the higher craving
ratings. In contrast, both cocaine and arousal were associated with significant changes in general mood ratings. but
there were no differences found between cocaine and arousal cues. We conclude that cocaine cues are specific to
cocaine related stimuli, and are not simply a measure of general mood or arousal. Our findings suggests that the
conditioned cue paradigm can be utilized as a relatively specific indicator of cocaine craving.
ACKNOWLEDGMENT:
Supported by NIAAA Grant RO1 AA1052201.
ALTERNATE
REINFORCER
MODULATION
FOLLOWING COCAINE STIMULI EXPOSURE
OF COCAINE-SEEKING
BEHAVIOR
S. A. Dudish-Paulsen1 , M. A. Hammer 1 , P. R. Pentel2 , and D. K. Hatsukami1
1
Department of Psychiatry, University of Minnesota; 2 Departments of Medicine and
Pharmacology, University of Minnesota; and Hennepin County Medical Center, Minneapolis,
MN
This study was designed to examine the effect of an alternative reinforcer on cocaine-seeking behavior following
exposure to cocaine-related stimuli. Six healthy females and males who reported using crack cocaine at least two
times a week for 6 months, and at least 1 g of crack in a 4-6 hr period, were recruited for an inpatient study. Three
experimental sessions were held on separate days, during which subjects were exposed to cocaine-related external
stimuli in a within-subjects design. The stimuli comprised a 5 min video of scenes showing cocaine use, followed
by handling cocaine-related paraphernalia. After exposure to the stimuli, subjects worked on concurrently-available
fixed-ratio tasks either for tokens that could be exchanged for money ($0.25, $5, or $15) or for tokens that could be
exchanged for deliveries of cocaine (0.4 mg/kg). The order of exposure to money token value was counterbalanced
across subjects, with each subject exposed to one money token value within a session and all money token values
across the three experimental sessions. Any combination of a total of 7 tokens could be earned each day and tokens
earned for cocaine deliveries were administered immediately following the work period. The results showed that
craving for cocaine increased significantly from baseline rates following stimuli exposure. However, significantly
fewer cocaine tokens were earned when the token value was either $5 or $15, compared to $0.25. This laboratory
model may prove useful in examining the effect of treatment medications on craving and cocaine-seeking behavior,
ACKNOWLEDGMENTS:
Supported by NIDA grants DA05844 and DA07097.
144
CRAVING AND WITHDRAWAL SYMPTOMS DURING AN AMBULATORY COCAINE
DETOXIFICATION PROGRAM
S. Day, P. S. Bordnick, J. Schmitz, and A. Stotts
University of Texas - Houston
The phenomenon of cocaine craving is discussed extensively in the literature, and is believed to be a withdrawal
symptom related to relapse/drug use. The exact role of craving during initial cessation of cocaine in currently
dependent subjects is unknown. This ongoing investigation is designed to examine daily craving, withdrawal
symptoms, and drug use in subjects participating in an outpatient detox program. It is hypothesized that craving
intensity will decrease as the number of days of abstinence increases. Subjects attend the detox program daily for
10 days or until they submit 5 consecutive cocaine-free urine samples. Subjects complete self-report instruments
assessing: craving, withdrawal symptoms, substance use, and identify events/triggers surrounding craving and/or
drug use episodes. Urine samples are also collected each day to verify abstinence. To date, the majority of subjects
(78%) who started the detox program have successfully abstained from cocaine use for 5 consecutive days.
Preliminary analysis suggests an association between craving intensity and number of days abstinent. The most
frequently reported withdrawal symptoms included: fatigue, anxiety, and agitation. This presentation will report on
multivariate analyses comparing craving and withdrawal symptoms between drug users versus non-users, as well as
compare cocaine only and cocaine/depression subjects during the detox program.
ACKNOWLEDGMENTS:
Supported by NIDA Grants DA-09262-02 and T32 DA-07247.
VALIDITY AND UTILITY OF CRAVING ASSESSMENTS IN COCAINE TREATMENT
E. G. Singleton, K. L. Preston*, L. Covi*, S. Ruckel**, A. Umbrichl-Schneiter*, and
M. L. Stitzer
Johns Hopkins University, *Intramural Research Program, National Institute on Drug Abuse,
National Institutes of Health, and **Nova Research Company, Baltimore, MD
This study evaluated several measures of cocaine craving including visual analogues (Multiple VAS); an one-item,
likert-type scale: the multidimensional, 45-item, Cocaine Craving Questionnaire (CCQ-Now); and a new, 14-item
brief version of the CCQ-Now. Participants were 13 volunteers who had completed at least three weeks of a 12week program of cognitive-behavioral-inlerpersonal counseling for the treatment of cocaine abuse and dependence.
The Multiple VAS detected significant decreases in craving and wanting, and increased needing cocaine among
participants at the end of the three week monitoring period. The craving VAS and the likert-type craving scale were
superior at predicting positive urines and self-reported cocaine use over the short-term (one week before or following
monitoring), although the strongest association was found between use in the last seven days and current intensity
levels of cocaine craving. Baseline scores on the four factors (dimensions of craving) from both versions of the
CCQ-Now were the best predictors of future use over the long-term (entire three weeks), with partial correlations
indicating that Compulsivily (Factor 3, “obsessive craving”) represented the greatest independent contribution to
this relationship. Significant intercorrelations existed among all craving measures, although each questionnaire was
tapping different aspects of cocaine use. Researchers should consider using more than one measure of cocaine
craving to assist in cross-study comparisons.
ACKNOWLEDGMENTS:
Program, NIDA, NIH.
Supported by NIDA grant P-50-DA-0925801 and the Intramural Research
145
COCAINE CRAVING: A REAL-TIME NATURALISTIC EVALUATION
P. S. Bordnick, J. M. Schmitz, A. Stotts, and S. Day
University of Texas - Houston
Craving is a popular term which has been poorly defined and measured. Most clinical data on craving in cocaine
dependent patients has been collected retrospectively, and thereby subject to various methodological flaws. To
overcome past limitations, the authors developed a method of collecting real-time descriptive data in the natural
environment about immediate events surrounding cocaine craving episodes. The purpose of this study is to: 1)
examine direct antecedents of cocaine use (both cognitive and behavioral), 2) identify various situational factors and
their relationship to cocaine craving, and 3) explore the relationship between craving and baseline psychosocial
variables (e.g., affect, coping skills, etc.). It is hypothesized that craving intensity will be the highest in cocaine
dated situations versus non-cocaine-related situations. Subjects were given measurement booklets for recording
craving, mood states, situations, and activities between the hours of 8:30 a.m. to 9:30 p.m. Subjects were
instructed to record information at 5 randomly pre-selected times, in temptation situations, and after a cocaine using
episode. Subjects call in their responses to a voice-mail telephone system that documents the time and date of the
call. Data collected so far suggests good compliance, as indicated by a mean response time of 16 minutes (SD=24)
following randomly scheduled time points. Data also reveal that subjects report greater craving intensity during
temptations assessments versus random assessments. Pilot data utilizing an electronic pager to prompt recording
will also be presented.
ACKNOWLEDGMENTS:
Supported by NIDA Grants DA-09262-02 and T32 DA-07247.
RETROSPECTIVE ASSESSMENT OF DRUG AND NON-DRUG CRAVING STATES IN
SUBSTANCE ABUSE PATIENTS
B. A. Flannery, S. Sheth, L. Spaulding, C. Thrower, L. W. Hemby, D. Goehl, A. V. Hole,
A. R. Childress, and C. P. O’Brien
Addiction Treatment Research Center, University of Pennsylvania School of Medicine and
VA Medical Center, Philadelphia, PA
Abused drugs act through brain substrates common to natural rewards such as food and sex, but the relationships
among the “cravings” (learned incentives) for drug and non-drug rewards has not been systematically studied. The
purpose of the ongoing study was to examine the relationships among drug, food, sexual cravings, and activities in
patients seeking treatment for cocaine or alcohol dependence. We developed the Retrospective Assessment of
Craving (RAC) interview to document these. cravings and activities over the six weeks prior to admission, using a
timeline follow-back approach. Upon completion of the RAC calendar, patients (50 thusfar) were also asked to
compare the pleasure states and craving states across all three categorie, and to rate the likelihood that craving a
activity in one category could lead to craving or activity in another. Drug craving and drug use were commonly
reported as co-occurring (on the same day). Across the six week period prior to admission, nearly half of the patients
reported neither craving nor use on a given day. This pattern actually increased in the weeks closest to treatment
admission. This may reflect a real decline in drug use for a subset of those planning to seek treatment, or possibly a
demand effect of the interview situation. The demand effects of the instrument will be explored through prospective
data collection with concomitant urinel/breathalyzer data. Men reported experiencing similarities between drug and
sex-related states at double the frequency that women reported these experiences. Women reported that craving and
use of cocaine or alcohol to be at its greatest at menses, while their sexual craving and activity were highest at the
late luteal stage of the menstrual cycle.
146
FREQUENCY OF AVERSIVE EVENTS IN COCAINE-DEPENDENT OUTPATIENTS
S. C. Sigmon, S. T. Higgins, C. J. Wong, and G. J. Badger
University of Vermont, Substance Abuse Treatment Center
Behavioral theory posits that a low density of alternative non-drug reinforcement. and perhaps a high density of
aversive events, increases vulnerability to drug abuse. while there is relatively extensive empirical support for this
position from controlled laboratory studies, there is little evidence from studies conducted in naturalistic settings.
In an initial study on this topic using the Pleasant Events Schedule (PES), cocaine-dependent patients reported
engaging in a significantly lower frequency of potentially reinforcing events than controls (Van Ellen et al., 1996).
The present study was conducted using the Unpleasant Events Schedule (UES) to examine whether cocainedependent patients report a higher frequency of aversive events in their everyday lives than controls. The PES and
UES are behavioral inventories originally developed to measure the density of potentially reinforcing and punishing
events in the lives of depressives (Lewinsohn and Amenson, 1978). In the present study, the UES was
administered to 53 cocaine-dependent adults 24 weeks after they entered outpatient treatment. We found little
evidence that cocaine-dependent patients experience a higher density of unpleasant events than conlrol subjects.
Cocaine-dependent patients differed significantly from normative controls on only 3 of the 9 UES subscales.
Among those 3 subscales, only the scale dealing with legal issues clearly supported a greater frequency of aversive
events for the cocaine-dependent sample, and even then the difference was only significant for younger subjects (i.e.,
age by group interaction). We only assessed the frequency of aversive events in this study and not the degree of
aversiveness of the events. Prior studies in deposed individuals suggest that the latter may be important in
distinguishing impaired subjects from controls. Overall, then, the present study found little evidence that cocaine
abusers experience a greater frequency of unpleasant events than control subjects, but further research is needed to
determine whether the degree of aversiveness of the unpleasanl events experienced might be greater in cocaine
abusers.
CONFIDENCE QUESTIONNAIRE SCORES AS PREDICTORS OF
SITUATIONAL
TREATMENT OUTCOME AMONG COCAINE-DEPENDENT OUTPATIENTS
C. J. Wong, S. T. Higgins, and G. J. Badger
University of Vermont, Substance Abuse Treatment Center, Burlington, VT
Measures of patients’ confidence in their ability to abstain from drug use in high-risk situations (i.e., situational
confidence) have predicted treatment outcome across various types of drug abuse. We have been studying baseline
situational-confidence as a predictor of treatment outcome among cocaine-dependent adults receiving therapy
combining the community reinforcement approach (CRA) and vouchers. This report describes results from a
recently completed clinical trial in which 70 cocaine-dependent adults were randomized to receive CRA-plusvouchers contingent on cocaine abstinence or CRA-plus-vouchers delivered independent of cocaine use. A modified
version of the Situational-Confidence Questionnaire (SCQ) was administered at 1, 6, 12, and 24 weeks after
treatment entry. We examined (a) whether subject or drug-use characteristics at intake predicted baseline SCQ
scores, (b) whether baseline SCQ scores predicted during-treatment cocaine abstinence, and (c) whether changes in
confidence during the course of treatment predicted or were predicted by cocaine abstinence. Greater number of selfreported grams of cocaine used per week at intake and having ever smoked cocaine were the two predictors of
baseline SCQ scores (r= -.35, p<.001; r= -.28, p<.01). Baseline SCQ scores did not predict cocaine abstinence for
patients overall (r= .22, p=.07), but did so for those assigned to the contingent-vouchers group (r= .51, p<.001).
Lastly, cocaine abstinence achieved during wks. 1-6, 1-12, and 1-24 was a stronger predictor of situationalconfidence measured at the end of those specified periods than the converse. These results provide important new
information on the dynamic relationships between situational confidence and cocaine use in cocaine-dependent
outpatients.
147
DIFFERENCES IN PRE-TREATMENT SUBSTANCE ABUSE AND SYMPTOMS,
TREATMENT DROPOUT AND RELAPSE IN COCAINE ABUSERS
S. K. Richards, R. C. McMahon*, and R. M. Malow*
Medical College of Virginia, Virginia Commonwealth University, Richmond, VA and
*University of Miami, Miami, FL
Differences in the number and nature of substances used in the thirty days prior to treatment entry among primary
cocaine abusers (n=217) were examined in relation to differences in symptom expression, treatment dropout, and
rates and patterns of relapse. The additional use of alcohol, or alcohol and marijuana by primary cocaine abusers
was not related to increased symptom expression as measured by MCMI-II scales of Major Depression, Anxiety,
and Bipolar Manic, higher rates of treatment dropout, nor higher overall rates of relapse. Cocaine only users
(n=60), cocaine/alcohol users (n=94), and cocaine/alcohol/Marijuana (n=63) users evidenced subclinical symptom
levels on MCMI-II scales of Major Depression (BR=69.69), Anxiety (BR=68.26), and Bipolar: Manic (BR=72.17).
Treatment dropout rate averaged 22.6% across the three groups. Rams of relapse (34.3%) and lost to follow up
(37.6%) were similar across the three groups over four, 3-month follow up periods (i.e. subjecls tracked 12 months
post-treatment). Among relapsers, those classified as cocaine only users at treatment intake relapsed to alcohol
(exclusively, prior to, or concurrent with first relapse to cocaine) much less frequently than cocaine/alcohol or
cocaine/alcohol/marijuana users. Also among relapsers. those classified as cocaine only users at treatment intake
relapsed to fewer substances than cocaine/alcohol/marijuana users.
CRACK COCAINE, ALCOHOL,
HOMELESS PERSONS
AND OTHER DRUG USE PATTERNS
AMONG
S. L. Usdan, J. E. Schumacher, J. B. Milby, C. McNomara D. Wallace, D. Stange, and M.
Michael
University of Alabama at Birmingham, Birmingham, AL and The University of Kansas
Alcohol or other drug use may be a trigger for cocaine use and a barrier to recovery. This study examined the coOccurrence of cocaine, alcohol and other drug use among treatment seeking homeless persons to determine whether
cocaine use occurred differently with alcohol than other drugs. It was hypothesized that less alcohol use is
associated with less cocaine use among homeless persons and that there is a greater relation between crack cocaine
and alcohol than between crack cocaine and other drugs. Subjects (N=49) participated in a treatment outcome study
that measured alcohol and other drug use by the Addiction Severity Index (days used in the past 30 days) at intake.
Subjects were 76.4% male and 82.7% African American with an average age of 38.2 (SD=7.4) years. Results from
bivariate analyses revealed a moderate correlation between days alcohol and days cocaine use (r=0.38, p<.006) and
low correlations between days marijuana use and cocaine use (r=0.23, p<.10) and days other drug use and cocaine
use (r=0.18, p<.20). Multiple regression analyses showed that 14.6% of cocaine use frequency was predicted by
alcohol use (R-squared=.146) and that adding other drug use (including marijuana) into the regression equation added
little to the predictive power (R-squared=.148). These results suggest that crack cocaine use is positively related to
alcohol use among homeless persons seeking treatment. Results also suggest that a greater association exists
between crack cocaine and alcohol than between crack cocaine and other drugs. This supports the notion alcohol
use can be a more important precursor to crack cocaine use than other drug use. These findings with crack smoking
are consistent with recent studies showing alcohol use can be a precursor to intranasal and IV cocaine use as well.
ACKNOWLEDGMENT:
Supported by NIDA grant R01 DA 08475.
148
ABSTINENCE CONTINGENCY MAY POSITIVELY IMPACT HOMELESS CRACK
ADDICTS’ NON-DRUG RELATED ACTIVITIES
C. McNamara, J. B. Milby*, S. L. Usdan, J. E. Schumacher, and D. Wallace
University of Alabama at Birmingham, Birmingham, AL and * Bitmingham VAMC
A decrease in non-drug related activities and friendships is a drug use correlate and complaints of too much free time
are common. Improvements in these domains are often predictive of rehabilitation. The Rehabilitation Checklist
(RC), a six item questionnaire regarding activities, friendships, and time allocation, was administered al baseline and
2 month follow-up to 106 homeless crack cocaine using subjects who enrolled in a treatment program comparing
the efficacy of day treatment (DT) (n=46) to day treatment with abstinent contingent housing (DT+) (n=60). It was
hypothesized that all subjects would evidence improvement from baseline to two month follow-up on the major
dimensions of the RC: number of friends, percentage of friendships with drug abstainers, number and frequency of
non-drug related activities engaged in weekly, and satisfaction with activities and free time. Day treatment
significantly improved the number of friendships, friendships with drug abstainers, weekly activities, satisfaction
with activities, and satisfaction with free time for all subjects regardless of condition. Additionally, paired T-test
revealed that DT+ demonstrated greater changes in weekly activities (DT + mean change = 2.3 vs. DT mean change
= 1.4. p =.02). The DT+ group showed greater improvement on a composite variable requiring subjects to engage in
at least 3 activities weekly, and report satisfaction with activities and bee time (48% change DT vs. 68% change
DT+ p=.03). DT + subjects demonstrated greater although not statistically significant improvements on most other
dimensions. While day treatment alone (DT) positively impacts quality of life variables related to rehabilitation,
such as friendships and activities, the addition of abstinent contingent housing (DT+) may increase this effect.
especiaIly with regard to number of activities engaged in and satisfaction with activities and free time. This implies
that abstinent contingent housing may be useful for impacting variables associated with sustaining abstinence such
as non-drug related activity and free time.
ACKNOWLEDGMENT:
Supported by NIDA grant RO1 DA08475.
MEASURES OF TEMPERAMENT AMONG DRUG ABUSERS IN TREATMENT
J. Campbell, W. Gabrielli, B. Liskow, E. J. Nickel, E. Penick, and H. M. Thomas
Departments of Psychiatry, VA Medical Center, Kansas City, M O. and University of Kansas
Medical Center, Kansas City, KS
Little information is available regarding temperament and relationship to outcome of treatment for drug abuse. We
evaluated temperament using the NEO Personality Inventory. an instrument assessing dimensions of temperament
in three primary domains: neuroticism, extraversion and openness. Each domain consists of 6 scales. Two additional
domains are assessed, agreeableness and conscientiousness. but do not have subscales. Subjects were drawn from an
oulpatienl community mental health treatment program and included a subgroup of subjects participating in a
pharmacologic trial of desipramine, carbamazepine or placebo. The NEO was administered at treatment entry and at
6-month follow-up. Subjects participated in 10 hours of group and individual treatment weekly. The Addiction
Severity Index was administered at treatment entry and al 6-month follow-up. Subjects in both groups had high
scores on the Neuroticism (N) scale; in the psychosocial--treatment only group, high N scale scores correlated with
higher ASI composite scores on drug use and treatment need at 6 month follow-up. Significant differences occurred
at baseline among the pharmacotherapy groups on many of the NEO scales; these outcome data will not be
presented al this time. Retention in treatment was generally not predicted by NEO scales.
ACKNOWLEDGMENT:
Supported by NIDA grant R18 DA-06954.
149
A THERAPIST ADHERENCE MEASURE FOR AN ANGER MANAGEMENT TREATMENT
FOR SUBSTANCE ABUSERS
M. S. Shopshire, R. W. Ouaou, P. M. Reilly, and H. W. Clark
San Francisco Treatment Research Center, University of California, San Francisco
We have developed a 12-week cognitive-behavioral anger management treatment (AMT) for substance abuse patients
that produces reductions in the disposition to experience anger (Reilly et al., 1995, 1996, 1997). The delivery of
the AMT was manual-guided. We developed a therapist adherence coding method and we are currently using the
method to assess therapist adherence in 10 cohorts of group participants. In this presentation, we discussed how the
method for coding therapist adherence was developed and reported preliminary findings from two cohorts. The
therapist adherence method assesses both the content and the process of patient-therapist interactions. Each
treatment session consists of a structured didactic teaching component and a more open-ended check-in component
where therapists deliver cognitive-behavioral interventions. An independent rater was trained to code audiotapes of
AMT sessions. Rater “drift” was assessed by a study investigator who did not serve as a study therapist. Inter-rater
agreement was adequate (r = .79). In the two cohorts that were rated, about 60% (58% and 52%) of the concepts
prescribed by the treatment manual were delivered in the didactic teaching component, and about 30% (23% and
29%) of the patient-therapist interactions during the check-in component consisted of interventions prescribed by the
treatment manual. We discussed procedures we have used to improve therapist adherence.
ACKNOWLEDGMENT:
Supported by NIDA grant P-50-DA-09253.
ANGER MANAGEMENT TREATMENT: COMPARISONS AND FOLLOW-UP
P. M. Reilly, M. S. Shopshire, and H. W. Clark
Department of Veterans Affairs Medical Center, University of California, San Francisco, CA
We demonstrated that a 12-week cognitive-behavioral anger management treatment (AMT) reduced levels of anger in
cocaine abusing patients (Reilly et. al., 1996). In addition to AMT. patients were enrolled in standard substance
abuse treatment. It is possible; however, that standard substance abuse treatment may have produced the observed
reductions in anger, rather than the AMT. To examine this hypothesis, we examined reductions in anger in a
comparison group (n = 10) of patients enrolled in standard substance abuse treatment. Trait-anger and angerexpression were measured at baseline and at 12-week follow-up. Trait-anger did not change, while anger-expression
actually increased, suggesting that AMT produced reductions in anger rather than mere enrollment in a substance
abuse treatment program. A second issue we addressed concerned levels of bait-anger and anger-expression at a 3month post-treatment follow-up. Trait-anger and anger-expression did not increase, and remained significantly (p <
.001) lower than baseline. These findings suggest that an anger management treatment is an important component
of sustance abuse treatment that warrants further study in controlled clinical trials.
ACKNOWLEDGMENTS:
Supported by NIDA Grant P50DA09253 and San Francisco TRC.
150
COCAINE-RELATED CHANGES IN BRAIN BLOOD FLOW
L. Lamki, B. A. Johnson, D. Simms, B. Fang, B. Barron, L. Wagner, P. S. Bordnick, R
Chen, R. Meisch, L. Vogelson, W. Maugans, and D. Overton
University of Texas Health Science Center - Houston, Houston, TX
Previous studies of cocaine-related changes in brain blood flow (BBF) have been conducted with semi-quantitative
Single Photon Emission Computerized Tomography (SPECT). Semi-quantitative SPECT does not allow for
measurement of absolute blood flow, and hence the correlation between reported changes in behaviors and BBF
using this technique are not well characterized. Here, we present the results of a new quantified technique for
measuring absolute BBF to specific brain regions during drug-taking. We found that in cocaine dependent subjects,
cocaine in comparison with placebo was associated with reductions in total BBF, and in reduced perfusion to areas
rich in dopaminergic innervation (e.g. putamen, superior temporal lobe, prefrontal cortex). These results
demonstrate the development of a new quantified technique for measuring absolute BBF using SPECT, and some
relatively specific blood flow changes during cocaine-taking.
ACKNOWLEDGMENT:
Supported by Advanced Technology Program # 011618 Texas
SPECT FOLLOWING IV PROCAINE IN COCAINE ADDICTION
B. Adinoff, M. D. Devous, M. S. George*, S. Best, D. Alexander, and J. K. Payne
University of Texas Southwestern Medical Center and VAMC, Dallas and *Medical Univ. of
SC, Charleston, SC
Previous investigators have suggested that a state of permanent limbic neuronal hyperexcitability may be present in
cocaine addicts, such mat spontaneous or cue-related episodes of limbic neuronal discharge may result in craving. In
order to explore this phenomena, we administered the limbic stimulus procaine to cocaine addicted patients and
controls. Methods: Twelve healthy controls (9 men, 3 women) and twelve patients with only cocaine dependence
(9 men, 3 women) were studied. Patients were 2-3 weeks abstinent. In two study sessions separated by 48 hours,
saline (1st) and procaine (1.38 mg/kg) (2nd) were administered intravenously (single blind), immediately followed by
the tracer 99mTcHM-PAO. A SPECT scan was obtained 90 min. after injection. rCBF was assessed both by t-image
analyses (Devous) and SPM (George). Subjective responses were assessed by analog scales (1-6). Results:
Controls endorsed significantly greater drug effecf, “bad" drug effect, and “dislike” of drug compared to patients.
Patients (n=5) demonstrated significantly (p<0.01) greater rCBF in anterior cingulate, inferior frontal, mesial
temporal, brainstem, occipital, and cerebellar regions compared to controls (n=5). Total lifetime days of cocaine use
was significantly correlated with brainstem (r=0.88) and right lateral temporal (r=0.69) procaine-induced activation.
Areas of increased rCBF following procaine are distinctly different than those reported following cocaine.
Discussion: These preliminary data suggest different biologic and subjective responses to procaine in cocaine
addicted patients and controls. Greater limbic rCBF in patients offers tentative support for the sensitization
hypothesis.
ACKNOWLEDGMENTS:
Supported by NIDA grant 1R21-DA10218-01 and UT Southwestern Medical Center.
151
[123I]ß-CIT SPECT IMAGING OF DOPAMINE TRANSPORTER AVAILABILITY IN
MAZINDOL-TREATED COCAINE ADDICTS
R. T. Malison1 , E. McCance 1 , L. L. Carpenter 1 , R. M. Baldwin1 , J. P. Seibyl1 , L. H. Price 2 ,
T. R. Kosten1 , and R. B. Innis1
1
Yale Univ. Sch. of Med., New Haven CT and 2Brown Univ. Sch. of Med., Providence, RI
The in vivo potency of mazindol for binding to striatal dopamine transporters (DAT) was assessed by [123I]ß-CIT
([123I]2ß-carbomethoxy-3ß-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT).
Cocaine-dependent subjects (n=6) underwent three SPECT scans, one before, between, and after subchronic (1 week)
administration of 2 mg/day and 4 mg/day mazindol. For each scan, subjects were injected with [123I]ß-CIT and
imaged 24 h later under equilibrium conditions. Measurable reductions in the specific to nondisplaceable
equilibrium partition coefticient, V3'' (which is proportional to DAT binding potential), were observed in only 4 of
6 subjects. A statistically significant effect for dose was found in this subset (df = 2, F = 72.05, p < 0.001,
repeated measures ANOVA), but not in the entire group (df = 2, F = 1.12, p = 0.37). Regression analysis of the
logit transformed data in the subset enabled estimation of the 50% displacement dose of mazindol (ED50 = 21
mg/day). These data suggest that low doses of mazindol (i.e., 2-4 mg) occupy a small percentage (i.e., < 25%) of
DAT in human cocaine abusers and that much higher, potentially intolerable doses (i.e., 20 mg/day) may be
required to antagonize cocaine binding in vivo.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-09250.
“BINGE” PATTERN ADMINISTRATION OF COCAINE ALTERS [ 11 C]ß-CIT BINDING IN
THE RAT BRAIN AS MEASURED BY PET
H. Tsukada, S. Nishiyama, T. Kakiachi, N. Harada, and *M. J. Kreek
Central Research Laboratory, Hamamatsu Photonlcs K. K., Hamamatsu, Japan and
* Laboratory of Addictive Diseases, The Rockefeller University, New York, NY
The effects of acute (2 days) and chronic (14 days) “binge” pattern cocaine administration, and also withdrawal from
chronic cocaine, on the dopamine transporter (DAT) were evaluated in the living rat brain using a high resolution
positron emission tomography (PET). Male Sprague-Dawley rats were injected in a “binge” pattern three times at
1-hr intervals with saline or cocaine (15 mg/kg) each day for 2 or 14 days. Furthermore, rats which received chronic
“binge” cocaine were withdrawn 1, 10 or 21 days with no injections of cocaine. The in vivo binding of [11C]ßCIT, an analog of cocaine. in the striatum was measured by PET. Neither acute nor chronic administration of saline
affected the [11C]ß-CIT binding in any conditions. The binding of [11C]ß-CIT was significantly reduced by either
acute or chronic “binge” cocaine administration. In rats which received acute “binge” cocaine administration, the
binding of [11C]ß-CIT returned within 4 hr to basal levels as observed in saline administered rats. In contrast, in
rats which received chronic “binge” cocaine, the binding of [11C]ß-CIT was significantly lower up to 1 day after the
last cocaine injection than in saline rats. During the withdrawaI period, the binding of [11C]ß-CIT increased
slightly, but significantly 10 days after the last cocaine injection, then returned to the basal level after 21 days of
withdrawal. These results indicated that DAT availability in rat striatum was physiologically altered by chronic
“binge” pattern cocaine administration and also by withdrawal from cocaine.
ACKNOWLEDGMENTS:
Supported in part by DA-P50-05130 and DA-K05-00049.
152
EFFECTS OF WITHDRAWAL FROM BINGE PATTERN COCAINE ADMINISTRATION ON
DOPAMINE D1 AND D2 RECEPTORS IN THE RAT BRAIN AS MEASURED BY PET
J . K r e u t e r 1 , H . T s u k a d a 2 , S . D . S c h l u s s m a n1 , T. Kakiuchi2 , S . N i s h i y a m a2 , E. M.
Unterwald3,1, A. Ho1, C. E. Maggos1, and M. J. Kreek1
1
The Rockefeller University, New York, NY; 2 Hamamatsu Photonics K.K., Hamamatsu,
Japan; and 3New York University Medical Center, New York, NY
Previous studies from our laboratories have shown that administration of cocaine to rats in a “binge” pattern for 14
days results in a significant decrease in binding of both D1 and D2 dopamine receptor antagonists in the striatum
(Tsukada et al., 1996). The present study investigated the effects of short-term and more prolonged withdrawal from
cocaine on in vivo binding of [11C]SCH23390 and [11C]N-metbylspiperone to D1 and D2 dopamine receptors, using
positron emission tomography (PET). Adult male Sprague-Dawley rats were injected with saline or cocaine HCl
(15 mg/kg) three times daily, at 1-hr intervals, starting 30 min. after the start of the light cycle, for 14 days. PET
scans were performed to measure D1 and D2 receptors on the 14th day of cocaine administration. and 1 and 10 days
after the last cocaine injection. Fourteen days of binge pattern cocaine injections produced a significant reduction in
D1 and D2 dopamine receptor binding, confirming our previous findings. After 1 day of withdrawal, a significant
decrease in the binding potential of [11C]SCH23390 was still found in the striatum. However, after 10 days of
withdrawal, the binding potential of [11C]SCH23390 returned to normal. After 1 day of withdrawal, a significant
decrease in binding of [11C]N-methylspiperone was also found in the striatum. Even after 10 days of withdrawal, the
binding to D2 receptor was still significantly reduced, showing that full recovery from the effects of cocaine on D2
receptors had not yet occurred.
ACKNOWLEDGMENTS:
Supported in part by NIH-DA-P50-05130 and NIH-DA-K05-00049.
EFFECTS OF LONG-TERM WITHDRAWAL AFTER CHRONIC BINGE COCAINE ON IN
VIVO D 1 AND D 2 DOPAMINE RECEPTOR BINDING USING POSITRON EMISSION
TOMOGRAPHY
C. E. Maggos 1 , H. Tsukada 2 , T. Kakiuchi2 , J. Myers 1 , S. Nishiyama2 , E. M. Unterwald 1,3 , S.
D. Schlussman1 , J. Kreuter 1 , and M. J. Kreek 1
1
Lab. of the Biology of Addictive Diseases, The Rockefeller Univ., 2 Central Res. Lab.,
Hamamatsu Photonics K.K., Japan, and 3 Dept. of Psychiatry, New York Univ. Med. Ctr.
Our previous positron emission tomography (PET) studies detected a decrease of in vivo binding immediately
following chronic (14 days) binge cocaine administration (CBC) for both [1C]SCH23390, a D1 dopamine receptor
antagonist, and [11C]N-methylspiperone (NMSP), a D2 dopamine receptor antagonist. The decrease in
[11C]SCH23390 binding levels returned to control levels after ten days of withdrawal from CBC, while the decrease
in [11C]NMSP binding was still observed after ten days withdrawal. The present study was designed to determine
the effects of a longer, 21 day withdrawal period on [11C]SCH23390 and espcially [11C]NMSP binding,
Previously studied timepoints, immediately following CBC and after 10 days of withdrawal, were also repeated for
both [11C]SCH23390 and [11C]NMSP binding in the present study. The present study confirmed that both
[11C]SCH23390 and [11C]NMSP binding were decreased immediately following CBC and that the decrease in
[11C]SCH23390 binding levels returned to control levels after ten days of withdrawal from CBC, while the decrease
in [11C]NMSP binding was still observed after ten days withdrawal. Furthermore, [11C]SCH23390 binding was
still at control levels after 21 days of withdrawal. The present data show that after 21 days of withdrawal from CBC
[11C]NMSP binding returns to control levels. This suggests that the change of in vivo [11C]NMSP binding to D2
dopamine receptors following CBC lasts longer than 10 days and therefore requires a longer period of abstinence for
normalization. This finding indicates that the plasticity of in vivo D2 dopamine receptor binding is different from
that observed in D1 dopamine receptor binding and may be important for development of pharmacotherapies for
cocaine dependent patients. REFERENCES: Tsukada, H.; et al., J. Neurosci., 16(23):7670-7677.
AKNOWLEDGMENTS:
Supported in part by DA-P50-01530 and DA-K05-00049.
153
COCAINE-INDUCED CEREBRAL BLOOD VOLUME REDUCTION IN FEMALES
T. J. Kukes, M. J. Kaufman, J. M. Levin, L. C. Maas, S. L. Rose, S. E. Lukas, J. H.
Mendelson, B. M. Cohen, and P. F. Renshaw
Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA
This study used dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) to dctermine the effect of
intravenous cocaine on cerebral blood volume (CBV) in female subjects. Using data from a previous DSC MRI
study of 9 age- and cocaine use-matched males, we also searched for gender differences. Healthy female subjects
(N=8, aged 27±2 years) reporting casual cocaine use (7±3 lifetime exposures) participated during the follicular phase
of their menstrual cycle. CBV was determined in an axial whole brain slice using a steady-state method with four
injections of gradoteridol (0.075 mmol/kg). Baseline CBV was determined from the area under the third bolus curve.
Cocaine (0.4mg/kg, i.v.) was administrered 10 minutes prior to the final bolus injection. Cocaine significantly
increased heart rate (170%±8%) (mean±SE) and blood pressure (120%±5%), and reduced contrast arrival time (a
measure of blood flow velocity) (p<0.0001). CBV was reduced following cocaine administration (29%±5%)
(p<0.008). In males, CBV was also reduced (20%±5%) (p<0.006). The gender difference in cocaine-induced
reduction of CBV was not statistically significant, suggesting that cocaine administration leads to comparable
degrees of vasoconstriction in men and women. A gender difference in the severity of perfusion abnormalities in
chronic cocaine-abusers has been reported, with females experiencing fewer defects than their male counterparts. The
present finding suggests that these differences are not explained by differences in vasoconstriction.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA09448, DA04059, DA00064 and DA00115.
LONG-TERM DOWN-REGULATION OF DOPAMINE D2 RECEPTORS FOLLOWING
COCAINE SELF-ADMINISTRATION IN MONKEYS
M. Nader, R. Mach, R. Ehrenkaufer, H. Gage, and T. Morton
Departments of Physiology and Pharmacology and Radiology, Bowman Gray School. of
Medicine, Wake Forest University, Winston-Salem, NC
The reinforcing effects of cocaine are believed to be mediated, in large part, through the dopaminergic system.
Positron Emission Tomography (PET) studies in humans have shown a persistent decrease in D2 binding potential
in cocaine abusers abstinent from cocaine for up to 4 months, compared to age-matched controls (Volkow et al.,
Synapse, 1993, 14:169). The purpose of the present study was to 1) evaluate the effects of long-term cocaine
exposure, using PET, in a monkey model of cocaine abuse, in which drug history could be controlled and 2) to
extend the cocaine withdrawal period to better determine the long-term consequences of cocaine self-administration.
PET studies using the D2 ligand [18F]4-fluoroclebopride (FCP) (Mach et al., Synapse, 1996, 24:322) were
conducted in three adult mate rhesus monkeys with an extensive history of i.v. cocaine self-administration (mean
total intake of 17 ± 3 g over - 3 years). PET studies were conducted at abstinence periods of 3 days to 302 days and
all data were compared to baselines obtained from cocaine-naive controls (n=6). Baseline levels of D2 binding
potential in control monkeys was 3.61 ± 0.58. There was a substantial and persistent decrease in D2 binding
Potential throughout withdrawal: 3-7 days: 3.0 (± 0.17), 17-30 days: 3.13 (± 0.06), 90-110 days: 3.07 (± 0.2) and
200-302 days: 2.87 (± 0.05). These data are consistent with previous reports in humans suggesting that chronic
cocaine abuse causes long-term alterations in central dopaminergic function and extend this finding to controlled
experimental conditions and up to 10 months of withdrawal.
ACKNOWLEDGMENTS:
Supported by grants DA 10584, DA 08468, NS 31907.
154
COCAINE ABUSE ALONE (WITHOUT CONCOMITANT ALCOHOL ABUSE) DOES NOT
CAUSE VOLUME CHANGES IN THE CEREBELLUM. COCAINE AND ALCOHOL COABUSE IS ASSOCIATED WITH VOLUME LOSS IN THE DORSAL VERMIS AND THE
CEREBELLAR HEMISPHERES: AN MRI VOLUMETRIC STUDY
D. Langlebcn, M. Johnson, C. Bloomer, and G. Fein
Department of Psychiatry, University of California at San Francisco and San Francisco
Veterans Affairs Medical Center, San Francisco, CA
In alcohol abusers, brain volume loss has been reported primarily in the superior ventral Vermis and to a lesser
extent in the dorsal Vermis and the cerebellar Hemispheres. Concurrent alcohol and cocaine abuse is common.
There is no data on the. effect of cocaine abuse on cerebellar volume in humans. We used MRI to examine the
effects on the cerebellar volume of chronic cocaine abuse with or without concurrent chronic alcohol abuse. The
subjects were abstinent for an average of 20 weeks at the time of image acquisition. Results indicate that in the
middle age chronic cocaine abuser who does not also abuse alcohol, no effect on the cerebellar volumes is evident.
In the cocaine and alcohol coabuser, the volumes of the cerebellar Hemispheres and the dorsal Vermis are reduced.
These findings suggest that cocaine alone has neither permanent nor independent effect on the cerebellar volume.
Hither the metabolic and hemodynamic effects of cocaine on the brain are not translated into persistent volume
changes in the cerebellum or such effects normalize over 20 weeks of abstinence. Our Cocaine/Alcohol group had a
volume loss in the cerebellar Hemispheres and the dorsal but not the superior ventral Vermis. The dorsal Verrnis is
preferentially affected by age and the effects in our study were largest in older subjects. Our results suggest
increased susceptibility of the dorsal Vermis of the older cocaine/alcohol coabuser to age related volume loss.
Absence of volume loss in the superior ventral Vermis in our cocaine/alcohol group could be explained if that
region was less affected by age than the dorsal Vermis or has recovered during abstinence.
REFERENCES: Available upon request from the first author.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-08365.
MORPHOLOGICAL CHANGES IN OPIOID DEPENDENCE
L. Pezawas, G. Fischer, K. Diamant, W. Plöchl, H. Eder, M. Thurnher, and S. Kasper
University Hospital of Psychiatry,
Austria
Clinical Department of General Psychiatry, Vienna,
Cerebrospinal fluid (CSF) space enlargement has been demonstrated in substance-related disorders like alcohol and
cocaine dependence. Experimental animal studies showed a reduction in shape and size of mesolimbic dopaminergic
neurons after chronic morphine administration. Other studies indicated a change of neurofilament and glial fibrillary
acid proteins after chronic opiate administration. Furthermore, frequent overdosing and toxicological effects of
“street”-heroin may lead to CSF space enlargement in opioid dependence. In our study, the pericortical and
ventricular CSF space of 21 male opioid-dependent patients was compared with an age- and sex-matched normal
control group. Considering serious problems with ratio and proportion measures, we used a battery of linear (cella
media index, Huckman number, frontal horn index), planimetric (cortical atrophy score) and stereological
volumetric measures in order to detect differences in cranial computerized tomography scans. We found a significant
ventricular and cortical brain atrophy in opioid-dependent patients. A higher degree of frontal lobe atrophy seemed to
be associated with a shorter period of abstinence before relapse. However, the etiology of brain atrophy in opioiddependent patients is still unclear, but experimental animal studies provide some evidence that long-term. chronic
opiate exposure is associated with visible changes of specific structures in the brain.
155
EFFECTS OF IBOGA AGENTS ON NICOTINE PREFERENCE AND ON NICOTINEINDUCED DOPAMINE RELEASE IN RATS
S. D. Glick, I. M. Maisonneuve, K. E. Visker, G. L. Mann, U. K. Bandarage*, and M. E.
Kuehne*
Department of Pharmacology and Neuroscience, Albany Medical College, Albany, NY and
*Department of Chemistry, University of Vermont, Burlington, VT
Ibogaine, an alkaloid found in Tabernanthe iboga, is claimed to be effective in interrupting dependence on opioids.
stimulants, alcohol and nicotine (smoking). While preclinical studies have examined its effects on opioid
(morphine), stimulant (cocaine), and alcohol self-administration, only neurochemical interactions of ibogaine with
nicotine have been reported. Ibogaine blocks nicotine-induced dopamine release in the nucleus accumbens, similar to
its effect on dopamine release induced by morphine. 18-methoxy-coronaridine (18-MC), a novel iboga alkaloid
congener, mimics ibogaine’s effects on morphine and cocaine self-administration without producing typical side
effects (e.g., tremor) of ibogaine. We have recently developed an oral self-administration model of nicotine
preference in rats. In the present study we compared ibogaine and 18-MC in terms of their effects on nicotine
preference and on nicotine-induced dopamine release. Both ibogaine and 18-MC produced dose-related decreases in
rats’ preferences for nicotine, and 18-MC, like ibogaine, blocked nicotine-induced dopamine release. 18-MC, and
perhaps other iboga alkaloid congeners, may be potentially useful in smoking cessation programs.
ACKNOWLEDGMENT:
Supported by NIDA grant DA03817.
MATERNAL AND CHILD PREDICTORS OF THE ONSET OF CIGARETTE USE: DATA
FROM THE N.L.S.Y. STUDY
A. M. Shillington
San Diego State University, School of Social Work, College of Health and Human Services:
San Diego CA
As part of an ongoing study conducted by the U.S. Department of Labor, the investigators of the National
Longitudinal Survey of Youth (NLSY) collected data on persons aged 14-22 in 1979. This nationally
representative sample has been interviewed annuatly with a retention rate of 89% as of 1994. In 1988, the study
was expanded to collect information on the children of this cohort and are interviewed every two years starting at
age ten regarding their substance use behaviors. As of 1992. (the most recent data available) there were 2,079
children interviewed for substance use. This sample is 52% male, 41% Black and 24% Hispanic with a mean age
of 12.4 years. Nearly a quarter of these children had used cigarettes with their mean age at onset being 10.5. This
study examines the risk and protective factors for the onset of cigarette use among children while controlling for
both child and maternal variables. High religiosity was protective against the onset of cigarette use particularly for
females. Having a close relationship with one’s mother was protective for Black. Hispanic, and female children
with those reporting a close relationship being half as likely to begin smoking compared to those with a more
distant relationship. Non-Black. Non-Hispanic youth were at highest risk for the onset of smoking. Children with
a higher number of behavioral problems were more likely to begin smoking. Males had no protective factors and
maternal lifetime use of cocaine was the highest risk factor for males to begin smoking. A history of poverty
status was a risk factor for the Non-Black, Non-Hispanic group. Maternal history of heavy alcohol use was a risk
factor only for Hispanics. Both Non-Black Non-Hispanic children and Hispanic children whose mothers had
smoked, were four times more likely to smoke compared to those with non-smoking mothers and as much as nine
times more likely. The implications are mat preventive and intervention efforts should take into consideration the
unique risk and protective factors for each ethnic and gender group.
156
SYNTHESIS AND NICOTINE ACETYLCHOLINE RECEPTOR BINDING PROPERTIES OF
EPIBATIDINE ANALOGS, POTENTIAL PET AND SPECT LIGANDS
H. Navarro*, F. Liang*, W. P. Ross*, Y. S. Ding**, N. Volkow**, M. J. Kuhor***, and F.
I. Carroll
*Research Triangle Institute, Research Triangle Park, NC; **Brookhaven National
Laboratory, Upton, NY; and ***Emory University, Atlanta, GA
(-)-Epibatidine [(-)-EB] is a naturally-occurring alkaloid with pM affinity for the
nicotinic acetylcholine
receptor (nACbR). A new, efficient synthesis of (±)-EB has been developed. This synthesis as well as the syntheses
of several EB analogs will be presented. The apparent affinity (Kapp) of EB and the analogs for the
nAChR was
assessed in competition binding experiments using [3H]norchloroepibatidine. Several analogs possessed affinity for
the
receptor comparable to that of EB. Norchlorofluoroepibatidine shows high specific binding to the nAChR
and promise as a PET ligand for me neuronal nicotinic acetylcholine receptor.
ACKNOWLEDGMENT:
Supported in part by a Tobacco Research Council grant.
RAT MODELS OF DRUG-SEEKING RELAPSE FOR ETHANOL OR NICOTINE
C. Chiamulera, E. Valerio, and M. Tessari
GlaxoWellcome S.p.A., Medicines Research Centre, Verona, Italy
The reexposure to drug-related stimuli or to the drug itself are important determinants of drug-craving. Therefore, it
appears that the experimental manipulation of these factors is crucial for the induction of drug-seeking behaviour in
laboratory animals. In a first set of experiments a tone was paired (600dB) with oral 8% ethanol (male Long Evans
rats) or intravenous 0.03 mg/kg nicotine (male Wistar rats) self-administration. When stability of responding for
drug self-administration was obtained, drug availability was discontinued and extinction developed (4-14 sessions).
The reexposure to the tone, but not of the drug, induced a significanl reinstatement of responding for the drug-paired
lever in me nicotine but not in the ethanol self-administration group. In a second set of experiments, with a similar
protocol of between-session extinction, we tested me effect of drug reexposure to rats with extinguished responding
for oral ethanol or intravenous nicotine. Reexposure to a limited amount of ethanol (0.18ml of 8% ethanol) caused
resumption of responding on the drug-associated lever. This effect was reduced by single pretreatment with
naltrexone 10mg/kg ip, a drug reported to be effective against craving for alcohol, We also observed that noncontingent nicotine priming induced reinstatement of responding. Reinstatement was not significant after priming
with the 0.03 mg/kg training dose of nicotine. On the other hand, a marked and significant reinstatement was
observed with lower doses (0.001, 0.003 or 0.01 mg/kg) of nicotine priming. Interestingly, nicotine priming after a
within-session extinction did not induce reinstatement of responding (0.01, 0.03 or 0.06 mg/kg nicotine) suggesting
a lack of responsiveness to the nicotine stimulus few hours after the end of me nicotine self-administration session
(2-5 hrs). In conclusion, these studies show that the presentation of drug-related CS and drug-priming are able to
induce drug-seeking in rats even after a long period of abstinence and suggest that the use of these models might
predict the efficacy of novel anticraving therapies.
157
ACCU DROP: TESTING A SMOKING CESSATION AID
P. Gariti and A. Alterman
University of Pennsylvania/Philadelphia VAMC Center for the Study of Addiction,
Philadelphia, PA
A preliminary open trial examined the efficacy of a 6 week nicotine fading protocol using a non-pharmacologic
agent, ACCU DROP in combination with cigarette tapering and brief motivational enhancement counseling.
ACCU DROP is an FDA approved corn syrup based food additive which is purported to trap a proportion of the
nicotine and tar when applied to cigarette filters. The subjects were 13 women and 5 men who smoked an average of
15 cigarettes daily (cpd). Subjects were seen weekly by a Ph.D. therapist for 20-30 minutes. The therapist used a
motivational enhancement approach to encourage Ss to declare their own plan for smoking cessation while using
the product, encouraged Ss to incrementally increase on a bi-weekly schedule the number of drops applied per
cigarette, offered the suggestion of decreasing the cpd in combination with using the drops, and monitored adherence
to the protocol. Sixty seven per cent (67%) of the Ss completed the six week protocol. Fifty per cent (50%) of the
Ss (9/18) reported nonsmoking at the end of the projected six weeks of treatment and 39% (7/18) reported being
continuously smoke-free one month later confirmed by CO readings <.009. There were no reports of increased
craving. Subjects reported satisfaction with the treatment and adherence to smoking cigarettes treated with the
ACCU DROPs. These preliminary findings support the potential utility of this alternative treatment approach.
TIME-OF-DAY OF RELAPSE DURING NICOTINE PATCH SMOKING CESSATION
TREATMENT: ANALYSIS OF SUBGROUPS
R. J. Green1, A. C. Bostrom 2, and D. P. L. Sachs1,2
‘Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center,
Stanford, CA and *Palo Alto Center for Pulmonary Disease Prevention, Palo Alto, CA
The overall results from a large scale (N=220), randomized, double-blind, placebo-controlled clinical trial evaluating
the safety and efficacy of a nicotine patch (Nicotrol) have been presented by Sachs, et. al., in Arch Int Med, 1993.
Using these data, we have performed further analyses, on only those subjects who lapsed to evaluate, on the day of
first lapse, the time-of-day when the first cigarette was smoked. Three predictors of lapse were studied: treatment
condition (active or placebo patch), sex, and degree of nicotine dependence (FTQ score: high 7 or low 6). Prior
to target quit day, mean time of first cigarette of the day was 07:23±148 min (±1 SD). On the day of first lapse, for
the active group, time of first cigarette was 16:02±321 min for low dependency women; 11:53±309 min for high
dependency women; 09:49±31 min for low dependency men; and 12:28±317 min for high dependency men. In the
placebo group, time of first cigarette was 14:11±320 min for low dependency women; 13:45±309 min for high
dependency women: 13:21±360 min for low dependency men; and 11:32±226 min for high dependency men. For
all eight subgroups, time-of-day of first cigarette on day of first lapse was significantly later than prior to target quit
day. Analysis of covariance of time of first cigarette on day of first lapse showed a significant three way interaction
between treatment condition. sex and degree of nicotine dependence (P < 0.05). Furthermore, there was a nearsignificant three way interaction on the second lapse day (P = 0.08) and a significant three way interaction on the
third lapse day (P = 0.01). Our results show that low dependency women ex-smokers receiving nicotine patch
treatment lapse significantly later in the day than all other subgroups.
ACKNOWLEDGMENTS:
Supported in part by funds from the Palo Alto Center for Pulmonary Disease
Prevention and McNeil Consumer Products Company
158
CORTISOL SYNTHESIS INHIBITION IN HEAVY SMOKERS
S. L. Frederick1, V. I. Reus1, and S. M. Hall2
1
University of California at San Francisco and 2San Francisco VAMC
Animal studies strongly suggest an interaction of the stress hormone corticosterone with dopaminergic pathways in
determining vulnerability to drug self-administration. Animals prone to self-administer drugs have a prolonged
corticosterone response to stress, and administration of corticosterone to non-self-administering animals enhances
the development of drug self-administration. Conversely, inhibition of corticosterone through surgical or
pharmacologic intervention reduces drug/alcohol self-administration. In this study, the effects of ketoconazole on
smoking behavior was evaluated in a double-blind crossover design with heavy cigarette smokers. Ketoconazole is
a commonly used antifungal medication that also inhibits cortisol syntheses. Participants engaged in two (2), three
hour sessions in which they completed inventories of mood and craving, gave carbon monoxide readings, and
smoked ad-lib using a cigarette-holder device measuring number and duration of puffs taken. Active and placebo
sessions were conducted two weeks apart (4 weeks for women) following one week of either placebo or
ketoconazole medication. Subjects were five men and two women who were current smokers and smoked an
average of 26.3 cigarettes/day. Five of the subjects received 400 mg. ketoconazole q.d. and two received 400 mg.
b.i.d. (800 mg/day). Preliminary analyses indicate that ketoconazole had no significant effect on the number of
cigarettes smoked, the number of puffs taken, total puff duration, or seconds per puff. Withdrawal as measured by
the Schiffman scale did not differ on ketoconazole vs. placebo days, nor did the change in withdrawal, CO level, or
craving from pre- to post-smoke. Inclusion of more subjects at the higher dose of ketoconazole may be necessary
to fully evaluate the potential efficacy of cortisol synthesis inhibition in reducing cigarette intake. In line with
animal findings, cortisol synthesis inhibition may be more useful in relapse prevention than in smoking or drug
cessation.
ACKNOWLEDGMENTS:
Supported by DA-09253 and DA-07250
CIGARETTE SMOKING DURING EARLY COCAINE ABSTINENCE
A. Radzius, J. E. Henningfield*, and D. A. Gorelick
NIH, NIDA/DIR, Baltimore, MD; *Johns Hopkins School of Medicine, Baltimore, MD; and
Pinney Associates, Bethesda, MD
Some, but not all, studies have reported increased cigarette smoking for 1 to 3 hours after a single dose of a
psychomotor stimulant, but there are no studies of smoking patterns during early cocaine abstinence. We addressed
this issue by assessing, with computerized cigarette dispensers, the ad lib smoking behavior of 12 cocaine-dependent
(DSM-III-R criteria) cigarette smokers (4 nicotine dependent no other current substance dependence, 11 with
Fagerstrom Tolerance Questionnaire scores > 5) housed on a closed research ward for another study. Prior Studies
validated that dispensing was an accurate reflection of actual cigarette smoking. Subjects (8 African-American men,
3 white men, 1 African-American woman) self-reported pre-admission mean [S.D.] daily 17.0 [10.3] cigarettes
smoked, mean age of 33.8 [6.1] years, and a mean last cocaine use of 0.6 [0.7] grams 1.8 [1.3] days prior to
admission. There was no significant difference between self-reported preadmission daily cigarettes smoked and the
number of cigarettes dispensed daily on the research ward over the first 7 days (prior to start of other study). These
findings suggest that early cocaine abstinence does not significantly alter ad lib smoking in a residential setting.
159
RECOVERING ALCOHOLIC VS NONALCOHOLIC SMOKERS
P. L. Navy, J. R. Hughes, L. J. Solomon, R. L. Riggs, and L. Caunt
HBPL, Departments of Psychology and Psychiatry, University of Vermont, Burlington, VT
Approximately 80% of recovering alcoholics smoke. Whether these smokers need more intensive or a different
therapy for smoking cessation is unknown. To begin to answer this question, smokers with and without a history
of alcoho1 dependence were compared (Pos Hx and Neg Hx, respectively). Subjects were recruited from prior studies
and from ads. Inclusion criteria were (a) no current symptoms of alcohol dependence (last year SADD score 9;
Davidson and Raistrick, 1986) and (b) an interest in quitting smoking in the next 6 months. Subjects with SADD
scores 9 for the period prior to the last year were designated Pos Hx Ss and those with a prior SADD score of 9
were designated as Neg Hx Ss. The groups were age and sex matched. Each subject completed a 45 minute
smoking history questionnaire. Pos Hx Ss scored higher on a nicotine dependence scale (FTQ; Fagerstrom and
Schneider. 1989; 7.8 vs 6.2, p < .001), and on a Craving/Addiction scale (from the SCQ; Copeland, Brandon, and
Quinn, 1995; 7.9 vs 7.2, p < .05). They also rated themselves as marginally more addicted than the Neg Hx Ss
(9.2 vs 8.4 on a 10 pt scale; p < .06). However, they did not rate Addiction Barriers (from the BSC; MacNee and
Talsma, 1995) as more important in contributing to the difficulty of smoking cessation than the Neg Hx Ss. Pos
Hx Ss rated External Barriers (a measure of social support/intluences) as more important than did Neg Hx Ss. Pos
Hx Ss did not have more smokers in their households than Neg Hx Ss. Results suggest Pos Hx Ss especially
should receive nicotine replacement and will probably need more intensive therapy, particularly one that targets
social influences and support.
REFERENCES: Available upon request from John Hughes.
ACKNOWLEDGMENTS: This project is supported by NIAAA grant AA-09430 and NIDA RSDA DA-00109.
OPEN TRIAL STUDY OF TRANSDERMAL NICOTINE REPLACEMENT THERAPY IN
SMOKERS WITH COMORBID MENTAL ILLNESS
S. A. Wyatt, P. Harris, K. Trudeau, T. Kosten, and D. Ziedonis
Yale University School of Medicine, Department of Psychiatry
Nicotine dependence is more common in the mentally ill population than in the general population. However, there
are few studies of smoking cessation in this population. This open label smoking cessation trial compares 36
subjects (PATCH) who chose eight weeks of transdermal nicotine replacement to 23 subjects (NO PATCH) not
electing to use nicotine replacement at a community mental health center in an urban setting. All subjects received
psychosocial treatment at least once per week. The schedule for transdermal nicotine replacement was 21mg/d x 4
wks, then reduced to 14 mgs/d x 2 wks, and finally 7 mgs/d x 2 wks. Variations from this schedule are noted and
evaluated in the results. Subjects included fifty-nine smokers (68% female(n =41), 82% Caucasian (n =49), mean
age=44.5) with comorbidity for either schizophrenia(n=19), depression(n =16), bipolar d/o(n=17), or schizoaffective
d/o( n =7). No significanl difference was noted between the two study groups in age, race, or Fagerstrom scores.
However, in the PATCH group there were 2.1 times the attempts at abstinence than the NO PATCH group (7.2 to
3.4 times respectively). Twenty two percent of the PATCH group bad achieved at least 3 months abstinence
compared to only 4% of the NO PATCH group. In addition, only 8% of the PATCH group remained unchanged at
the conclusion of the study compared to 48% of the NO PATCH group. Notably, there was little difference in
treatment outcome between types of mental illness, however individual sample sizes were small. These results lend
evidence for improved outcome with the use of nicotine replacement in this population.
ACKNOWLEDGMENTS:
Supported by NIDA P50-DA04060 (TK) and K20-DA0193 (DZ).
160
EFFECTS OF AN ALTERNATIVE REINFORCER AND VARYING RESPONSE
REQUIREMENT ON SMOKING BY SCHIZOPHRENICS
J. W. Tidey, S. T. Higgins, and W. K. Bickel
Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT
Cigarette smoking and drug abuse are more prevalent among schizophrenics than the general population. In the
present study, we used a behavioral-economics approach to examine the effects of varying response requirement and
availability of an alternative reinforcer on smoking by schizophrenics under controlled laboratory conditions. The
behavioral-economics perspective predicts that smoking will decrease when its price (i.e., response requirement) and
opportunity cost (i.e., forfeiture of an alternative reinforcer) are high. Six volunteers were recruited from a local
mental hcalth center and had initial carbon monoxide (CO) readings of at least 18 ppm, indicative of heavy
smoking. Before each session, subjects went required to provide CO samples indicating recent (5-6 hrs) abstinence
from smoking. Subjects responded for the opportunity to smoke by pulling a plunger which was interfaced with a
microcomputer. The response requirement to obtain two cigarette puffs varied across sessions, ranging from 50 to
6400 responses. In half of the test sessions, subjects also were able to respond on another lever to earn a small
amount of money. At high response requirements, response output and cigarette smoking decreased. Regardless of
response requirement. smoking decreased when a competing alternative reinforcer was available. Combining both
factors produced maximal decreases in response output and smoking. These results are similar to those observed
previously in non-schizophrenic smokers, suggesting that smoking and perhaps other drug abuse by schizophrenics
may be controlled by contingency-management and other behavioral interventions known to be efficacious in nonschizophrenics.
ACKNOWLEDGMENTS:
Supported by NIDA grants RO1-DA-08076 and T32-DA-07232.
STUDIES ON ANALOGS OF THE DELTA-OPIOID AGONIST, SNC80: THE SEARCH FOR
SELECTIVE DELTA ANTAGONISTS
J. Janetka, K. McCullough† , C. Dersch† , H. Xu† , R. Rothman† , and K. Rice
Bethesda,
NIDDK, NIH,
Laboratory of Medicinal Chemistry,
Psychopharmacology Sect. IRP, NIDA, NIH, Baltimore, MD
MD and
†
Clinical
Delta ( ) opioid receptors have been reported to he involved in (a) mediation of analgesia. (b) the development of
opioid tolerance and dependence, (c) regulation of the mesolimbic dopaminergic pathway, and (d) mediation of some
effects of cocaine. SNC80 is a non-peptide opioid receptor agonist which has been shown to be highly selective
for opioid receptors from in vitro binding assays and smooth muscle bioassays. Highly selective d antagonists are
required to further study receptor function. Our goal in this study was to discover novel selective opioid receptor
antagonists. Burroughs Wellcome reported that compound 5 which contains a cis-2,5-dimethylpiperazine scaffold
relative to the trans-2.5-dimethylpiperazine of SNC80 was a selective antagonist. We synthesized compounds 16, and determined that they are all selective for the d receptor from in vitro binding assays with IC50 (µ ) ratios of
4.3 to 2985. It was found that the most potent and selective compound in the series was compound 5.
Interestingly, compounds 1, 3, and 5 have the same R stereochemistry at the dibenzylic center (C7) of SNC80 and
are the most selective in each diastereomeric series.
SNC80
BW373U86
1
2
3
4
5
6
161
R=allyl, R'=Me, 7R, 5R, 2S
R=allyl, R'=H, 7R(S), 5R(S), 2S(R) (±)
R=H, R'=Me, 7R, 5R, 2R
R=H, R'=Me, 7S, 5R, 2R
R=Me, R'=Me, 7R, 5R, 2R
R=Me, R'=Me, 7S, 5R, 2R
R=Me, R'=H, 7R, 5R, 2R
R=Me, R'=H, 7S, 5R, 2R
A NOVEL SYNTHESIS OF A PHENYLDECAHYDROISOQUINOLINE RELATED TO
MORPHINE
T. Fursy, A. Nemazany, J. L. Flippen-Anderson*, H. Xuˆ, R. B. Rothmanˆ, A. Hewlett + , B.
Berglund+, and K. C. Rice
Laboratory of Medicinal Chemistry, NIDDK, NIH, Bethesda, MD; *NRL, Washington, DC;
CPS, IRP, NIDA, Baltimore, MD; and + St. Louis University, Medical School, Department of
Pharmacology, St. Louis, MO
The oxide bridged 4a-phenyldecahydroisoquinoline ring system 1 is a morphine partial structure and drugs within
this series exhibit potent agonist or antagonist profiles depending on the nitrogen substituent. We now report a
novel synthesis of the isomeric ring system 2 in six steps from the commercially available 3-methoxyphenethyl
amine. This approach for the synthesis of morphine related structures utilized an acid catalyzed inlramolecular
cyclizadon in which the aromatic ring was tethered to an octahydroisoquinoline ring system via an oxygen atom.
The structure of amine 2 was unambiguously established by single crystal X-ray analysis of the oxalate salt which
revealed the trans-decahydroisoquinoline configuration. Compound 2 failed to show significant binding to mu, delta
and kappa-opioid receptors and the brain cannabinoid receptor.
ANATOMICAL DISTRIBUTION OF A NOVEL KAPPA2 OPIOID RECEPTOR IN GUINEA
PIG BRAIN VISUALIZED WITH [125I]IOXY
J. S. Partilla*, Q. Ni*, K. C. Riceˆ, D. Mateckaˆ, and R. B. Rothman*
*CPS, DIR, NIDA, NIH, Baltimore, MD and ˆLMC, NIDDK, NIH, Bethesda, MD
Previous studies demonstrated unique opioid receptor distributions in guinea pig brain sections at the level of the
caudate putamen. Mu, delta, and kappa, receptors were depleted by the irreversible ligands BIT, FIT, and UPHIT,
and opioid receptors were labeled with the opioid antagonist [125I]IOXY and subjected to autoradiographic analysis.
The objective of this study was to characterize further these unique binding sites (designated kappa2). Kappa2 binding
was quantitated by autoradiography in specific regions of four different levels of guinea pig brain (olfactory bulb,
caudate putamen, hippocampus, and substantia nigra) for a total of 37 determinations across all levels. The kappa2
distribution was then compared with the binding sites labeled by [125I]DAMGO (mu), [125I]deltorphin II (delta), and
[125I]IOXY under kappa1 conditions to identical regions in adjacent guinea pig brain sections. The results are: (1)
kappa2 binding greatly exceeded mu and delta binding in all regions; (2) kappa2 binding exceeded kappa, binding in
all regions except the deep cortex at the level of the hippocampus; (3) the kappa, distribution was different than that
of mu, delta or kappa, receptors. These results provide further evidence for the existence of a novel opioid binding
site in guinea pig brain.
ACKNOWLEDGMENT:
Generously supported by NIDA Intramural Research Program.
162
MOLECULAR CHARACTERIZATION OF LIGAND-RECEPTOR INTERACTIONS OF RTI4614-4 AND ITS FOUR STEREOISOMERS
H. Xu1 , Y. F. Lu1 , J. S. Partilla 1 Q. X. Zheng 1 J. B. Wang 2 , G. A. Brine 3 , F. I. Carroll1 , K.
1
C. Rice 4 , and R. B. Rothman
1
CPS, DIR, NIDA and 4 LMC, DIR, NIDDK, NIH, Baltimore and Bethesda, MD;
Baltimore, MD; and 3RTI, Research Triangle Park, NC
2
UMAB,
Previous data, obtained with cloned rat µ receptors, demonstrate that the “super-potent” opiates, RTI-4614-4 and its
four stereoisomers differ in binding affinity, potency, efficacy and intrinsic efficacy. We speculate that this results
from binding to different domains of the µ opioid receptor. Molecular modeling (Tang Yun et al., 1995) of fentanyl
derivatives binding to µ receptors indicated that important residues are Asp147, Tyr148, Trp318 and His319.
Asp147 (TMH3) was required to interact with the positively charged opiate agonist in forming potent electrostatic
and hydrogen-bonding interactions. In this study, the role of weak electrostatic and hydrogen-bonding
inceractions of the O atom of the carbonyl group and me phenyl ring structures of RTI-414-4 and its four
stereoisomers with residues Tyr148, Trp318 and His319 were explored through site-directed mutagenesis. Tyr148, in
the TMH3, Trp318, His319 in the TMH7 were individually replaced with phenylalanine or alanine. Mutation of
Tyr148 reduced the binding affinities of the RTI-4614-4 and its stereoisomers (2-7 fold), but did not alter me
aftinities of the peptide µ agonist DAMGO, the antagonist naloxone and the non-selective opiates etorphine and
buprenorphine. Mutation of Ttp318 eliminated me ability to bind different opioid ligands (DADL, bremazocine and
IOXY). TMH7 histidine substitution with alanine yielded a receptor with significantly reduced binding affinities for
the opioid ligands tested. These results indicate the importance of these residues for the binding of fentanyl
derivative to the µ receptor. Functional studies using the mutant receptors in transfected cos-7 cells will provide
additional insight into the mechanism of action of RTI-4614-4 and its four stereoisomers.
ACKNOWLEDGMENTS:
Generously supported by NIDA Intramural Research Program
EVIDENCE FOR INACTIVATION OF cAMP DEPENDENT PROTEIN KINASE IN SPINAL
CORD BEING INVOLVED IN MORPHINE WITHDRAWAL IN RATS
Z. Wenhua, Z. Yahai, Z. Fuqiang, and Y. Guodong
Ningbo Institute of Microcirculation and Henbane, Ningbo, China
This laboratory has shown that inactivation of cAMP dependent protein kinase (PKA) within me spinal cord during
the morphine withdrawal in rats cannot be explained by increasing intracellular cAMP levels, Additional studies are
needed to identify whether inactivation of PKA in spinal cord mediates the morphine withdrawal. The present study
was undertaken to examine the effects of Sp-cAMPS, a potent membrane-permeable inhibitor of PKA, Rp-cAMPS,
a specific membrane-permeable inhibitor of activation of PKA. or calyculin A, an inhibitor of protein phosphatase
by intrathecal injection on the morphine withdrawal. Catheterizalion of the spinal subarachnoid space was
performed by inserting a length of PE10 tubing, terminated in me T11-T12 segments of the spinal cord. Male
Sprague Dawley rats (n=7, in each group) were made morphine dependence after recovery from the surgical procedure
Pretreamtent with 90 nmol/kg SP - cAMPS (i.t) or 100 pmol/kg calyculin A (i.t), the total rating of naloxone (4
mg/kg,ip) precipitated withdrawal signs across the session were 5.5±2.3 and 15.7±3.6, which were different
significantly from that of placebo (27.8±5.9). while concurrent with 100 nmol/kg RP-cAMPS (i.t) could not
inhibit the withdrawal symptoms. The observations showed that inactivation of PKA in the spinal cord may
account for the activation of protein phosphatase and enhance of PKA holenzyme re-association, which mediate the
morphine withdrawal.
163
PHOSPHORYLATION OF MU OPIATE RECEPTOR AND DOPAMINE TRANSPORTER
R. A. Vaughan1 , J. B. Wang 3 , Y. Yu3 , R. A. Huff1 , and G. R. Uhl1
1
Molec Neurobiol, NIDA-IRP, Baltimore, MD; Depts of Neurology and Neurosci, JHUSM;
and 3Dept Pharmacol, Sch Pharm, UMAB, Baltimore, MD
Phosphorylation regulates the activities of a number of important brain proteins. The primary amino add
sequences of the dopamine transporter (DAT) and µ opiate receptor (µOR) reveal consensus phosphorylation sites
for several protein kinases. Phorbol esters that stimulate PKC activity regulate dopamine uptake and µ receptor
desensitization. Phospho-DAT and µOR can be demonstrated in expressing cultured cells, brain slices and/or
synaptosomes following incubation with [32P]-orthophosphate, immunoprecipitation with specific antibodies,
SDS-PAGE and autoradiography. Several lines of evidence support the specificity of labelling in each case.
Pbosphorylation levels of both proteins are increased by PKC. Evidence for possibly-rapid turnover of phosphate
incorporation comes from studies with and without phosphatase inhibitors. Mu receptor phosphorylation levels are
also enhanccd by agonists in a fashion that is not blocked by the PKC blocker staurosporin, but relates to the
potency and intrinsic activity of the agonist. Methadone, which stimulates phosphorylation better than morphine
despite lower agonist potencies than morphine in two test systems, provides an exception to this relationship.
Phosphorylation/dephospborytation events provide possible mechanisms for rapid regulation of circuits important
for cocaine and opiate reward. Conceivably, these adaptive mechanisms could play roles in the activities of agonist
replacement/substitution/blocking therapeutics for opiate and even cocaine dependence
DOSE-DEPENDENT EFFECTS OF HEROIN ON MESOLIMBIC MODULATION OF
SYNAPTIC TRANSMISSION IN THE DENTATE CYRUS
J. R. Criado, S. C. Sleffensen, R.-S. Lee, and S. J. Henriksen
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
Conditioning stimulation of the VTA produces a robust facilitation of perforant path to hippocampal dentate
population spike (PS) amplitudes that is inhibited by alcohol. Similar cellular substrate(s) for alcohol and opiates
has been suggested. However, it is still unclear whether heroin has an effect on mesolimbic modulation of
hippocampal function. Previous studies have shown that opioids, acting via µ receptors, generally enhances
perforant path evoked activity in the dentate gyrus. Moreover, opiates and opioid peptides have been shown to
enhance transmission of auditory sensory information from the entorhinal cortex to the dentate gyrus. To
understand further the neuropharmacological substrates of opioid abuse, we sought to pharmacologically characterize
the effects of heroin on VTA-induced facilitation of synaptic transmission in the dentate gyrus of anesthetized
Sprague-Dawley rats. Stimulation of perforant path (0.1 Hz) produced typical evoked recordings in the dentate
gyrus. High frequency stimulation (HFS; 400 Hz for 10 ms) of the VTA markedly increased PS amplitudes, but
had no effect on perforant path to dentate population excitatory postsynaptic potentials. Our results indicated that
systemic administration of a high dose of heroin (0.6 mg/kg) significantly increased VTA facilitation of perforant
path to dentate responses. On the other hand, VTA facilitation was markedly reduced after administration of a lower
dose of heroin (0.1 mg/kg). The fact that naloxone given systemically (5.0 mg/kg), but not locally into the dentate
gyrus, markedly decreased baseline VTA facilitation of PS amplitudes indicate that endogenous opioids may mediate
this modulation of dentate physiology via an extra-hippocampal mechanism(s). These results demonstrate the
importance of opioid mechanisms on subcortical modulation of hippocampal function.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-08301 to SJH and AA-10075 to SCS.
164
ELECTROPHYSIOLOGICAL SUBSTRATES OF HEROIN SELF-ADMINISTRATION
R.-S. Lee, J. R. Criado, S. C. Steffensen, J. L. Giacchino, P. Griffin, S. Casalman, G.
Berg, and S. J. Henriksen
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
Mesolimbic dopamine (DA) neurons projecting from the ventral tegmentat area (WA) to the nucleus accumbens
(NAcc) are a critical component of the neural substrates mediating opiate reinforcement. A recent study
demonstrated that a DA-independent mechanism within the VTA itself mediates the rewarding properties of
morphine only when animals were previously naive or in non-deprived opiate states. To understand further the
neuropharmacological substrates responsible for opiate reinforcement, we are characterizng the neuronal responses
of NAcc and VTA non-DA neurons during the acquisition of heroin self-administration. Our data suggest that
during the initial sessions of heroin self-administration. an anticipatory increase in NAcc unit activity was observed
seconds before the rat nosepoke for a heroin infusion. However, this anticipatory increase in NAcc unit activity was
not present after seven sessions of heroin self-administration. As expected, non-contingent administration of heroin
in freely-moving rats and systemic administration of heroin in anesthetized rats markedly suppressed spontaneously
active VTA non-DA neurons. Administration of naloxone (5 mg/kg) not only reversed these effects, but produced a
rebound excitation. During acquisition of heroin self-administration, lever pressing for a heroin infusion produced a
marked suppression in the activity of VTA non-DA neurons. However, later in the same session (after 5 lever
presses), we observed a marked desensitization of the heroin-induced suppression of VTA non-DA neuronal activity.
These results demonstrate complex neurophysiologicat interactions in the NAcc and the VTA during the acquisition
of heroin self-administration. Characterization of the neuropharmacological mechanisms responsible for these
effects might provide us with valuable information on the basis for the addictive properties of heroin.
ACKNOWLEDGMENTS:
Supported by grants DA-08301, DA-00201, M-10075.
MICROINJECTIONS OF CTOP INTO THE VENTRAL PALLIDUM
DEVELOPMENT OF SENSITIZATION TO CHRONIC MORPHINE
BLOCK THE
P. I. Johnson and T. C. Napier
Department of Pharmacology, Neuroscience and Aging Institute Maywood, IL
The ventral tegmental area (VTA) is critical for the development of an opioid-induced sensitized motor response
whereas the nucleus accumbens (NAC) is important for the expression of this behavior. Given the direct
projections from the VTA and the NAC to the ventral pallidum (VP), and the probability of generalized system
alterations following chronic drug exposure. it is likely that the VP plays a role in the opioid sensitization
phenomenon. The following study investigated this possibility. Once a pretreatment baseline activity was
determined for each subject, rats were randomly assigned to one of three groups: the Sat-Sal group (n = 6) received
an intra-VP micminjection of saline (0.5 ml/side) 10 min prior to an ip saline injection; the Sal-Mor group (n = 6)
received an intra-VP microinjection of saline (0.5 ml/side) to min prior to an ip injection of morphine (10 mg/kg),
and the CTOP-Mor group (n = 6) received an intra-VP microinjection of the mu receptor antagonist, CTOP (2.1
mg/0.5 ml/side), 10 min prior to an ip injection of morphine (10 mg/kg). This procedure was repeated daily for 5
consecutive days. Two days after the final drug injection, all rats received an acute morphine (10 mg/kg. ip)
challenge with no intra-VP treatment ANOVA analysis with planned contrasts revealed that only the rats in the
Sal-Mor group displayed a sensitized motor response to the acute morphine challenge (400% increase over
pretreatment baseline activity; p < 0.001). Scheffe’s post hoc tests revealed that the Sal-Mor group was different
from the Sal-Sal and the CTOP-Mor groups (p < 0.001, whereas the Sal-Sal and CTOP-Mor groups were not
ditferent from each other (p = .78). Because opioid blockade in the VP inhibits the development of morphineinduced sensitization, it appears that the VP is important in the opioid sensitization phenomenon.
ACKNOWLEDGMENTS:
Supported by USPHSGs DA05651 to PU and DA05255 to TCN
165
DYNORPHIN RELEASE FROM THE PREOPTIC ANTERIOR HYPOTHALAMUS DURING
INTERLEUKIN-1 FEVER
L. Xin, E. B. Geller, M. R. McCafferty, G. H. Sterling, and M. W. Adler
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA
We have demonstrated that µ-opioid receptor agonists induce hyperthermia when they are administered into the
brain, while the -opioid receptor agonist dynorphn A1-17 (Dyn) induces hypothermia. The pyrogenic cytokine
interleukin-1 (IL-1), injected into the brain, increases -endorphin ( E) release from the preoptic anterior
hypothalamus (POAH) and produces fever. Because the IL-l-induced fever can be entranced by pretreament with the
-opioid receptor antagonist nor-BNI, and there is a tonic basal release of both -E and Dyn from me POAH, we
postulate that there may be a functional balance, in terms of thermoregulalion, between the two peptides within the
POAH. In the present study, we investigated whether Dyn release from this region changed during IL-1-induced
fever. Microdialysis samples were collected from the POAH of freely moving S-D rats every 30 min at a rate of 4
µl/min for 4 hrs and analyzed for Dyn level by radioimmunoassay. Baseline release of Dyn was 0.3 - 0.58
fmol/fraction. Microinjection of IL-I (1000 LD induced a 130-180 % increase in Dyn release over baseline 60-90
min after injection. The Dyn increase occurs later than the -E increase (30 min) during IL-1 fever. Because the
increase in Dyn release follows that of -E and pretrearment with the -opioid receptor antagonist nor-BNI enhances
the IL-1 fever, it suggests that an endogenous opioid peptide balance system and/or a feedback regulatory mechanism
may exist in the POAH during cycokine-induced fever.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 00376.
MORPHINE DIFFERENTIALLY MODULATES HPA AXIS ACTIVITY IN RATS WITH OR
WITHOUT WATER DEPRIVATION STRESS
Y. Zhou, R. Spangler, C. E. Maggos, K. S. LaForge, A. Ho, and M. J. Kreek
Laboratory of Biology of Addictive Diseases, The Rockefeller University, NY
Acute administration of exogenous opioids (e.g., morphine) in the rat stimulates secretion of hypothalamicpituitary-adrenal (HPA) hormones: adrenocorticotropin (ACTH), beta-endorphin and corticosterone (B). The present
studies investigated the effects of morphine on the HPA activity under two different conditions: with or without
water deprivation (WD) stress. Six injections of morphine (6.25 mg/kg/injection, s.c.) or saline were given every 2
hours during the light cycle. Animals were divided into 2 groups: one with water supply (morphine, n=12; saline,
n=12); another with WD beginning 30 min before and during morphine or saline administration. Animals were
sacrificed 30 min after the last morphine or saline injection. Plasma ACTH and B were measured by RIA. The
levels of proopiomelanocortin (POMC) mRNA in both the anterior lobe (AP) and the neurointermediate
lobe/posterior lobe of the pituitary gland, as well as in the hypothalarnus (Hypo) and amygdala were measured.
Results: (1) Morphine alone caused significant elevations of both ACTH and B levels in the absence of WD; WD
alone also significantly inreased ACTH levels. However, the WD rats treated with morphine failed to show any
increases in ACTH or B levels. (2) Morphine alone significantly elevated CRF mRNA in the hypothalamus.
However, the rats treated with morphine under WD condition did not show any CRF mRNA increases. (3)
Morphine alone did not change POMC mRNA levels in the AP; WD alone significantly increased AP POMC
mRNA. However, the WD-induced increase of AP POMC was attenuated by morphine. (4) In the Hypo, morphine
alone significantly increased POMC mRNA; whereas WD alone had no effects. Further, the stimulatory effects of
morphine on the Hypo POMC were also absent during WD. These observations suggests that the effects of
morphine on the HPA activity may be altered by external stressors.
ACKNOWLEDGMENTS:
Supported by NIDA P50-DA05130 and DA00049.
166
DYNORPHIN A1-13 ELEVATES SERUM PROLACTIN LEVELS BY AN OPIOID RECEPTOR
MECHANISM: CONTROLLED STUDIES OF NORMAL VOLUNTEERS
L. Borg, J. Schluger, S. Maniar, M. Porter, M. Gunduz, A. Ho, and M. J. Kreek
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, NY, NY
In an earlier pilot study1, we have shown that dynorphin A1-13 effects an elevation of serum prolactin levels in
human subjects. Since prolactin release in humans is primarily under tonic inhibition by dopamine, dynorphin
presumably acts to lower dopaminergic tone in the tubero-infundibular system. Therefore, placebo-cotrolled
studies of dynorphin A1-13 effects was conducted in healthy normal volunteer subjects with no history of drug or
alcohol abuse. 1) To study dosage effects, low (120 mgm/kg body weight) and high (500 mg/kg body weight)
dose dynorphbin A1-13 were given iv. To determine if any effect is mediated by an opioid receptor mechanism. 2)
naloxone (10 mg) a specific opioid antagonist, was given iv 30 minutes before iv low dose dynorphin A1-13. 3)
naloxone (30 mg) was injected 30 minutes before giving low dose dynorphin A1-13. 4) nalmefene (30 mg), a
different specific opioid antagonist with greater receptor activity was given 30 minutes before low dose dynorphin
A1-13. Blood specimens for prolactin levels were obtained over 6 hours, and assayed by RIA. As in the pilot study.
we found that dynorphin A1-13 in normal volunteers causes a prompt, dose-dependent rise in serum prolactin
(p<0.05), peaking at 10-40 minutes. Naloxone, a primary µ opioid receptor antagonist, had a modest effect at 10
mg (pc<0.05) and a greater, longer lasting effect at 30 mg (p<0.001) in attenuating dynorphin-induced elevation of
serum prolactin. Nalmefene, also primarily a m opioid receptor antagonist but with more opioid effect also
attenuated the dynorphin elevation of serum prolactin (p<0.05). These findings confirm that dynorphin affects the
physiology of prolactin release, through an opioid receptor mechanism. 1Kreck, M.J.; Ho, A.; and Borg, L. NIDA
Res Monogr 141:108, 1994.
ACKNOWLEDGMENTS:
NIH-NIDA P50-DAO5130, NIH-MDA KO5-DA00019, NY State:OASAS,
GCRC (M01-RR00102) from the National Center for Research Resources at the NIH.
RESPIRATORY STIMULATION DUE TO PRECIPITATED OPIOID WITHDRAWAL AND
ITS INHIBITION IN RHESUS MONKEYS
S. Kishioka and J. H. Woods
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Ml
We previously reported that respiratory parameters, that is, respiratoryfrequency (f) and minute volume (Ve), were
increased in µ-opioid withdrawal in rhesus monkeys (INRC, 1996, Long Beach, CA). Clonidine (alpha2adrenoceptor agonist), MK-801 (NMDA antagonist) and diltiazem (Ca++ channel blocker) have been reported to
suppress some opioid withdrawal signs. In this experiment we examined whether clonidine, MK-801 and diltiazem
suppressed naltrexone-induced morphine and heroin withdrawal estimated by respiratory parameters in rhesus
monkeys. Six adult rhesus monkeys were exposed to normal air and air mixed with 5% CO2: f, Ve and tidal
volume (Vt) were measured using a pressure-displacement plethysmograph technique. To produce the acute
dependence, monkeys were given morphine (10 mg/kg/day) or heroin (0.32 mg/kg/day) for two consecutive days,
Twenty-four hrs later, naltrexone (0.001 - 1 mg/kg) was administered using a cumulative dosing procedure.
Clonidine (0.01 and 0.1 mg/kg), MK-801 (0.1 mg/kg) or dilthiazem (40 mg/kg) was injected 30 min before
naltrexone administration. In monkeys that were pretreated with morphine or heroin, f and Ve were increased dosedependently following administration of naltrexone (antagonist-precipitated opioid withdrawal). Clonidine dosedependently suppressed naltrexone-precipitated respiratory stimulation in both morphine- and heroin-pretreated
monkeys. Alternatively, a large dose of MK-801 and diltiazem failed to alter the naltrexone-precipitated increases
in respiration in these monkeys. These results suggest that drugs that are known to suppress some signs of opioid
withdrawal not necessarily affect all aspects of the opioid-antagonist precipitated withdrawal syndrome in acutely µopioid dependent monkeys.
ACKNOWLEDGMENTS:
Supported by the M.H. Seevers Fellowship Fund and USPHS Grant DA-00254.
167
DISCRIMINATIVE STIMULUS EFFECTS OF NALOXONE AND NALTREXONE
ADMINISTERED S.C. AND P.O. IN MORPHINE-TREATED RHESUS MONKEYS
C. A. Gauthier and C. P. France
Department of Pharmacology, Louisiana State University Medical Center, New Orleans, LA
The current study evaluated the discriminative stimulus effects of naloxone and naltrexone after oral and parenteral
administration. Four morphine-treated (3.2 mg/kg/day) rhesus monkeys discriminated between s.c. injections of
naltrexone (0.01 mg/kg) and saline while responding under a fixed-ratio 5 schedule of stimulus shock termination.
Subjects were named in daily sessions consisting of several discret 15-min cycles, with each cycle comprising a
10-min time-out followed by a 5-min response period. The discriminative stimulus effects of naloxone and
naltrexone were evaluated every 15 min over a 2-hour period. For p.o. administration, drugs were mixed in fruit
punch. When administered s.c., naloxone or naltrexone produced greater than 90% drug-appropriate responding at a
dose of 0.032 or 0.01 mg/kg, respectively. When administered p.o., naloxone or naltrexone produced greater than
80% drug-appropriate respondiug at doses of 3.2 or 1.0 mg/kg. respectively. When administered s.c., the onset of
action was 15 min for both drugs; when administered p.o., the onset of action was 30 min for naloxone and 45 min
for naltrexone. Although both drugs were at least 60 to 100-fold more potent s.c. as compared to p.o., there was
little or no difference in the potency of naloxone and naltrexone overall. These results fail to support the view that
naloxone might be especially useful for some therapeutics (e.g. Talwin Nx) because of its reduced bioavailability
after p.o. administration.
ACKNOWLEDGMENT:
Supported by USPHS grant DA05018.
EVIDENCE OF PHARMACOLOGICAL SELECTIVITY IN PIGEONS DISCRIMINATING
FENTANYL. BREMAZOCINE AND WATER
C. D. Cook and M. J. Picker
Department of Psychology, University of North Carolina, Chapel Hill, NC
The discriminative stimulus effects of opioids with activity at mu and kappa receptors were examined in pigeons
discriminating the mu opioid fentanyl. the kappa opioid bremazocine and water in a three-choice discrimination task.
Apparent pkB values obtained for naloxone as an antagonist of fentanyl were higher than those obtained against
bremazocine. Morphine and l-methadone substituted for the fentanyl stimulus, U50,488 and U69,593 substituted
for the bremazocine stimulus, and pentobarbital failed to substitute for either stimulus. Opioids with activity at
both mu and kappa sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)ketoclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced fentanyl responding without
producing bremazocine responding. At doses that did not substitute for the fentanyl stimulus, (-)-NANM,
levallorphan, nalorphine and nalbuphine antagonized partially the bremazocine, stimulus. Butorphanol and
buprenorphine antagonized bremazocine at doses that substituted for fentanyl, yet ethylketocyclaxocine and (-)ketocyclazocine failed to antagonize bremazocine. The present findings indicate that in this three-choice task the
fentanyl-like substitution patterns produced by these opioids are similar to those reported in pigeons discriminating
either fentanyl or bremazocine from saline (i.e., two-choice tasks). In this task, however, the level of kappa
antagonist activity observed was considerably less than that obtained in pigeons trained to discriminate bremazocine
from saline.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA10277, DA07327 and DA07244.
168
DISCRIMINATIVE STIMULUS PROPERTIES OF THE PARTIAL MU AGONIST
DEZOCINE
M. A. Smith and M. J. Picker
Department of Psychology, University of North Carolina, Chapel Hill, NC
The purposc of this investigation was to evaluate the discriminative stimulus effects of the partial mu agonist
dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, the mu agonists fentanyl, I-methadone,
morphine, butorphanol, buprenorphine, nalbuphine and (+)-propoxyphene substituted completely for the dezocine
stimulus. The (-)-isomers of cyclazocine, n-ahylnormetazocine and metazocine, but not their respective (+)-isomers,
also produced high levels of substitution for the dezocine stimulus. Naloxone antagonized the stimulus effects of
dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized
fentanyl’s rate-decreasing effects did not systematically alter the rate-decreasing effects of dezocine and (+)propoxyphene. The mu-selective, noncompetitive antagonist beta-funaltrexamine was more effective against the
stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. The delta agonists BW373U86 ad
SNC80 produced high levels of substitution for the dezocine stimulus, and these effects were reversed by a dose of
naltrindole that had no effect on the dezocine stimulus. The kappa agonists bremazocine, spiradoline, U50,488 and
U69,593, as well as various nonopioid compounds failed to substitute for the dezocine stimulus. The present
fmdings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, is less efficacious at
the mu receptor than either morphine or fentanyl, and its rate-decreasing effects are not mediated by activity at mu,
kappa or delta opioid receptors.
ACKNOWLEDGMENT:
Supported by NIDA grant DA10277
DRUG DISCRIMINATION IN PIGEONS SUCCESSIVELY TRAINED TO DISCRIMINATE
THE MU OPIOID BUTORPHANOL AND THE KAPPA OPIOID BREMAZOCINE
M J. Picker, C. D. Cook, D. Morgan, and M. A. Smith
Department of Psychology, University of North Carolina, Chapel Hill, NC
In Phase 1, pigeons were trained to discriminate butorphanol(1.0 or 5.6 mg/kg) from saline using a standard, two
key, food-reinforced, drug discrimination procedure. During substitution tests, the mu opioids morphine and
fentanyl substituted completely for the butorphanol stimulus, whereas the kappa opioids bremazocine, U50,488 and
U69,593 produced predominantly saline-appropriate responding. In Phase 2, the same pigeons were retrained to
discriminate bremazocine (0.017 mg/kg) from saline. After this discrimination was established, tests revealed that
(1) bremazocine, U50,488 and U69,593 substituted completely for the bremazocine stimulus, (2) as in Phase 1,
complete substitution was obtained with butorphanol, morphine and fentanyl, (3) naloxone was more effective as
an antagonist of the bremazocine stimulus than the butorphanol stimulus, (4) chronic administration of
bremazocine produced tolerance to the bremaxocine stimulus but not to the butorphanol stimulus, (5) selected doses
of butorphanol shifted the bremazocine curve to the left in an effect-additive manner, whereas selected doses of
bremazocine shifted the butorphanol curve to the left in an effect-additive manner, and (6) one year of training with
bremazocine did not alter the dose-effect curve for the butorphanol stimulus, the present findings indicate that the
discriminative control produced butorphanol was retained during extensive training with bremazocine, and that
discriminative control exerted by butorphanol and bremaxocine could be differentiated using various pharmacology
probes.
ACKNOWLEDGMENT:
Supported by NIDA grant DA10277.
169
MORPHINE AND NALTREXONE ENHANCE GBRl2909-INDUCED ROTATIONAL
BEHAVIOR
H. L. Kimmel and S. G. Holtzman
Emory University School of Medicine, Atlanta, GA
In nigrally-lesioned rats, the mu-opioid receptor agonist morphine potentiated amphetamine- and cocaine-induced
turning. To investigate further the relationship between brain opioid and dopamine systems, we examined the effects
of morphine and opioid antagonists on turning induced by the selective dopamine uptake inhibitor, GBR12909.
GBR12909 (3.0-30 mg/kg) dose-dependently produced turning that was potentiated by morphine (0.1-3.0 mg/kg)
and the nonspecific opioid receptor antagonist naltrexone (0.3-3.0 mg/kg), but not by naloxone (0.3-3.0 mg/kg) or
the selective opioid receptor antagonists -funaltrexamine (mu) (3.0-10 µg), naltrindole (delta) (3.0-10 µg), and norbinaltorphimine (kappa) (3.0-10 µg). These results leave unclear what, if any, role opioids have in GBR12909induced turning. However, the observed effects of naltrexone and naloxone suggest a novel difference between the
actions of these two drugs.
ACKNOWLEDGMENTS:
Supported by Grants DA00541 Research Scientist Award K05 DA00008, and
NRSA Predoctoral Fellowship F31 DA05692-01, all from NIDA, NIH.
STATE-DEPENDENT LEARNING:
AFFECTED BY DRUG DOSE
PERFORMANCE ON A COMPLEX MAZE TASK IS
J. M. Stahl, K. E. Brakke, S. N. Lewis, and C. L. Lawrence
Department of Psychology, Morris Brown College, Atlanta, GA
State-dependent learning (SDL) is a phenomenon closely associated with drug discrimination (DD) research. In
SDL. a response learned in one chemical state fails to transfer completely to another chemical state. In most
research to date, simple response topographies, such as operant conditioning lever-pressing or T-maze performance,
have been used to evaluate SDL and DD effects. In this study, performance on a more complex task, completion of
Small’s (1901) Hampton Court maze, was evaluated. Thirty naïve adult male Long-Evens hooded rats were given
injections of either saline or morphine solution and then introduced to the - for five trials per day until they
reached criterion performance of three days with stable running time awl less than one error per day. Once the
learning curve for the first state was established, subjects were switched to the other condition and a new learning
curve was established. Results indicated that runtime increased at morphine doses of 10 mg/kg and 15 mg/kg, but
not at 6 mg/kg, regardless of whether the switch was from saline to morphine or vice versa. Errors increased when
animals initially switched from morphine to saline for all doses. The number of trials required for all groups to
return to errorless performance was significantly less than in the initial drug state, indicating interruption of retrieval
rather than loss of information. When subjects switched back to the original state, no significant performance
decrements occurred. These results are consistent with a state-dependency interpretation.
ACKNOWLEDGMENT:
Supported by NIDA-MIRD grant 5R24DA07256-06.
170
R O L E O F 2-OPIOID RECEPTOR
MORPHINE-DEPENDENT MICE
IN
NALOXONE-INDUCED
PLACE
AVERSION
IN
H. Kato, T. Suzuki, M. Misawa, and H. Nogase*
Department of Pharmacology, School of Pharmacy, Hoshi University, Japan. *Basic Research
Laboratories, Toray Industries, Inc., Japan
It has been reportted that the expression of naloxone-induced place aversion can be measured using conditioned place
preference (CPP) paradigm in morphine-dependent rats. The aim of the present study was (1) to establish a
measuring method of naloxone-induced place aversion in morphine-dependent mice using the CPP paradigm, and (2)
to examine the effects of 2-opioid receptor antagonists on the naloxone-induced place aversion. In the morphine&pet&m mice, naloxone (0.3-3 mg/kg, s.c.) significantly produced a place aversion in a dose-dependent manner.
The naloxone-induced place aversion was significantly suppressed by pretreatment with clonidine or diazepam. These
fmdings are consistent with previous reports using rats, suggesting that the naloxone-induced place aversion in the
morphine-dependent mice can be an index of the degree of physical dependence on morphine using the CPP
paradigm. Therefore. we investigated the effect of -opioid receptor antagonists on the naloxone-induced aversion
using this paradigm. Pretreatment with NTI (1-5 mg/kg, s.c.), a non-selective -opioid receptor antagonist, and
naltriben (NTB; 0.05-0.5 mg/kg, s.c.), a selective 2opioid receptor antagonist, but not with 7benzylidenenaltrexone (BNTX; 0.3-3.0 mg/kg. s.c.), a selective 1 opioid receptor antagonist, during chronic
morphine treatment suppressed the naloxone-induced place aversion. These findings suggest that -opioid receptors,
especially 2-opioid receptors, may be involved in the development of physical dependence in morphine-dependent
mice.
IN FOOD AND MORPHINE OPERANT
GENETIC DIFFERENCES
BEHAVIOR IN FOUR INBRED RAT STRAINS
REINFORCED
S. Martin*, C. García-Lecumberri@, J. A. Crespo*, R. Ferrado*, S. Izenwasser#, G. Elmer#,
and E. Ambrosia*
* Departamento de Psicobiología, UNED, Madrid, Spain; @Departamento de Psic.Biológica y
de la Salud, UAM, Madrid, Spain; and #Division of Intramural Research, NIDA/NIH,
Baltimore, MD
It is well known that exists large individual variability in response to drugs of abuse. In a previous work (Ambrosio
et al., Behav. Pharmacol., 6(3), 1995), we have shown that there are significant differences in the rate of acquisition
of morphine self-administration behavior in four inbred strains of rats(Lewis>>Fischer344,NBR and ACI). In order
to determine if the genetic differences found could become extensive to natural reinforcers like food. we have studied
that possibility in the above cited four inbred rat strains on a Fixed Ratio (FR) and a Progressive Ratio (PR)
schedule of reinforcement. Eleven male rats of each inbred strain were trained to lever press for food pellets on a
FR1 schedule in 60’ sessions daily for 8 days. Following this acquisition period, subjects were put on a PR operant
schedule in 3 h sessions over an additional 15 days period. Three months later, all these four inbred strain groups
were surgically prepared to intravenous self-administer 1 mg/kg/injection of morphine on the previous PR schedule
in 23 h sessions dally for 15 days, followed by two weeks of extinction period. On the PR schedule, the response
requirements for each food pellet or i.v injection escalates according to the series: 2.3,5,7,11,15… The number of
the reinforcers earned before responding ceased was defined as the breaking point. Rate of acquisition for food pellets
on FRIschedule was significantly greater in Lewis and NBR rats compare to Fischer 344 and ACI rats. There were
no significant differences in breaking points for food pellets on PR schedule between the four inbred strain tested.
Breaking points for 1 mgl/kg/injection of morphine were significantly higher in Lewis rats compare to the other
inbred rat strain. There were no significant differences during the extinction period. These results contirm a
significant main effect of genotype in the reinforcing effects of morphine as measured by a PR schedule of
reinforcement, but they also suggest that Lewis rats could have a high capability to learn or perform operant lever
pressing tasks that might be interpreted as drug preference in operant conditioning paradigms.
ACKNOWLEDCMENT:
Supported by DGICYT Grant PB93-0290.
171
COMPARISON OF THE REINFORCING EFFECTS OF INTRAVENOUS AND
INTRANASAL HEROIN IN HUMANS
S. D. Comer, E. D. Collins, and M. W. Fischman
New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia
University, New York, NY
Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week
inpatient study comparing the effects of intranasal (placebo, 12.5, 25, 50, 100 mg) and intravenous (placebo, 6.25,
12.5, 25, 50 mg) beroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon
they had the opportunity to self-administcr all or part of the morning heroin dose or money amount. Participants
responded under a modified progressive-ratio schedule (PR 50, 100, 200, …, 2800) during a 10-trial selfadministration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/1001 of the
money amount. The PR value inreased independently for each option, the total amount of heroin and/or money
chosen during the self-administration task was given at the end of the task. Participants received i.v. solution and
i.n. powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related
increases in break point values by both routes of administration. The mean dose that maintained half-maximal
responding (ED50) for i.v. and i.n. heroin were 12.3 and 51.1 mg, respectively. Although i.v. heroin was
approximately 4-fold more potent than i.n. heroin, the maximal break point values for both routes were not
significantly different. A similar difference in potency between the i.v. and i.n. routes was also found for subjective
effects ratings and physiological effects. Ratings of "nodding,” were elevated after i.v., but not i.n. heroin.
Correspondingly, task performance was more severely impaired after i.v. heroin. These results demonstrate
similarities in efficacy, but differences in potency, for the reinforcing effects of i.v. and i.n. heroin.
ACKNOWLEDGMENT:
Supported by NIDA grant DA09236.
BEHAVIORAL ECONOMIC ANALYSES OF BUPRENORPHINE SELF-ADMINISTRATION
IN BUPRENORPHINE-MAINTAINED OUTPATIENTS: EFFECTS OF AN ALTERNATIVE
REINFORCER AND DISASSOCIATION OF SUBJECTIVE AND REINFORCING DRUG
EFFECTS
N. M. Petry and W. K. Bickel
University of Connecticut and University of Vermont
Eight buprenorphine-maintained, opioid-dependent outpatients participated in a two-phase study in which they first
received low, standard, and high doses of buprenorphine in an exposure phase and then chose between doses of
buprenorphine and amounts of money in a choice phase. When the amount of money available and cost of
buprenorphine was low (e.g. $.30) in the choice phase, subjects self-administered the maximal doses of
buprenorphine, available up to 32 mg/70 kg. As the amount of money available and cost of buprenorphine increased
to $20, buprenorphine self-administration decreased to the standard maintenance dose or even lower. We applied a
behavioral economic analysis to buprenorphine self-administration and found that demand for buprenorphine is
inelastic. Thus, while subjects modified buprenorphine self-administration based on its price, changes in drug
consumption were proportionally lower than changes in price. In the choice phase, subjective reports of opioid
agonist and withdrawal symptoms did not vary whether subjects self-administered low or high doses of the drug.
However. changes in subjective reports of opioid agonist and withdrawal effects increased over 200% when subjecis
received high and low doses of buprenorphine. respectively, during the exposure phase. These results demonstrate
that (1) buprenorphine self-administration varies with the presence of altemative reinforcers, (2) demand for
buprenorphine is inelastic in buprenophine-maintained individuals, (3) the subjective and reinforcing effects of
buprenorphine are not synonymous, and (4) the subjective effects of buprenorphine may depend on its
administration.
172
EFFECTS OF SCOPOLAMINE ON MORPHINE REINFORCEMENT AND REINSTATMENT
OF RESPONDING BY RHESUS MONKEY
F. Zhang, W. Zhou, Z. Wang, and G. Yang
Ningbo Institute of Microcirculation and Henbane, Ningbo, China
A naive rhesus monkey was trained to self-administer morphine (0.1 mg/kg/injection) which was paired with 5” red
stirnulus tight for a daily 4 hour session under a FR1 schedule. Cumulative record of responding exhibited bursts of
responding for morphine administration. 90% morphine infusions were taken in the first 2 hour. Five pre-session
treatment of scopolamine decreased the total morphine intake and delayed the initiation of responding in a dose
related manner (0.025 - 0.75 mg/kg). Response pattern was changed after scopolamine treatment at high doses
(0.25 mg/kg). Few morphine infusions were taken at the beginning of session followed by a long delay (over 120
min) without responding. Chronic effect of scopolamine (0.25 mg/kg) was administered. The treatment causes
45% decrease of response rate by morphine priming compared with control. These results suggest that acute
scopolamine treatment might decrease the total morphine intake, delay the initiation of responding in morphine selfadministration, and chronic treatment inhibit the reinstatemenl of responding.
ROLE OF NMDA RECEPTOR IN THE EXPRESSION OF DIAZEPAM WITHDRAWAL
SIGNS
M. Tsuda, T. Suzuki, and M. Misawa
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan
To clarify the role of NMDA receptor in the expression of diagram withdrawal signs, the present study
investigated the effects of NMDA receptor antagonists on the DMCM-induced diazepam withdrawal seizure by
subchronic treatment with diazepam in mice and on the abrupt withdrawal signs by discontinuation of the long-term
treatment with diazepam in rats. In the experiment using mice, diazepam (16 mg/kg) was injected i.p. once a day for
6 days. The seizure threshold of DMCM was evaluated at 48 hr after the last injection of diazepam. NMDA
receptor antagonists MK-801 and ifenprodil were injected s.c. and i.p., respectively, 30 min before the DMCM
infusion. Withdrawal from subchronic diaazepam treatment elicited a significant decrease in the seizure threshold of
DMCM. The decreasc in the seizure threshold of DMCM was abolished by pretreatment with MK-801 and
ifenprodil. In the experiment using rats, rats were treated with diazepam-admixed food for 30 days. The concentration
of diazepam in the food was gradually increased from 1 to 12 mg/g of food. Abrupt withdrawal was induced by
substituting normal food for drug-admixed food, and withdrawal signs were observed at 27, 30, 33, 36, 39, 42 and
45 hr after withdrawal. MK-801 and ifenprodil was injected i.p. 30 min prior to the observation. After the last
injection, withdrawal signs were observed over 6 days. Several withdrawal signs were induced by abrupt withdrawal
signs. Pretreatment with MK-801 and ifenprodil drastically suppressed the abrupt withdrawal. These findings
suggest that overactivation of NMDA receptor may be an important role in the expression of the diazepamwithdrawal signs.
173
RELATIONSHIP BETWEEN REINFORCING AND DISCRIMINATIVE EFFECTS OF
GABAERGIC DRUGS IN BABOONS: A WITHIN-SUBJECT ANALYSIS
N. A. Ator
Behavioral Biology Research Center, Johns Hopkins University School of Medicine,
Baltimore, MD
Five baboons were trained to discriminate midazolam maleate (0.32 mg/kg, i.v.) under a two-lever, food-maintained
drug verus no-drug procedure. Reliable dose-dependent generalization occurred in tests with i.v. chlordiazepoxide and
zolpidem, less so with imidazenil and not with pentobarbital. The baboons then were trained under an i.v. drug selfadministration procedure in which a drug injection depended upon completion of a fixed-ratio 160-response
requirement on a third lever on the intelligence panel. Completion of the response requirement was followed by a 3hour timeout; a maximum of 8 injections were available in each 24-hour period. Generalization to midazolam,
chlordiazepoxide, zolpidem, imidazenil, and pentobarbiral then was studied under conditions in which the baboon
self-administration drug dose and the drug discrimination session turned on automatically 10 or 15 min afterward.
Generalization results were not consistently different from those when the doses had been delivered response
independently. Greater drug reinforcement was found with midazolam, zolpidem, and pentobarbital than with
chlordiazepoxide and imidazenil. With all drugs, doses that did not occasion midazolam-lever responding maintained
self-injection, thus further indicating the functional difference in drug conlrol of behavior under the drug
discrimination and the drug self-administration paradigms.
ACKNOWLEDGMENT:
Supported by NIDA Grant DA-04133.
COMPARISON OF THE ACUTE ACTIONS OF DIAZEPAM, LORAZEPAM AND
ZOLPIDEM USING RADIOTELEMETRY
E. E. Elliot and J. M. White
Department of Clinical and Experimental Pharmacology, University of Adelaide, South
Australia
Acute administration of benzodiazepines produces muscle relaxation, sedation, anxiolysis and, in rodents,
hypothermia. The imidazopyridine zoipidem is a hypnotic non-benzodiazepine with high affinity for the BZ1
receptor. In humans it possesses only mild anticonvulsant, muscle relaxant and anxilytic properties. This study
compared the acute actions of the benzodiazepines diazepam and lorazepam with those of the non-benzodiazepine
zoipidem. Spontaneous locomotor activity (SLA), electromyographic activity (EMG) and body temperature were
recorded by radiotelemetry. This is a new technique in small laboratory animals which enables the simultaneous
gathering of multiple measures, without removing animals from their home cage and with minimal handlingrelated and restraint stress. Hooded Wistar rats, n=7 per group, were surgically implanted with radioelectrodes
whilst fully anaesthetised. Transmitters were inserted into the abdomen and two electrodes were sutured into the
left thigh muscle. One week after recovery. animals were administered either diazepam (5 - 20 mg/kg), lorazepam
(6.25 - 25 mg/kg), zolpidem (2.5 - 10 mg/kg) or vehicle (1 ml /kg) via SC injection. SLA, EMG and temperature
were recorded every 10 minutes for one hour after injection. Diazepam (10 mg/kg), lorazepam (12.5 mg/kg) and
zolpidem (5 mg/kg) produced sedation and muscle relaxation of a similar magnitude. Hypothermia was greatest
after administration of diazepam > lorazepam > zolpidem. Zolpidem produced little change in body temperature
compared to vehicle controls. These data suggest that the imidazopyridine zolpidem has a similar profile of acute
effects in comparison to the benzodiazepines diazepam and lorazepam. However, the relative magnitude of the
effects differed, with zoipidem producing less muscle relaxation and hypothermia than the two benzodiazepines.
174
BEHAVIORAL EFFECTS OF DIAZEPAM: INFLUENCE OF GENDER AND MENSTRUAL
CYCLE PHASE
T. H. Kelly, C. S. Emurian, C. A. Morlin, L. R. Hays, K. M. Muse, and S. J. Legan
Departments of Behavioral Science (THK, CSE), Psychiatry (CAM, LRH), OB/GYN (KMM),
and Physiology (SJL), College of Medicine, University of Kentucky, Lexington, KT
This study examined the effects of gender and menstrual cycle phase on the behavioral effects of diazepam. Six
male and six female healthy adults, blind to the study drug, gave written consent and participated on three
consecutive days per week over eight consecutive weeks (i.e., across successive menstrual cycles). Menstrual cycle
activity was monitored prior to the study. On test days, subjects consumed a standard meal at 5:30 p.m., received
drug at 6:30, and completed 20-minute sessions consisting of computerized performance tasks and visual-analog
(VAS) ratings of drug effect 0, 0.5, 1, 2, 3, 4 and 5 hours after drug administration, and upon waking the next
morning. Each of 3 doses (0, 5 and 10 mg/70 kg) of diazepam was administered orally 1 day each week in random
order. Blood samples were collected prior to the first day of each week to monitor hormone levels. Study days
coincided with four cycle phases (early follicular, late follicular, early luteal and late luteal). Diazepam altered
visual-analog ratings of drug effect and several dimensions of task performance, including response rates during a
psychomotor performance task and during both the acquisition and performance components of a learning task. The
magnitude and tune-course of effects of diazepam were generally similar for females and mates. No evidence of
residual next-day effects was obtained on any measure Interactions between the behavioral effects of diazepam and
phase of the menstrual cycle were also observed on several measures, including response rates during the
psychomotor performance task and on ratings of drug effect. These results indicate that the behavioral effects of
diazepam in females vary across the menstrual cycle, but are similar between males and females when data from
female participants are pooled across menstrual cycle phases.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA 09098 and P-50-DA 05312
ROHYPNOL ABUSE IN FLORlDA
S. R. Calhoun, D. R. Wesson, G. P. Galloway, and D. E. Smith
Haight Ashbury Free Clinics, San Francisco, CA
Use of “roofies” has been widely reported in the media, in connection with sexual assault and also as a drug of
abuse. The identity of “roofies” is reported or assumed to always be Rohypnol (flunitrazepam), a benzodiazeipine
not marketed in the US, but smuggled in primarily from Latin America. We investigated patterns of “roofie” abuse
in Florida among adolescents and young adults. Sixty-three interviews were conducted in the Miami area 9 in
Gainesville and 20 in Tampa. A total of 62 interviewees (41 in Miami, 8 in Gainesville, and 12 in Tampa) reported
having used “roofies,” and of these persons, 66 percent (24 in Miami, 6 in Gainesville, and 11 in Tampa) provided
at least one description of the tablets they took that were incompatible with any known dosage form of Rohypnol.
An additional 45 % (17 in Miami, 5 in Gainesville, and 6 in Tampa) described tablets that were insufficiently
detailed to determine whether the tablets they took were Rohypnol or another medication. Descriptions of tablets
taken that were either positive or probable identifications of Rohypnol were provided by 29% of the users. (Many
subjects provided multiple descriptions, and indicated that the appearance of “roofies” was variable.) Some of the
descriptions raised the possibility that counterfeit preparations were also available, and one type of counterfeit tablet
has subsequently been confirmed by forensic analysis. Our research suggests that in addition to ftunitrazepam, the
pattern of “roofie” abuse includes a number of other drugs.
175
PKPD MODEL FOR STIMULATORY AND SEDATNE EFFECTS OF ALPRAZOLAM:
TIMING PERFORMANCE DEFICITS
A. C. Heatherington* and C. E. Lau
*University of Washington, Seattle, WA; and Rutgers University, New Brunswick, NJ
Alprazolam increased the shorter (non-reinforced)-response rate (SRR) and decreased the reinforcement rate (RR) in a
time- and dose-related fashion of a contingency-controlled timing behavior, differential reinforcement of low rate
(DRL 45-s). We hypothesized that the rate changes observed were readily interpretable as functions of alprazolam
concentration during 3-h session, a period for investigating the onset, peak and disappearance of alprazolam effect in
rats. An integrated PKPD model was developed for three s.c. doses (1.25-7 mg/kg) and one i.v. dose (1.2 mg/kg) to
study the pharmacokinetics (PK, n=4) and pharmacodynatnics (PD, n=7), respectively. The two peaks of SRR
following s.c. alprazolam were. modeled as a stimulation-sedation PD model incorporating two opposing effect-link
sigmoid Emax functions. This model suggested that alprazolam possesses both stimutatory and sedative effects in a
continuous, but sequential fashion, which corresponded to low- (EC50 0.09 µg/ml) and high- (EC50 0.18 µg/ml)
concentration effects, respectively. The i.v. dose identified the second peak as a transient, “rebound” phase in the
recovery from drug effect, and the first peak (absent following i.v. dose) as the transition phase before onset of the
sedative effect. The RR, characterized by the indirect response model (IC50 0.02 µg/ml), is an index for evaluating
the deficit in timing performance. This model hypothesizes coexistence between stimulation and sedation
components for alprazolam, which may help delineate possible mechanisms for rebound side effects and of tolerance
in humans.
EFFECTS OF DRUGS OF ABUSE ON TEMPORAL DISCRIMINATION IN RATS
S. Baron, D. W. Wright, and C. R. Wenger
University of Arkansas for Medical Sciences, Department of Pharmacology and Toxicology,
Little Rock, AR
The effects of drugs of abuse reprsentative of several pharmacological classes were examined in five rats trained to
discriminate between two delay periods (3 s vs 10 s). Rats were first required to emit five consecutive responses
upon a center lever after which one of two delay periods was presented. After a three second delay, rats were required
to respond once on one of two levers, and after a ten second delay once on the other lever for food presentation.
Upon completion of training rats responded with high accuracy (> 85%). Pentobarbital (0.1 - 13 mg/kg), diazepam
(0.03 - 10 mg/kg), and phencyclidine (0.1 - 10 mg/kg) disrupted acuracy but at doses that also decreased response
rates on the center lever. Amphetamine (0.01 - 5.6 mg/kg) and cocaine (0.3 - 13 mg/kg) did not produce significant
disruption of accuracy up to and including doses that completely suppressed responding in some rats. The
muscarinic antagonist scopolamine (0.003 - 1 mg/kg) dose-dependently reduced response rates and accuracy, whereas
the quaternary analogue methscopolamine (0.003 - 1 mg/kg) did not disrupt accuracy up to and including rate
suppressing doses. These results are consistent with those reported for the effects of drugs of abuse on measures of
working memory and support the concept that drugs of abuse disrupt several aspects of cognitive function.
ACKNOWLEDGMENT:
Supported by NIDA grant DA05815.
176
MATCHING-TO-SAMPLE PERFORMANCE OF PIGEONS: EFFECTS OF SEDATIVEHYPNOTICS AND RESPONSE BIAS
C. A. Dayer and G. R. Wenger
University of Arkansas for Medical Sciences, Department of Pharmacology and Toxicology,
Little Rock AR
To study the effects of pentobarbital, diazepam, and phencyclidine on both reference memory and working memory,
6 pigeons were trained under two matching-to-sample schedules. Under one schedule the ted-sample stimulus was
presented 3 times more often than the green-sample stimulus. The ratio was reversed under the other schedule. It
was hypothesized that such a training history would induce a response-bias model of reference memory useful for
separating effects of drugs on reference and working memory. Drug testing was conducted under a no-bias condition:
each sample stimulus was presented an equal number of tunes. Under both schedule conditions, pentobarbital (5.6
13 mg/kg), diazepam (1-5 mg/kg) and phencyclidine (1-3 mg/kg) decreased matching accuracy in an equivalent
fashion. Likewise, no schedule dependent effects were observed on the rate of responding for any drug. Under the red
bias condition, when doses of pentobarbital and diazepam were administered that decreased accuracy, an increase in
ted-key responding was observed. A similar effect was not observed when the pigeons were biased toward green.
Phencyclidine did not unmask a response bias under either training condition. These results suggest that these drugs
have little effect on reference memory over the dose ranges studied.
ACKNOWLEDGMENT:
Supported by NIDA grant DA05815.
EFFECTS OF DRUGS OF ABUSE AND REINFORCEMENT SCHEDULE ON MATCHINGTO-SAMPLE PERFORMANCE
K. Byrnes, C. A. Dayer, and G. R. Wenger
University of Arkansas for Medical Sciences, Department of Pharmacology and Toxicology,
Little Rock AR
The effects of pentobarbital, diazepam and phencyclidine were determined in 6 pigeons responding under a matchingto-sample schedule reinforced under a secondorder variable interval 100 sec (VI100) and, in a counterbalanced
fashion, under a fixed-interval 100 sec (FI100) schedule of reinforcement. Under control conditions, overall
matching accuracy was slightly higher under the VI100 schedule than the FI100 schedule, there were approximately
7 and 8 trials per food presentation under the FI100 and VI100 schedules, respectively, and the rate of responding to
the sample stimulus presentation of each trial was slightly higher under the VI100 than the FI100 schedule. In
spite of these differences, the effects of pentobarbital, diazepam and phencyclidine were similar under both schedules
and little systematic difference was seen on overall percent matching accuracy or rate of responding. Likewise, the
results were very similar to those previously reported in pigeons responding under matching-to-sample schedules in
which every correct match resulted in food presentation. These results suggest that the effect of these drugs on
working memory is not significantly altered by the schedule of reinforcement.
ACKNOWLEDGMENT:
Supported by NIDA grant #DA05815.
177
EFFECTS OF SEDATIVE/HYPNOTICS AND STIMULANTS ON SYMBOLIC DELAYED
MATCHING PERFORMANCE IN RATS
G. R. Wenger and D. W. Wright
University of Arkansas for Medical Sciences, Department of Pharmacology and Toxicology,
Little Rock, AR
Five rats were trained to respond under a delayed symbolic matching-to-sample baseline using a 3-sec delay.
Baseline performance was characterized by approximately 80% matching accuracy and a 1.3 sec matching response
latency. Experimental sessions terminated after 3600 sec or 60 trials in which the correct matching response was
emitted. Pentobarbital, phencyclidine and d-amphetamine decreased matching accuracy at doses which did not
significantly affect matching response latency or the number of trials completed per session. Still higher doses of
pentobarbital (18 mg/kg) and phencyclidine (10 mg/kg) decreased matching accuracy and the number of trials
completed per session, and increased matching response latency. Diazepam decreased matching accuracy andthe
number of trials completed per session, and increased matching response latency at the same dose (10 mg/kg).
Cocaine did not affect performance at doses up to and including 18 mg/kg. These results are similar to what has
teen repotted in rats responding under both a 10-sec delayed alternation baseline and a matching-to-position baseline
with delays of 3, 10 and 30 sec. Thus, there would appear to be less separation in the rat compared to the pigeon
between doses which decrease working memory function and doses which decrease motor function.
ACKNOWLEDGMENT:
Supported by NIDA grant DA05815.
ANTECEDENT INFLUENCES ON HIV VULNERABILITY AMONG AFRICAN AMERICAN
MEN
A. F. Brunswick and M. Flory
Columbia University (Public Health/Sociomedical Sciences), New York, NY
This is a study of contributors to heterogeneity in HIV infectivity, i.e., differential vulnerability to HIV infection.
Postulating that vulnerability derives from a complex of social and biological factors, it is focused on states
anteceding exposure, particularly those related to the disadvantaged societal position of African Americans. The
influence of social structural and psychosocial factors antecedent to exposure to HIV was tested with data from a
prospective cohort study of 150 African American men, currently ages 35-41 who have been followed over 25 years
and live study points since adolescence, using multivariate logistic analysis with three risk behaviors (IDU, malemale sex, heterosexual risk) controlled. Results showed that post adolescent demoralization, rather than temporally
more proximal factors, had a significant effect. The effect was limited to, and conditioned, IDU risk. Specifically,
IDUs with high demoralization had infection rates of 67% contrasted with 14% among earlier, low demoralized
IDU's. Rigorous testing of potential confounders, including differences in injecting patterns and/or needle risk
behaviors, general health status and depression did not reduce this effect. This evidence that psychosocial
infIuences, antecedent to HIV exposure, modified risk infection for HIV among male IDU’s underscores the urgency
for early, i.e., adolescence and younger, drug prevention interventions for African American youth that includes
attention to social contextual factors and youths’ response to them.
ACKNOWLEDGMENT:
Research supported by NIDA Grant RO1-DAO5142.
178
HIV AND RISK BEHAVIORS IN AFRICAN-AMERICAN PARTURIENT WOMEN
E. S. Banstra, S. S. Churchill, M. J. O’Sullivan, C. E. Morrow, B. W. Steele, O. W.
Gomez, R. C. Duncan, and D. D. Chitwood
University of Miami, Departments of Pediatrics, Obstetrics and Gynecology, Clinical
Pathology, Epidemiology and Public Health, and Sociology, Miami, FL
Objective: To determine the relationship between HIV infection and behavioral risk factors among inner-city,
African-American, partutient women. Methods: The study was part of a longitudinal investigation of the impact
of in utero cocaine exposure on infant neurodevelopment. The sample included 1,802 African-American women
delivering at 20 weeks gestation at the UM/Jackson Memorial Hospital. ELISA with Western Blot confirmation
was used to assess HIV status. Tobacco, alcohol, marijuana, cocaine/crack, and other drug use; sexual behaviors; and
physical and sexual abuse were determined by detailed maternal interviews. Toxicology assays were performed on
maternal and infant urine and infant meconium, Logistic univariate and stepwise multivariate analyses were used.
Results: 116 (6.4%) women were HIV-positive at delivery. 1,326 (74%) had no documented cocaine/crack use;
91(50%) used cocaine-crack before pregnancy only; 385 (21.4%) used cocaine/crack during pregnancy.
Adjusted O.R.
2.09
1.97
1.38
1.06
0.42
Demographics and Risk Behaviors
Cocaine/Crack Use During pregnancy
Physical Abuse Ever
# Sex Partners Past Year
Maternal Age at Delivery
Condom Use Past Year: Never vs. Always
(95% C.I)
(1.29 - 3.39)
(1.24 - 3.11)
(1.18 - 1.61)
(1.02 - 1.10)
(0.27 - 0.67)
Conclusion: HIV infection correlated significantly with cocaine/crack use during pregnancy, physical abuse ever,
number of sex partners past year, and older maternal age. The results for condom use appear to be due to the large
number of women (n--679) with no condom use and only one sexual partner in the past year.
ACKNOWLEDGMENTS: Supported by MDA DA-06656; CSAP SPO 3524; GCRC MO1-RR-05280.
GENDER DIFFERENCES IN METHADONE MAINTENANCE PATIENTS
A. A. De Jesus, A. Umbricht-Schneiter, R. Pickens, and K. L. Preston
National Institute on Drug Abuse, Division of Intramural Research, Baltimore, MD
An investigation of familial substance abuse and psychosocial variables in opiate and cocaine abusers was conducted
during a 35-week outpatient pharmacologic and behavioral management treatment study at the Addiction Research
Center. Of the three hundred seven participants, 37% (115) were female and 46% (142) were African-American.
Fifty-one percent of the female enrollees were African-American. Drugs of choice were heroin (100%); cocaine
(80%); benzodiazpines, marijuana, and alcohol (15%). Five percent of the participants reported using heroin only.
Mean age was 37. Women differed from men on a number of characteristics: having a spouse/significant other
IVDU (58-33%, p=.000); having a mother with a substance abuse history (30-19% p=.010); having sisters with
substance abuse histories (53-34%, p=.013): later age of 1st regular drug use (mean =17.9-16.3, p=.022) and 1st
regular use of heroin (mean=21.9-19.7, p=.0.37); less likely to be employed (37-18%, p=.000), and less stable
occupation (33-15%, p=.000). There were no gender differences in the following characteristics: marital status,
number of criminal charges and incarcerations, and life time number of sexual partners. This suggests some
likelihood that women substance abusers may become vectors of HIV transmission which would spread to non-drug
using sexual partners and unborn children. Transmission of HIV is entirely conceivable in light of the large number
of sexual partners reported by participants in this study (43.95, SD 9.95), lack of regular condom use, and continued
needle sharing with others in their social network, including IV drug using sexual partners.
179
PREVENTION OF HIV FROM UNPROTECTED SEX AND DRUG USE BY AFRICAN
AMERICAN WOMEN THROUGH COMMUNITY AND CULTURAL INTERVENTION
D. J. Geyen, H. M. Guidry, I. Holmes, and J. M. Beal
Sam Houston State University, Beaumont City Health Department, and Prairie View A&M
University
The increasing number of African Americans afflicted with HIV/AIDS give reason to direct attention to this
segment of the population, Researchers and service providers need a better understanding of the role of culture,
gender, and socioeconomic factors in the transmission of HIV among group. The study focuses on preventing the
spread of HIV from unprotected sex and drug use by African American women via community and cultural
intervention. Moreover, the study investigates the relationship between pre and post assessment relative to subjects
attitudes regarding HIV, and the effectiveness of intervention for preventing the transmission of HIV. A cohort of
women mostly African Americans from the lower socio economic stratum of Beaumont, TX agreed to volunteer as
subjects. The subjects were identified by the health department for being at risk for transmitting HIV. Subjects took
part in a day long program, sponsored by the health department and the university. The intervention encompassed
education on the different ways of spreading HIV. The findings suggested that community and cultural intervention
showed effectiveness and differences in attitudes regarding risky behaviors that contribute to me spread of HIV.
UNPROTECTED SEX WITH HIV INFECTED DRUG USERS
C. F. Kwiatkowski, R. E. Booth, G. Weissman*, and D. John
University of Colorado School of Medicine, Denver, CO and *Health Resources and Services
Administration, Rockville, MD
Currently, injection drug users (IDUs) comprise 32% of AIDS cases reported to the Centers for Disease Control and
Prevention. Unprotected sex with an HIV seropositive partner represents the greatest risk for contracting HIV
among non-IDUs. The current study assessed the extent to which HIV seropositive drug users placed others at risk
of infection through unprotected sex, and investigated demographic and behavioral factors contributing to risky sex
behavior. Structured interviews were conducted as part of a three year, multi-site research project directed by the
Health Resources and Services Administration and the National institute on Drug Abuse. Responses from 106
sexually active, HIV seropositive drug users in Denver, Detroit, New Orleans, St. Louis, and West Palm Beach
were analyzed. Significant demographic differences across the five cities were controlled for in analyses of me
predictors of unprotected sex. Results of a multiple logistic regression revealed that respondents having unprotected
sex were more likely to be White, to have injected cocaine, to have teen told they had HIV/AIDS symptoms in the
last six months and to have been told they were symptomatic more often than those not having unprotected sex.
Implications are discussed with regards to future research needs and the educational needs of HIV seropositive drug
users.
ACKNOWLEDGMENT: Supported by NIDA Grant DA06912.
180
PREVENTING HIV/AIDS AMONG MIDDLE-AGED AND ELDERLY PERSONS WHO USE
INJECTION DRUGS
M. M. Wong
UCLA Drug Abuse Research Center
Middle-aged and elderly persons are not immune from the hazards or consequences of excessive and abusive drug use,
such as traffic accidents and fatalities, overdose, and in particular, contracting and spreading HIV/AIDS. As middleaged persons of today become elderly in the beginning of the twenty-first century, it will become a health priority to
provide HIV/AIDS outreach and treatment services for a segment of the population that is often mistakenly
characterized as having low risk for contracting and spreading this disease. Injection drug use with dirty needles and
promiscuity continue to occur in this nation’s older populations, due in part to generational influences, via the
permissive attitudes and openness to experience during the 1960s to the early 1970s, and enduring the horrors of the
Vietnam War (war veterans). Current efforts to prevent HIV/AIDS target younger populations, fueling the
misperception that HIV/AIDS is a scourge of the young. However, these same behavior choices are made by
middle-aged and, to a lesser extnt, elderly people. Prevention efforts for older populations may include components
from effective prevention protocols for younger populations: (1) social support groups that target issues of
advanced age; (2) psychotherapy on an outpatient basis; and (3) education about safer injection drug use and sex
practices.
ACKNOWLEDGMENT:
Supported by NIDA grant T32-DA07272.
NEEDLE EXCHANGE AVAILABILITY AND PARTICIPATION AMONG INJECTION DRUG
USING WOMEN
J. D. Rich1 , J. Astemborski2 , D. K. Smith3 , E. Schoenbaum 4 , K. Davenny 5 , P. Schuman6 , and
D. Vlahov2
1
Brown University, Providence, RI; 2 Johns Hopkins University, Baltimore, MD; 3 CDC,
4
5
6
Atlanta, GA; Montefiore/Einstein, Bronx, NY; NIH/NIDA, Rockville, MD; and Wayne
State University, Detroit, MI
Objective: To describe Needle Exchange Program (NEP) participation in women injection drug users (IDUs).
Methods: NIDA/HERS substudy questionnaire was administered to all women enrolled in the multi-site HER
Study who reported injection drug use within six months at semi-annual follow-up visits between January and
December 1996. NEP administrators were contacted in all four cities. Results: Two hundred women reported
injection drug use within 6 months; 71% were HIV positive; 39% reputed obtaining at least some syringes at a
NEP. Women were more likely to use NEP in cities where needle exchange was more available (48% v.
14% p<.01). There was no difference between HIV positive and HIV negative women (43% vs 38% p= 0.6). NEP
participants were more likely to inject within 2 days, (66% vs. 34% p<.01), to inject cocaine (71% vs. 55% p=.04).
or to inject a speedball (79% vs. 54% p<.01). Daily injectors were more likely to participate in NEP than less
frequent injectors of cocaine (63% vs 35% p=<.01), heroin (56% vs 30%,p<.01). and speedballs (66% vs
334%,p<.01). 19% reported using contaminated rinse water or syringes, of whom 61% did not use NEP.
Conclusions: Sixty-one % of injection drug using women did not participate in needle exchange programs.
Injection drug using women who reported heavier and more frequent drug use were more likely to participate in
needle exchange programs. Availability of an established NEP is an important predictor of NEP use. Infrequent
users may require more outreach. Further studies of obstacles to NEP use by injection drug using women are needed.
ACKNOWLEDGMENTS:
Support by NIDA grant DA-00268 and a cooperative agreement by CDC and
NIDA U64/CCU106795.
181
TRENDS IN SELF-REPORTED HIV RISK BEHAVIOR: INJECTION DRUG USERS IN LOS
ANGELES
D. Longshore
UCLA Drug Abuse Research Center
This paper reviews trends in HIV risk behaviors across serial samples of injection drug-using arrestees between
1987 and 1995. Current needle sharing and past-year needle sharing with strangers steadily declined. Past-year
needle sharing at shooting galleries has remained low. Bleach use among needle sharers increased sharply. Through
1993, no increase had occurred in avoidance of needle sharing for as long as one year. In 1994-95, however, pastyear needle sharing sharply declined, possibly as a result of new needle exchange programs. No change occurred in
number of sex partners, but condom use became much more prevalent among nonmonogamous injectors. Needle
exchange may have a unique role in reducing the risk of HIV transmission among Los Angeles drug users.
A TWO-WAY RELATIONAL MODEL BETWEEN DRUG USE AND HIV/AIDS
V. N. Shaw, M. D. Anglin, and D. Longshore
Drug Abuse Research Center, University of California, Los Angeles, CA
The relationship between AIDS and drug abuse seems obvious to the commonsense public: the dire consequence of
a bad behavior. Reflected in academic theorizing is an one-way model that traces AIDS to drug abuse through four
routes. Fiit is intravenous drug use: drug users sharing needles in shooting galleries and other settings may contract
and spread AIDS. Second is sex for drugs: drug users engaging in sex for or with drugs may contract and spead
AIDS. Third is drug effects: drug users involved in impulsive and unprotected sex under the influence of drugs may
contract and spread AIDS. Fourth is drug culture: drug users practicing antisocial behavior supported by a culture of
deviance and rebellion may contract and spread AIDS. A two-way model is needed. When HIV infection becomes
self-recognized, it may trigger drug abuse: if AIDS patients never abused drugs befor, use of marijuana and
analgesic drugs for pain relief can initiate them into dependent drug use. It may worsen drug abuse: people with HIV
may engage in high-risk drug use as a coping strategy. It may also terminate drug abuse: people with HIV may
rediscover the meaning of life and be determined to live it free of drugs. Confinement in treatment terminates drug
abuse for seriously ill AIDS patients as well. The two-way model treats HIV/AIDS as both a dependent and an
independent variable and studies how HIV/AIDS influences and is influenced by drug abuse. With regard to the
AIDS risk reduction model, the two-way model encompasses it since ARRM stands half-way in the AIDS-drug
relationship by beginning with AIDS education, HIV knowledge, and AIDS fear rather than the verified infection of
HIV or experienced effect of AIDS. ARRM may also branch out into risk reduction and risk augmentation models
as HIV-negative drug users who have lived a risk lifestyle for years may perceive themselves as invulnerable and
therefore continue or engage more in HIV-risk behavior.
ACKNOWLEDGMENT:
Supported by NIDA Grant T32-DA07272
182
DOES KNOWLEDGE OF HIV RISK-REDUCTION STRATEGIES PRODUCE BEHAVIORAL
CHANGE IN INJECTION DRUG USERS (IDUs)?
L. A. Marsch and W. K. Bickel
Department of Psychiatry, University of Vermont, Human Behavioral Pharmacology
Laboratory, Burlington, VT
The process by which knowledge about HIV risk-reduction strategies is translated into its behavioral counterpart
was investigated in injection drug users (IDUs) in the context of an exploratory survey study. Twenty-nine opiate
dependent IDUs in treatment at the Substance Abuse Treatment Center at the University of Vermont completed
questionnaires designed to assess their 1) previous HIV/AIDS education, 2) level of accurate knowledge about
HIV/AIDS, 3) estimated perceived risk of contracting AIDS, 4) estimated ability to refrain from engaging in HIV
risk behaviors, and 5) degree of actual HIV-risk behaviors. Results indicated that IDUs typically have a high level
of general knowledge regarding the prevention of the transmission of the AIDS virus (mean accuracy=84.62%;
SEM=0.14%), which was significantly correlated with the number of days of their previous HIV/AIDS educational
experiences (r=0.385, p<.05). No significant correlations between participants’ level of accurate knowledge and
their high levels of either drug-related (r =-0.167, ns) or sex-related HIV risk behavior (r =-0.272, ns) were evident.
In addition, participants had a low perceived risk for contracting AIDS (mean =20.31%, SEM=3.57%), which did
not correlate with either their high level of drug-related (r=0.157, ns) or sex-related HIV risk behaviors (r =-0.046,
ns). Findings suggest that HIV/AIDS education may promote the acquisition of accurate AIDS-related knowledge
among IDUs; however, knowledge alone may he insufficient to produce behavioral changes. Rather, IDUs appear
to dissociate their HIV-risk behavior from their personal perceived risk for contracting AIDS. As a result,
interventions which train IDUs to accurately assess their likelihood of contracting AIDS based on their high-risk
behavior may prove effective in promoting behavioral change.
ANTISOCIAL PERSONALITY DISORDER, SOCIOPATHY, AND RISK FOR HIV
INFECTION IN INJECTION DRUG USERS
K. Tourian, A. Alterman, D. Metzger, M. Rutherford, J. S. Cacciola, and J. R. McKay
University of Pennsylvania, and the Philadelphia Veterans Affairs Medical Center,
Philadelphia, PA
A significant percentage of injection drug users (IDUs) have antisocial personality disorder (APD). APD has been
found by some researchers to he an additional risk factor for human immunodeficiency virus (HIV) infection in
IDUs. The present study evaluated the association of sociodemographic characteristics and substance abuse history
from the Addiction Severity Index, and several measures of antisocially, to behaviors associated with HIV risk, a
measured by the Risk Assessment Battery (RAB), in 289 opiate-dependent methadone-maintained subjects. The
measures of sociopathy were the DSM-III-R diagnosis made by the Personality Disorder Examination, the
California Psychological Inventory- Socialization Scale (CPI-So) and the Psychopathy Checklist- Revised (PCLR). The presence of various risky behaviors was predicted with linear and logistic regression analyses more
consistently by measures of personality traits associated with sociopathy (PCL-R and CPI-So) than by a diagnosis
of APD. Personality traits of sociopathy may he more useful than an APD diagnosis in identifying at-risk patients
for intensive HIV risk reduction interventions.
ACKNOWLEDGMENTS:
of Veterans Affairs.
Supported by NIDA grants #DA00172, DA05186, DA05858 and the Department
183
ANTISOCIAL PERSONALITY DISORDER IS NOT ASSOCIATED WITH POOR
IMPROVEMENT IN HIV RISK BEHAVIORS AMONG COCAINE USERS
W. M. Compton, III; 1 L. B. Cottler1 ; E. L. Spitznagel2 ; A. B. Abdallah1 ; and T. Gallagher 3
1
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO;
Department of Mathematics, Washington University School of Medicine, St. Louis, MO;
and 3 Department of Sociology, Kent State University, Kent, OH
2
Previous work has documented that antisocial personality disorder (ASPD) is associated with increased rates of HIV
risk behaviors and with worse substance abuse treatment outcomes. The question addressed by this paper is whether
cocaine users with ASPD respond to an HIV risk-reduction intervention as well as cocaine users without the
disorder. The study subjects were 333 cocaine users followed up at 18 months as part of a NIDA-funded treatment
demonstration project. Improvement was found for the group as a whole across a wide range of HIV risk behaviors.
Improving significantly (p < .05) from baseline to the 18 month follow up were several drug-related behaviors:
current cocaine dependence, drug injection, injection equipment sharing, and use of syringes that were not cleaned.
Several sex-related risk behaviors also improved significantly: having multiple sex partners, being intoxicated
during sex, giving drugs for sex, receiving money for sex and receiving drugs for sex. When the sample was
stratified by ASPD status, very similar improvement was seen in respondents with and without ASPD. To
examine further the relationship of ASPD to change in HIV risk behaviors, separate logistic regression models of
improving and worsening risk behaviors were tested. What we found was no association of ASPD with
improvement (or lack thereof) in HIV risk behaviors but a possible association of ASPD with worsening HIV risk
behaviors. It appears that cocaine users with ASPD improve their HIV risk behaviors just as much as those
without ASPD hut are at higher risk for the development of such behaviors.
ACKNOWLEDGMENTS:
Funded by NIDA Grants DA00209 and DA06163.
RISKS FOR HIV SEROCONVERSION IN THE COLLABORATIVE INJECTION DRUG
USERS STUDIES (CIDUS)
E. Monterroso, S. Holmberg, B. Byers, J. Wu, J. Von Bargen, and the CIDUS Principal
Investigators
Epidemiology Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and
TB Prevention, Centers for Disease Control, Atlanta, GA
Objectives: To determine risk factors for HIV seroconversion among injection drug users (IDUs) in six U.S.
study sites (NYC [2], LA County, Chicago, San Jose, and Baltimore). Methods: Participants were street-recruited
using word of mouth and “snowball” techniques interviewed with a standard questionnaire, and asked to return for
follow-up. HIV serostatus was determined at baseline and at follow-up visits 6-12 months after. Results: At
baseline, 3,775 IDUs bad been recruited in the CIDUS; 47% were re-recruited for at least one follow-up visit. At
baseline, the mean age was 37 years, 36% were female, 39% African American, 33% Hispanics, 50% single, 57%
homeless, and 55% bad less man a high school education. There were 19 seroconversions in 1323 “person-years” of
observation (HIV incidence = 1.4/100 person-years). In a logistic regression analysis, risk independent factors for
seroconversion included crack smoking; injecting “speedball;” injecting heroin; being an IDU from the East Coast:
injecting more than they had six months previously; and, injecting at someone else’s home; 80-100% of
seroconverters bad at least one of these risks (all P-values <0.05). Conclusion: These preliminary data indicate
seroconversion for IDUs in the CIDUS is multifunctional. Crack smoking plays an important role probably by
increasing the number of unprotected sex acts. HIV prevention programs targeting IDUs should include “safe sex” as
well as “safe injection” messages.
184
GENDER DIFFERENCES IN RECENT CRACK USE AND HIV RISK AMONG NONINJECTING USERS OF HEROIN
A. Neaigus, M. Miller, S. R. Friedman, X. Andrade, A. Atillasoy, G. Ildefonso, and D. C.
Des Jarlais*
National Development and Research Institutes, Inc. and *Beth Israel Medical Center, New
York, NY
Introduction: Crack use has been found to be associated with HIV infection among both non-injectors and
injectors. We examine, within gender, whether non-injecting users of heroin (NIUs) who report having never
injected drugs and having recently used crack (in the prior 30 days) are more likely to be seropositive for HIV,
hepatitis B and hepatitis C, and are more likely to engage in high-risk behaviors and have high-risk drug and sexual
partners than NIUs not using crack. Methods: Two hundred sixty-nine NIUs recruited out-of-treatrnent in NYC
who reported using heroin al least once in the last 30 days and having never injected drugs, were interviewed
between March 1996 and April 1997 at intake into a cohort study on transitions to injecting. They were asked about
their HIV risk behaviors and drug and sexual partners, and were counseled and tested for HIV, hepatitis B and
hepatitis C. Results: The sample was 74% male, 26% female; mean age 34.3, S.D.= 8.2; 35% AfricanAmerican, 31% Latino, 28% white, and 6% other race/ethnicity; 109 (41%) recently used crack (of whom 19 (17%)
were women and 90 (83%) were men). Among women, but not among men, recent crack use was significantly
associated with being infected with HIV (OR = 17.8; 95% CI = 3.3, 95.8) and HBV (OR = 4.6, 95% CI = 1.5,
14.2). and was a trend for HCV (OR = 2.9, 95% CI = 0.9, 10.1, p < 0.10). Among women, recent crack use was
associated with exchanging sex for money or drugs (11% vs, 08, p < 0.05), and with having sex partners who were
crack users (OR = 13.1, 95% CI 3.3, 50.9). Among men, recent crack use was associated with using heroin with
current drug injectors (OR = 2.2, 95% CI = 1.1, 4.4) and at commercial multi-user settings (OR = 4.4, 95% CI 1.2,
16.6). Conclusion: Women NIUs who have never injected and who use crack have been and continue to be at
high-risk for sexually transmitted HIV and HBV; they may also be a potential vector for the transmission of these
pathogens. Among men, NIUs who have never injected and who use crack may be at high risk of becoming
injectors. Interventions among NIUs should give increased attention to crack users within this group.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-09920.
INTERVENTION EFFECTIVENESS AMONG COCAINE SNORTERS AT RISK FOR HIV IN
RIO DE JANEIRO, BRAZIL
J. A. Inciardi1 , H. L. Surratt1 , D. C. McBride 2 , and P. R. Telles 3
1
University of Miami School of Medicine, Miami, FL; 2 Andrews University, Berrien
Springs, MI; and 3State University of Rio de Janeiro, Rio de Janeiro, Brazil
Established in 1993, by the National Institute on Drug Abuse, the PROVIVA Project has provided HIV risk
reduction counseling to over 1,000 current cocaine users in Rio de Janeiro. The primary aims of this initiative are
to reduce the spread of HIV/AIDS among street drug users, and to evaluate the efficacy of a controlled experimental
intervention designed to decrease risky drug use and sexual behavior. All clients complete a detailed risk assessment
interview at baseline. participate in standardized HIV pre-test and post-test counseling sessions, and are offered HIV
testing. Participants are then re-interviewed in 3 months to determine whether reductions in HIV risk behaviors
bave occurred. Through February 1997, complete data were available on 511 cocaine snorters who were primarily
male (83.6%). young (median age 29 yrs.), poorly educated (84.7% had fewer than 8 years of schooling), and 9.0%
tested HIV-positive. Preliminary analyses of pre- and post-intervention measures reveal a significant decrease in
occasions of cocaine use, as well as a significant increase in occasions of protected vaginal sex for males. These
data suggest that the intervention model, originally designed for drug users in the U.S., may have applications for
reducing HIV risk among street populations in other nations.
ACKNOWLEDGMENT:
Supported by NIDA Grant DA 08510.
185
CONDUCTING RESEARCH ON THE AIR BRIDGE: HJV RISK BEHAVIOR AMONG
PUERTO RICAN DRUG USERS
D. Oliver*, A. Finlinson**, S. Deren*, R. Robles**, J. Andia*, H. Colón**, and M.
Shedlin***
*National Development and Research Institutes, Inc, New York, NY; **Universidad Central
Del Caribe, Bayamón, PR; and ***Sociomedical Resource Associates, Inc., Westport, CT
High rates of seropositivity have been reported among Puerto Rican injection drug users (up to 50%) and crack
smokers (10-20%) in PR and NYC, with significant differences in risk behaviors among drug users in both
locations, yet there is a high rate of mobility between the two sites. Our previous research indicated that 88% of PR
drug users in NYC have been to PR. This connection between the two locations which has been termed the “air
bridge”, provides the opportunity to study the impact of mobility, socioculturat factors and environment on risk
behaviors in a single ethnic group. This paper will describe the qualitative methodologies developed to do the first
phase of a multi-year qualitative and quantitative study of HIV risk behavior determinants among Puerto Rican drug
users in Bayamón, PR and East Harlem, NY. New methodological approaches were needed to insure data collection
for all key domains, and comparability between the two sites. Development and content of new guidelines for
conducting mapping, field observations, focus groups and life history interviews will be described, including
methods to standardize meanings between the two sites (e.g., rather than targeting shooting galleries as sites for
observations, selecting observation sites based on behaviors (e.g., locations where drugs are used). Methodological
problems and their solutions will be summarized, and preliminary findings of differences between the two sites will
be presented.
ACKNOWLEDGMENT:
Research funded by NIDA grant #R01 DA10425.
HIV PREVENTION WITH DRUG USERS: A DATABASE AND SYNTHESIS OF
RESEARCH
S. Tortu, J. Schmirler, R. Hamid, R. Booth,* F. Pearson, and J. B. O’Kane
National Development and Research Institutes, Inc. NYC, NY and *University of Colorado
Health Sciences Center, Denver, CO
The effectiveness of behavioral methods of HIV risk reduction is a major public health concern. Efforts to reduce
risk have been ongoing since the mid-80’s. At present, a growing body of research must be synthesized, evaluated
and made accessible for use by both researchers and practitioners. This poster describes a NIDA-funded project
which, in the first phase, developed a database using information derived from efficacy studies of behavioral
interventions which targeted high risk drug users for HIV prevention. Using information from this first phase, we
will determine the feasibility of developing a range of products in later phases. Some products, (e.g., a citation
database with descriptions of prevention strategies and critical, evaluative summaries) will be written in nontechnical language to make the information accessible to those without research expertise. Other products (e.g.,
meta-analytic summaries) will be of interest primarly to researchers. Proocedures used to develop the database and
extract information are described. Preliminary results of the first phase, consisting of an annotated bibliography, are
available for distribution.
ACKNOWLEDGMENT:
Funded by NIDA grant 1 R43 DA10673-01.
186
POSTER SESSION II
IMPACT OF DRUG AND ALCOHOL TREATMENT AND A BRIEF COMMUNICABLE
DISEASE INTERVENTION ON RISK BEHAVIORS
J. A. Flaherty and T. M. Brady
Division of Addictions, Department of Psychiatry, University of Illinois/Chicago
This paper examined bow drug use and high-risk heterosexual behavior of substance abuse clients evolve during the
first weeks of an outpatient, abstinence based. substance abuse treatment program, In addition, we aim to identify
demographic and drug use correlates of sex trading through descriptive statistics and logistic regression.
Hypotheses: Substance use will decrease with time in treatment; men will purchase commercial sex and trade
drugs for sex with greater frequency than women; women will exchange sex for money and drugs with greater
frequency; and crack cocaine will be the most important drug use correlate of sex trading. Design: Anonymous
cross section of clients taken prior to STD/HIV education sessions from March 1996 to May 1997. Methods:
Outpatients were surveyed with the Risk Assessment Battery (Metzger) and 167 questionnaires were analyzed.
Simple cross tabulations were presented to illustrate the patterns of behavior by the exposure variable - - time in
treatment. Logistic regression was used to estimate the strength of the association between various correlates of
high-risk behavior. Data was presented as EXP (b) to estimate odds ratios and confidence intervals. ANOVA was
used to analyze a summary measure of these behaviors plus multiple sexual partners. Results: Self-reported drug
use and alcohol consumption decreased sharply with time in treatment. Commercial sex and sex trading varied by
age, sex, and time in treatment. In this small sample from Chicago, snorting cocaine, not smoking crack, and sex
were the only significant correlates of high-risk sexual behavior. Conclusion: With 10% to 22% of all clients
engaging in some form of high risk sexual behavior during the course of their treatment, programs should continue
to integrate substance abuse treatment with some form of HIV/STD education, screening, referral and/or therapy.
RETENTION AND HIV RISK-REDUCTION IN A NATIONAL TREATMENT SAMPLE
(DATOS)
K. M. Broome, G. Joe, and D. D. Simpson
Institute of Behavioral Research, Texas Christian University, Fort Worth, TX
The prevalence of HIV among injection drug users, particularly drug-using women, means intervention efforts
directed at reducing injection and risky sexual behavior are increasingly important. However, clients must remain in
treatment long enough to benefit from these efforts, This study examined HIV risk outcomes during the 1-year
period after discharge, comparing early dropouts and longer-tenure clients from long-term residential (LTR).
outpatient methadone maintenance (ONM), and outpatient drug free (ODF) modalities of the NIDA-funded Drug
Abuse Treatment Outcome Study (DATOS). Analysis of covariance was used to assess the relationship among
gender. treatment tenure, and post-treatment injecting, condom use, and number of sex partners (while holding
pretreatment behavior statistically controlled). In both LTR and OMM, longer-tenure clients exhibited lower
frequencies of injection at follow-up, and in LTR they also had fewer sex partners following treatment. Among
women in LTR, early dropouts had more post-treatment sex partners than men, but longer-tenure women did not.
Longer treatment especially for women, may be vital to reducing the spread of HIV and underscores the
consequences of early dropout from treatment.
Supported by NIDA Grant UOI -DA10374 as part of a Cooperative Agreement on
ACKNOWLEDGMENTS:
the Drug Abuse Treatment Outcome Study (DATOS).
187
DRUG ABUSE TREATMENT AND RISKY SEX
S. Hsieh,* D. Longshore*, and the Cooperative Drug Abuse Treatment Outcome Study
Consortium
*UCLA Drug Abuse Research Center
This paper presents evidence regarding the possibility of a cumulative effect of drug abuse treatment on risky sexual
behavior among a sample of 6,620 cases entering drug abuse treatment in the United States in 1991-93. These
cases were participating in the Drug Abuse Treatment Outcome Study (DATOS). Analyses tested the relationship
between lifetime treatment exposure and risky sex by drug users during the year before DATOS intake. Analyses
controlled for age, drug use severity, history of antisocial conduct, and other factors that might have confounded the
relationship between treatment exposure and risky sex. Results indicated that users with mote lifetime treatment
exposure had significantly lower scores on risky sex. This finding is consistent with the hypothesis that treatment
has long-term cumulative effects on drug users HIV risk behavior.
HIV SERVICES AMONG CLIENTS IN DRUG TREATMENT: DIFFERENCES BY GENDER,
MODALITY, AND RISK STATUS
C. E. Grella1 and R. M. Etheridge2
1
University of California, Los Angeles, Neuropsychiatric Institute, Drug Abuse Research
Center and 2National Development and Research Institutes
This study examined the extent and type of services related to HIV risk reduction received by clients in the Drug
Abuse Treatment Outcome Study (DATOS). Data was collected from clients after three months in long-term
residential, outpatient drug-free and methadone maintenance treatment and after one month in short-term inpatient
treatment. Clients in residential treatment were mosl likely to receive HIV-related services compared with the other
modalities. Across all four modalities, men were more likely than women to receive HIV-related services regarding
sex-risk reduction, health care options, and general knowledge about HIV, with no difference in services regarding
needle-risk reduction. Individuals were classified into high and low sex-risk categories based on: whether they
exchanged sex for drugs or money, had a high-risk sex partner (i.e., a sex partner who is HIV-positive. a man who
has sex with men. an injection drug user, or a sex worker), or had more than two sex partners and did not
consistently use condoms. High sex-risk males were more likely to receive sex-risk reduction services, although
high sex-risk females were not. A logistic regression equation indicated that men. African-Americans, Hispanics,
individuals who were alcohol dependent, and sex workers were more likely to receive HIV-related services, whereas
individuals who were employed full-time or had health insurance were less likely to receive HIV-related services,
controlling for type of drug treatment modality and other variables. These findings suggest that high sex-risk
women may not be receiving needed services for HIV sex-risk reduction within drug treatment programs, particularly
women who have a high-risk sex partner or multiple sex partners.
ACKNOWLEDGMENTS:
U01-DA10377 to NDRI.
Supported by the National Institute on Drug Abuse, U01-DA10378 to UCLA and
188
EFFECTS OF STAGE OF CHANGE AND HIV RISK-REDUCTION COUNSELING ON
BLACK CRACK/COCAINE USERS
F. Y. Abram*, L. B. Cottler**, and W. M. Compton**
*School of Social Service, Saint Louis University, St. Louis, MO and **Department of
Psychiatry, Washington University School of Medicine, St. Louis, MO
St. Louis’ EachOneTeachOne (EOTO) Cooperative Agreement research project data are used to examine the effects
of Stage of Change and Standard vs. Enhanced Counseling on the HIV risky behaviors of 861 out-of-treatment.
black crack/cocaine users 3 months after intervention. Results show similar changes in HIV risky behaviors across
four stages of change: the precontemplation stage, contemplation stage, action stage. and maintenance stage. Most
study participants, regardless of their stage of change al baseline. improved by reducing or maintaining lower levels
of HIV risky behaviors. Specifically, 57% reduced or maintained a low level of non-injection drug use; 93%
abstained from injection drug use or reduced their level of injection drug use; 81% reduced their number of sex
partners or abstained from sex; and 70% reduced the percent of times not using a condom when having sex or
abstained from sex. The Standard Interrvention Group and the Enhanced Intervention Group had similar reductions in
risk related to number of sex partners and injection drug use. The Enhanced Group had a statistically significantly
higher percent of improvement in non-injection drug use (62% compared to 51% for the Standard Group), but less
improvement in the percent of times not using a condom when having sex (66% compared to 75% for the Standard
Croup). When Stage of Change is controlled, the precontemplators are more affected by the Enhanced Counseling
than those in later stages of change. Implications are that street outreach, recruitment, and targeting out-oftreatment drug users at earlier stages of change for interventions may prove to be more effective than waiting until
they reach later stages of change and/or enter treatment.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-08324 and a NIDA Minority Research Supplement.
NODE-LINK MAPS, AIDS-RISK LEVELS, AND RESIDENTIAL DRUG ABUSE
TREATMENT
U. Pitre and D. F. Dansereau
Institute of Behavioral Research, Texas Christian University, Fort Worth, TX
The investigation examined the influence of pre-treatment AIDS-risk levels and node-link mapping on client ratings
of treatment programs. Node-link mapping is a visual representation strategy that has been shown to reduce drug and
needle use and facilitate group counseling. Probationers (n = 288) mandated to a 16-week residential drug abuse
treatment program received either mapping enhanced (n = 149) or standard counseling (n = 139), and were classified
on the basis of intake data to be at either high (n = 140) or low risk (n = 148) for AIDS. Participants completed a
variety of measures at intake, midterm and endterm. A series of 2 (Counseling method: Mapping vs. Standard) X 2
(AIDS-risk levels: High vs. Low) multivariate analyses of variance were conducted. The dependent variable
probationers’ ratings of: a) their motivation to acquire certain life skills (i.e., emotional control, improved
cognition. and life-management skills); b) their reported treatment self-efficacy and motivation; c) their evaluations
of themselves in treatment (i.e., their treatment progress, success, and engagement, and affect toward treatment); and
d) their psychological well-being (i.e., anxiety, depression, and self-esteem). Those at high AIDS-risk reported
significantly (p < .05) lower treatment self-efficacy and motivation, and lower psychological well being (e.g.,
anxiety and depression) than those with low AIDS-risk. High AIDS-risk mapping probationers reported
significantly (p < .05) higher motivation to acquire life-skills (e.g., emotional control and life management skills)
than their counterparts in standard counseling. Low AIDS-risk probationers receiving mapping reported significantly
(p < .05) higher treatment engagement and session participation than their counterparts who received standard
counseling. The results suggest that AIDS-risk levels affect evaluations of drug abuse treatment programs, and that
exposure to mapping-enhanced counseling may ameliorate some of the disadvantages that accompany high AIDSrisk levels while also providing benefits to those at low AIDS-risk.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-08608.
189
AIDS RISK BEHAVIORS, COCAINE USE, AND TREATMENT OUTCOMES
B. E. Havassy* and S. M. Boles†
*Department of Psychiatry, Treatment Outcome Research Group, Sch. of Med., Univ. of CA,
San Francisco, CA †Center on Addiction and Substance Abuse at Columbia University, NY
HIV risk practices and relationships to treatment outcome were studied in 444 cocaine-dependent Ss in private
chemical dependency treatment programs during 1989 - 1991. The hypothesis was that risky drug use and sexual
practices are related and linked to an increased probability of relapse to cocaine use. Ss were recruited prior to
treatment entry and provided data on drug and alcohol use. symptoms of cocaine dependence, and route of cocaine
administration. They provided data on HIV risk drug use and sexual practices. Ss were followed for 12 months (4
quarters) following treatment entry and provided data about their cocaine use and urine specimens to confirm selfreports. There were 49 IVDUs in the sample, not all of whom injected cocaine. For non-injectors, smoking crack
was significantly related to risky sexual practices. For IVDUs. risky sexual practices and needle risk were
significantly and positively correlated. Notable differences between IVDUs and non-injectors in patterns of
correlations were observed. There were no differences between IVDUs and non-injectors on the outcome variable,
number of quarters of cocaine use post-treatment entry. This outcome measure was unrelated to all of the risk
measures for IVDUs and non-injectors. Linear regressions were Performed regressing number of cocaine dependence
symptoms, route of administration, sex risk scores, and for IVDUs, needle risk scores, on quarters of cocaine use.
The models were not significant. The hypothesized relationship between risky needle use and sex practices was
obtained, but there was no evidence to support a linear positive relationship of these behaviors to treatment
outcome. Data reveal that IVDUs and non-injectors have different patterns of sexual practices and therefore they
might benefit from differently targeted AIDS prevention interventions.
ACKNOWLEDGMENTS: Supported by grants R18 DA05582, R18 MH50856, T32 DA077250, P50
DA09253.
DRUG USE/HIV RISK OUTCOMES BY TYPE OF DRUG TREATMENT
J. A. Hoffman, H. Klein, D. C. Clark, and S. Rodriquez
Friends Research Institute, Washington, DC
Hypothesis: Participation in drug treatment will result in greater reductions in drug use and drug-related HIV risk
when type of drug treatment is compared to no treatment. Sample: Data source: national database for NIDA
Cooperative Agreement for AIDS Community-Based Outreach/Intervention Research Program. Eligibility:
Adults who used cocaine or heroin in previous 30 days and were not in treatment during 30 days prior to baseline;
sample: Cocaine Users (CU) who did not use heroin (N=4,806, 91% no drug treatment; 8.3% HIV+), Heroin
Injectors (HI) who did not use cocaine (N=690; 62% no drug treatment; 5% HIV+), and Dual Users (DU) who used
both cocaine and heroin (N=3,156; 79% no drug treatment; 10.5% HIV+); 2/3 male, 2/3 African American.
Methods: For each of the three drug user groups, comparisons were made between people who had not received
any drug treatment between baseline and six months follow-up and those who participated in at least 14 days of
either methadone detoxification methadone maintenance, outpatient treatment, residential treatment, or prison/jailbased treatment. Results: For CUs, outpatient treatment resulted in greater reductions in crack use compared to no
treatment (10 vs. 6 days, p<.0001). Although residential treatment showed greater reductions in crack use (9 days),
this was not significant. For HIs, methadone maintenance resulted in greater reductions in heroin use than did no
treatment (14 vs. 7 days, p<.0001). Residential treatment was also associated with a 14-day reduction in heroin use.
but due to an N of 12, this was not significant For DUs. methadone maintenance or outpatient treatment resulted
in gteater reductions in heroin use man did no treatment (14 vs 10 vs 4 days, p<.0001). Reductions in sharing
needles, cookers, or cottons did not differ significantly for any type of treatment for any group. Implications:
AIDS outreach/intervention was effective in reducing drug use and drug-related HIV risk behavior. Some drug
treatment modalities facilitated greater reductions in crack or heroin use beyond outreach alone, but did not produce
greater reductions in other types of drug-related HIV risk. Greater emphasis on getting drug users into drug
treatment, and enhancing HIV risk reduction education during treatment, may be needed.
190
HIV RISK REDUCTION AMONG HOMELESS CRACK SMOKERS COMPLETING DAY
TREATMENT AND AFTERCARE
J. E. Schumacher, D. Ross, J. B. Milby, R. DiClemente, P. Sekar, and M. Michael
University of Alabama at Birmingham School of Medicine, Birmingham, AL
Crack cocaine use has been directly linked to increased risky sexual behaviors, like trading sex and crack.
Participants in a 2 group treatment outcome study completed the AIDS Risk Assessment for Crack Cocaine Users
(ARA-C) at intake and treatment completion after 6 months. Information was collected related to crack and alcohol
use, sexual behaviors, and sex and crack use behaviors. The ARA-C measures seven HIV risk constructs: Self
Control (SCon), Sexual Negotiation (SNeg), Sex and Crack (SCk), Condom Use (CUse), Partners (P), IV Use
(IV), and Sexual Behavior (SBeh) represented by a standardized risk value from 0 (lowest risk) to 100 (highest risk)
for each construct. Subjects (N=68) were 71.2% male, 85.6% African American, with an average age of 37.7
(S D =6.97) years. Results using T-tests and McNemar’s tests (past 6 months from baseline vs treatment completion
after 6 months) were: daily crack use (62% vs 15%, p <.05); daiiy alcohol use (36% vs 17%, p <.05); number of
different sex partners (9.7 vs 3.3, p<.05); number of sex partners with whom used crack (7.1 vs 1.8, p <.05); times
traded sex for crack (8.2 vs 2.6, p<.05); times traded crack for sex (10.3 vs 1.2, p<.05); use condom with
spouse/mate nearly every time (44% vs 56%); and use condom with dale/trick nearly every time (44% vs 50%).
Significant reductions (p <.05, T-tests) from intake to treatment completion were found for the following HIV
constructs: SNeg (53.1 vs 45.8); SCk (10.3 vs 3.3); CUse (37.0 vs 30.7); P (7.2 vs 2.0); SBeh (13.9 vs 7.6), and
IV (20.6 vs 6.3). No significant change was shown for SCon (53.3 vs 47.4). Findings suggest important HIV risk
factors associated with crack cocaine using Lifestyle were reduced after 2 months of day treatment and 4 months of
aftercare. Implications for including HIV risk reduction intervention during drug treatment are made. Treatment
group differences will be analyzed.
ACKNOWLEDGMENT:
Funded by NIDA R01 DA 08475.
EFFICACY OF A STRUCTURED MANUAL FOR IMPROVING DRUG COUNSELING
AMONG SUBSTANCE ABUSERS WITH HIV
S. Shoptaw, D. Nahom, D.L. Frosch, M. Portnoff, R. A. Rawson, and W. Ling
Los Angeles Addiction Research Consortium, UCLA Dept. of Psychiatry, W.L.A. VAMC
Drug abusers with HIV have multiple and often severe problems with a host of issues, including housing,
transportation, physical and psychiatric illnesses, substance use, and finances that can overwhelm even the most
enthusiastic of counselors. Training programs that provide structured methods for working with substance abusers
with HIV may help increase counselor efticacy and reduce burnout and consequent attrition of qualified personnel.
This study evaluated the impact upon counselors of being trained to use a structured treatment manual for substance
abusers with HIV. A total of 99 counselors from 34 clinics across the United States were randomly assigned to
‘Immediate’ or ‘Delayed training. Counselors from clinics in the ‘Delayed’ condition were trained after six month
foiiow up assessments. We hypothesized that counselors in the ‘immediate’ training condition would show higher
self-efiicacy. lower bum-out, greater perceived clinic quality, a counseling style that is more cognitive-behaviorally
oriented, and better HIV knowledge, when compared with counselors in the ‘Delayed condition at six month followup. Findings suggest a limited impact of the training on counselor variables. Counselors in the ‘Immediate’ training
group showed a mom cognitive-behaviorally oriented counseling style (t(71)=2.61, p<.05). No differences were
found in self-efficacy, burnout perceived clinic quality, or HIV knowledge. Overall HIV knowledge was very low,
with counselors in the ‘Immediate’ training condition answering 58.17% (S.E.M. = 1.97) of questions in a
knowledge survey correctly. These findings imply that counselors who work with substance abusers with HIV need
more intensive interventions than brief training and structured manuals.
191
DRUG TREATMENT STAFF AND AIDS: RESPONSE TO DEATHS IN PROGRAMS
J. L. Sorenson, A. Mascovich, S. Kaplan, K. Delucchi, S. Folkman, J. London, D. Eaves,
and M. Groves
University of California, San Francisco, at San Francisco General Hospital
We examined reactions to deaths among clinical staff from drug treatment programs specializing in HIV disease.
Subjects were 65 paraprofessional (PP) and 18 professional (PRO) staff in San Francisco programs. PPs (former
substance abusers with BA/BS or less) were more likely to be men and nonwhites. Procedures involved individual
interviews using quantitative measures of personality, job characteristics, exposure to deaths, and staff difficulties
(distress about deaths, grief, burnout, stress, psychological symptoms, and records of absences from work). Focus
groups provided qualitative information. Our hypotheses were that exposure to patient deaths predicts staff
difficulties, and PPs display more staff difficulties. Results: Staff knew a mean of 14 people who died in the past
year, including 10 who had died related to AIDS. PPs and PROs did not differ in exposure to deaths. In general
exposure to deaths did not predict staff difficulties, although there were some moderate relationships with distress
about deaths and absences from work. In general PPs and PROs were more similar than different on most measures
of staff difficulties, although there were some differences in psychological symptoms, burnout, and stress that may
be explained by background and personality differences between PPs and PROs. Implications: Exposure to
patient deaths was substantial, but we did not detect an influence on level of staff difficulties. Staff expressed a need
for better training in dealing with deaths.
ACKNOWLEDGMENTS:
P50DA09253.
Supported by UARP Grant R95-SF-076, and NIDA Grants ROIDA08753, and
CASE MANAGEMENT OF SUBSTANCE ABUSERS WITH HIV INFECTION: SERVICE
UTILIZATION AND COSTS
C. L. Masson, C. S. Phibbs, J. L. Sorensen, R. L. Okin, J. W. Dilley, and M. H. Jacoby
University of California, San Francisco at San Francisco General Hospital, and San
Francisco. CA and Palo Alto VA Medical Center, Palo Alto, CA
We report on health service utilization among 190 substance abusers with HIV who were not in substance abuse
treatment. Participants are in an on-going randomized controlled trial of a case management intervention. Preenrollment levels of medical, mental health, and substance abuse service utilization were assessed in preparation for
a future cost effectiveness analysis of case management at one-year follow-up. Data was obtained from a review of
computerized records at San Francisco General Hospital and the San Francisco County Health Department. Data
was grouped into emergency, outpatient. inpatient, day service, residential, methadone detoxification. and
methadone maintenance services obtained over a one-year period prior to enrollment in case management.
Preliminary analyses show that in the year before study participation 92% of study participants used medical
services, 18% used mental health services, and 65% used substance abuse services. The most frequently used
services were outpatient medical services (82% of participants), inpatient medical services (72% of participants), and
emergency medical services (60% of participants). Future analyses will examine the impact of case management on
health outcomes at one-year follow-up. Case management may be helpful in increasing use of appropriate
medical, mental health, and substance abuse services. It is important to develop cost-effective interventions for
substance abusers with HIV infection.
ACKNOWLEDGMENTS:
Supported by NIDA grants RO1DA08753, T32DA07250, and F32DA05768.
192
DRUG DEPENDENCIES AND PSYCHIATRIC ILLNESSES AMONG AIDS PATIENTS
D. L. Haller, K. S. Ingersoll, D. Dawson, and C. Wager
Medical College of Virginia, Virginia Commonwealth University, Richmond, VA
This was an exploratory study of 253 HIV infected patients admitted to a CMHS/SAMHSA funded AIDS/mental
health speciality clinic. Baseline data revealed that subjects were 37 years old, 3/4ths mate, and 2/3rds African
American; 52% were heterosexual; 41% homosexual, and 7% bisexual. Although heterosexual contact was the
most frequent mode of transmission, 43% of cases were attributable to substance abuse. Rates for substance abuse
were: 10% ETOH only, 24% drug only, 22% both ETOH and drug, and 44% neither. On the CIDI, co-morbidity
was found for substance abuse and type 2 (vegetative) depression and for substance abuse and anxiety disorder. On
the MCMI-III, comorbidity was found for schizoid personality (ETOH), ASP (ETOH and drug abuse), and BPD
(ETOH and drug abuse). Personality “profiles” for 4 substance use subgroups (ETOH only, drug only, both,
neither) reveal less psychopathology for non-substance abusers with more Axis I pathology for alcohol abusers and
more Axis II pathology for polysubstance abusers. Finally, although no between groups differences were found
with regard to cognitive functioning, MMHC patients evidenced neuropsych impairments of 2-3 times the
magnitude found in the general public. Findings suggest the need for screening for co-morbid conditions in HIV
infected patients applying for medical care.
DRUG ADDICTION AND TREATMENT CAREERS AMONG CLIENTS IN DATOS
M. D. Anglin, Y.-I. Hser, and C. E. Grella
University of California, Los Angeles, Neuropsychiatric Institute, Drug Abuse Center
Considerable heterogeneity in patterns of addiction and treatment career histories was observed among the 10,010
clients participating in the NIDA-sponsored Drug Abuse Treatment Outcome Study (DATOS). First treatment entry
was on aver-age Seven years after the initiation of use of heroin or cocaine, although clients differed in duration of
addiction and treatment careers across modalities. Approximately one-half of the clients had no prior treatment
experience. About one-half of DATOS clients with prior treatment had received treatment within the prior year and
they utilized a variety of types of treatment modalities. Regression analyses demonstrated that prior drug treatment
utilization was associated with being female and African American; having longer employment history, more severe
drug dependence, and prior mental health treatment; injecting drug use, and engaging in sex work and criminal
activities. Younger age at first treatment was associated with shorter duration of employment, more severe drug
dependence, earlier onset of drug use. prior alcohol treatment, and fewer types of illegal activity. Approximately
one-third of clients received additional or ongoing treatment during the one-year follow-up period, most frequently
from outpatient drug-free programs. Analysis of cocaine users in outpatient drug-free treatment showed that
individuals with prior treatment were more likely to be abstinent at follow-up if they received more services;
similarly, individuals with prior treatment and longer duration in DATOS treatment were mom likely to be
abstinent at follow-up than those with shorter treatment duration. Career-based research suggests that the drug
treatment system needs to provide a range of approaches and services to address client heterogeneity.
ACKNOWLEDGMENTS:
DA00139 (Hser).
Supported by NIDA grants U01-DA10378, K02-DA00146 (Anglin) and K02-
193
WE BUILT IT, BUT MOST DIDN’T COME: TREATMENT ENTRY AND RETENTION
AMONG OUT-OF-TREATMENT INJECTION DRUG USERS
R. E. Booth, C. F. Kwiatkowski, F. Pinto, D. John, and T. J. Crowley
University of Colorado, School of Medicine
The HIV epidemic and the rising number of injection drug users (IDUs) infected with the disease has led,
increasingly, to calls for an emphasis on substance abuse treatment as a means to reduce its spread.
Recommendations to enhance the attractiveness of treatment for out-of-treatment IDUs include elimination of
waiting lists, rapid intake, and treatment on demand. In this study, we report findings on the comparative effects of
two intervention strategies, each with a free and a payment condition, in increasing treatment entry and retention.
Using a two-by-two factorial design, IDUs were randomly assigned to either motivational interviewing (focusing on
entering treatment) or an HIV risk reduction intervention (focusing on changing HIV risk behaviors), with or
without 90 days of free treatment. All participants were offered rapid treatment intake, transportation to the
treatment facility, and a waiver of the intake fee at the clinic. Findings from nearly 200 IDUs showed that 39%
entered treatment, including 38% assigned to motivational interviewing and 39% to HIV risk reduction. By
payment condition, 50% of those receiving free treatment entered compared to 27% for those paying. Treatment
retention at 90 days was as follows: motivational interviewing, 33%; harm reduction, 49%; free treatment, 59%,
no free treatment, 15%. Predictors of treatment entry, other than free vs. paid treatment, included African American
ethnicity, a perception of having a 50% or greater chance of getting infected with HIV, being in the “Determination”
stage of change, prior drug treatment experiences, and not injecting or smoking cocaine. Predictors of treatment
retention included free vs. paid treatment. These findings call for further efforts to enhance the perceived benefits of
treatment.
ACKNOWLEGMENT:
Supported by the National Institute on Drug Abuse, Grant DA09832-01.
REACHING AND ENROLLING DRUG USERS FOR HIV PREVENTION: A MULTI-SITE
ANALYSIS
R. M. Cunningham-Williams*, L. B. Cottler*, W. M. Compton*, D. Desmond**, W.
Wechsberg***, W. Zule**, and P. Deichler***
*Department of Psychiatry, Washington University School of Medicine, St. Louis, MO;
**University of Texas-San Antonio Health Sciences Center, San Antonio, Texas; and
***Research Triangle Institute, Durham, NC
Since 1994, six additional sites participated in a NIDA-funded Cooperative Agreement aimed at examining rates of
HIV risk behaviors and evaluating HIV risk reduction interventions among out-of-treatment drug injection and crack
cocaine users. The St. Louis site recently showed gender and HIV risk behavior differences among those contacted
by through street outreach and those who actually enrolled in the study (Cunningham, et. al., 1996). The current
study is a cross-site replication of fit year street outreach and study enrollment data from 2 other NIDA
Cooperative Agreement Sites (San Antonio, TX and Durham/Wake County, NC). The following findings were
replicated at least one site: Recruitment: 1) More eligible men than eligible women were contacted by CHOWS;
2) No striking racial differences were found among street contacts and eligible street contacts; 3) Over 1/2 of street
contacts and over 1/2 of eligible street contacts were not current injectors; Enrollment: 1) Compared to eligible
street contacts, fewer enrollees were HIV tested; 2) Compared to eligible women street contacts, a higher proportion
of enrollees were women; 3) A smaller proportion of drug users without any previous drug treatment/treatmentseeking history were enrolled in the study. These findings indicate that we are reaching and enrolling our target
population, but that the sites differ in the effectiveness and accuracy of the street outreach method. Street outreach
alone may not be enough to recruit women and current injectors into HIV prevention studies.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-08324, DA-00209, DA-07471, and DA-08007.
194
RE-ENGAGEMENT OF DROP OUTS FROM A DRUG TREATMENT PROGRAM
K. Stuven, M. F. Goldstein, and S. Deren
National Development and Research Institutes, Inc., New York, NY
Hypothesis: While it is well known that clients lend to cycle in and out of the drug treatment system, this
phenomenon has not been well researched and little is known about those who drop out. Drop out rates for
methadone treatment are typically 33% within 3 months and 50% within 6 months. There are very few studies in
which an attempt has been made to reengage drop outs. despite the fact that it often lakes an addict several tries to
be successful in a treatment program and that drug treatment (particularly methadone treatment) has been shown to
be effective as HIV prevention. The present study hypothesis is that outreach and counseling techniques can be used
to re-engage these drop outs, and they will show greater rates of treatment re-enrollment. HIV risk reduction and
decreases in drug use than a randomly assigned control group. Methods: The project seeks to reengage persons
who have recently dropped out of an MMTP. Initial client contact will be made by an outreach worker who will
offer a “low-threshold” service. After the outreach contact. the client will be invited to participate in a variety of
groups (recovery, support, relapse prevention) as well as individual counseling, at the project field site. The
randomly assigned control group will be offered passive (paper) referrals to community services. Both groups will
be assessed at: drug treatment intake, shortly after drop out, at 6 months, and one year post drop out. A total of 700
clients will take part in the study over a 4 year period. A description of the project components and preliminary
findings for intake assessments will be presented.
ACKNOWLEDGMENT:
Research funded by NIDA grant #RO1 DA10312.
RELATIONSHIP BETWEEN RESISTANCE TO LEARNING ONE’S HIV SEROSTATUS AND
DISCLOSING COCAINE USE
A. Lundy, E. Gottheil, R. Sterling, S. Weinstein, and R. Serot
Jefferson Medical College, Philadelphia, PA
Recent advances in the treatment of HIV-positive individuals, as well as efforts to reduce the spread of AIDS, have
made early detection of HIV status even more important than formerly. Most drug abuse treatment clinics now
encourage their patients to undergo HIV testing. but many patients avoid learning their serostatus by refusing to be
tested or failing to obtain test results. This possible sign of denial may be related to others such as the
underreporting of cocaine use and persistence in engaging in HIV-risky behaviors. In our population of inner-city
cocaine abusers, 778 former patients were interviewed 9 months after being admitted to a 3-month intensive
outpatient treatment program. Of these 21% reported never having been tested, and 9% having been tested but not
knowing the results. In addition. 522 of the former patients claimed not to have used cocaine during the 30
preceding days, although 32% of these submitted urines which tested positive, a clear indication of underreporting.
These data were related in that those who had avoided learning their serostatus were substantially more likely to
conceal their recent use of cocaine than those who had obtained test results (41% vs. 29% p< .01. They also were
al much higher risk of HIV infection (above the median on the RAB), (60% vs. 42%, p< .001). One practical
implication of these results is that self-report data may give a distorted picture of the relationships among cocaine
use. AIDS-risky behaviors, and HIV status.
ACKNOWLEDGMENTS:
Supported by NIDA grants R18 DA06166 and RO1 DA09787.
195
VALIDITY OF A BRIEF OPIOID ABUSE SCREEN FOR PREDICTING CURRENT HEROIN
USE IN HOSPITALIZED HIV-INFECTED DRUG USERS
A. Umbricht-Schneiter, N. Thomas, M. J. Tucker, W. Hawkins, and K. L. Preston
NIDA Intramural Research Program, Baltimore, MD
Drug users [DUs] represent 25% of HIV-infected cases. In some metropolitan areas, HIV-infected DUs make up a
large proportion of hospitalized patients as they are at risk for opportunistic infections. Discrimination between
current and former DUs is necessary for targeting appropriate interventions. Clinicians lack guidelines for assessing
reliably drug use histories. The CAGE Screen has been used effectively to elicit symptoms suggestive of alcohol
abuse problems. Based on that model, we adapted an 8-item questionnaire from the National Household Survey on
Drug Abuse for use as a Brief Opioid Abuse Screen [BOAS] to elicit current heroin use [CHU]. This study
evaluates validity indices of 1) self-reported last heroin use for predicting an opioid-positive urine test; 2) the BOAS
for predicting CHU in hospitalized HlV-infected DUs. Patients (N = 507) were admitted on 845 occasions to the
inpatient AIDS service of an inner-city academic center, and were screened by questionnaire for heroin and cocaine
use; urine samples were tested for opioids by OnTrak®. Of 495 responders, 359 (73%) self-reported use of heroin or
cocaine and were considered DUs. Among these, 303 (84%) had used heroin (65% male, 92% African-American,
mean age 39.4 ± 0.4 years); heroin users were classified as CHUs if they self-reported heroin use within the last
month, or abstainers [no use in last month]; they were evaluated for opioid withdrawal. Only 84 (44%) were CHU;
CHU were more likely to have opioid-positive urine (p<.000) (sensitivity 0.81, specificity 0.72, positive predictive
value 0.76 [PPV], negative predictive value 0.85 [NPV]). Each item on the BOAS correlated with CHU (p<.000)
(ranges for sensitivity: 0.66 - 0.82, specificity: 0.61 - 0.84, PPV: 0.72 - 0.86, NPV: 0.64 - 0.78). Clinical
Institute Narcotic assessment withdrawal scores were high in CHU [5.4 ± 0.4] and low in abstinent DUs (2.8 ± 0.5)
(p<.000). In hospitalized HIV-infected DUs, self-reported heroin use in the last month or a positive response on the
BOAS is a reliable indicator of current use, and each correlates with opioid withdrawal.
A REVIEW OF THE UTILITY OF A NOVEL URINE HIV-1 TEST METHODOLOGY IN DUF
POPULATIONS
R. Van Maanen and B. D. Johnson
Calypte Biomedical Corporation, Alameda, CA and *National Development and Research
Institutes, Inc., New York, NY
Berries et al. (1995) and MacGregor et al. (1994) have favorably reported on the safety, simplicity, and high subject
acceptance of a urine test for HIV-1 antibodies in recovering alcoholics and subjects attending a methadone clinic,
The epidemiologic utility of unlinked mine HIV-1 antibody testing in DUF populations was investigated by two
NH- sponsored DUF sites in Manhattan and Los Angeles, and one multicounty CALDUF site sponsored by CSAT
and California ADP. As expected, HIV-1 prevalence in Manhattan (17.1%, n= 1,615) was significantly higher than
in two Los Angeles studies (2.9%, n = 2,900 and 1.7%, n = 359) and CALDUF (1.2%, n = 1,961). HIV-1
prevalence in self-reported lDUs was 1.8 times and 1.6 times higher than that of all arrestees in Manhattan and
CALDUF respectively, and male:female prevalence rates were 1:1.5 and 1:1.9 in Manhattan and CALDUF
respectively. Manhattan DUF data suggest that in unlinked epidemiologic studies. reliable prevalence data are
possible without the expense of Western blot confirmation by employing an elevated cutoff value in the Urine
HIV-1 EIA. The Calypte Urine HIV-1 EIA makes it possible to conveniently evaluate HIV-1 prevalence in a
previously untestable population of high-risk DUF subjects, with no additional sample collection costs.
References available upon request from senior author.
References available upon request from R. Van Maanen Fax: 510-814-8408.
ACKNOWLEDGMENTS:
D. Anglin, K. Annon, B. Danila UCLA DARC for California DUF data.
196
A PRELIMINARY INVESTIGATION OF LAMOTRIGINE FOR COCAINE ABUSE IN HIVSEROPOSITIVE PATIENTS
A. Margolin, S. K. Avants, and T. R. Kosten
Department of Psychiatry, Yale University
Theoretical considerations as well as preclinical data suggest a potential role for excitatory amino acid antagonists
in the treatment of cocaine addiction. Here we report on results from a preliminary study in which eighteen HIVseropositive cocaine dependent, opiate-agonist maintained patients received lamotrigine (300 mg/day), an indirect
glutamate release inhibitor, on either a standard induction schedule (n=8; full dose beginning week 6) or accelerated
induction schedule (n=10; full dose beginning week 3) for 12 weeks. Outcome measures included cocaine use
assessed by three times weekly urine screens as well as pre- and post-treatment neuropsychological assessments.
Results showed a significant 50% decrease in percent of cocaine positive urine screens in the standard induction
group, but no decrease in the accelerated induction group. There were fewer reports of side-effects and fewer dropouts in the standard-induction lamotrigine group compared to the fast induction group. Neuropsychological
assessments showed decrements in the Trail Making Tests and improvements in the Controlled Oral Wad
Association test in both groups, but no other changes in cognitive functioning. We conclude that standard-induction
lamotrigine is well-tolerated and warrants further investigation for the treatment of cocaine abuse in this patient
population.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA09250, DA00277(SKA), and DA00122(TRK).
NEUROCHEMICAL CHANGES IN COCAINE USERS WITH HIV-1
L. Chang, T. Ernst, I. Walot, R. Jose-Melchor, M. Leonido-Yee, and E. Singer
Departments of Neurology and Radiology,
Medicine, Los Angeles, CA
Harbor-UCLA Medical Center, UCLA School of
Introduction: Previous proton magnetic resonance spectroscopy (1H MRS) studies in brains of HIV patients
showed increased choline compounds (CHO) in the early stages and decreased N-acetyl aspartate/creatine (NA/CR) in
the later stages of the disease. The aim of this study is to determine whether cocaine use has an effect on the
neurochemical abnormalities of HIV patients. Methods: 18 HIV cocaine users and 17 HIV patients wee compared
to 29 normal subjects. MRI and 1H MRS were performed on a GE 1.5 T MR scanner. 1H MRS voxels (3-50cc) were
in the mid-frontal gray, frontal white matter and basal ganglia. Data were acquired using PRESS with
TE/TR=30/3000 ms. Absolute quantitation including cerebrospinal fluid (QCSF) measurement were performed
using brain water as an internal reference. Results: ANOVA showed significantly elevated %CSF (p = 0.002) in
the gray matter of HIV patients compared to HIV cocaine users and the normals. In the white matter, both the HIV
and HIV cocaine users showed lower NA/CR (p = 0.04) and higher CHO (p = 0.002) while the HIV patients showed
higher Ml/CR (p = 0.003) and higher MI (p = 0.0001) compared to normal controls. In the basal ganglia, both
NA/CR (p = 0.03) and MI/CR (p = 0.05) were elevated in HIV and HIV cocaine users due to a lower CR.
Furthermore, CD4 showed inverse correlation with % CSF (in HIV) and with MI (in HIV cocaine users) while
AIDS dementia complex (ADC) staging positively correlated with CHO in HIV patients. Discussion: This study
found abnormal metabolites in both HIV patients with and without history of cocaine addiction. Increased CHO
suggests increased cell membrane turnover while increased MI suggests increased glial activities in HIV. No
significant effects were observed in HIV patients due to cocaine use; however, the rate of progression of the disease
may be different and remains to be evaluated.
ACKNOWLEDGMENT:
Supported by NIDA (00280 K-20).
197
RHESUS MONKEY BEHAVIORAL BATTERY: ACQUISITION AND PERFORMANCE
WITH DRUG AND VIRAL MANIPULATIONS
M. R. Weed, M. A. Taffe, I. Polis, A. C. Roberts*, T. W. Robbins*, G. F. Koob, and L.
H. Gold
The Scripps Research Institute, La Jolla, CA, and Cambridge University, Cambridge, UK*
A computerized behavioral battery based upon human neuropsychological tests has been developed to assess
changes in cognitive performance of rhesus monkeys resulting from neurotoxicity produced by MDMA or infection
with simian immunodeficiency virus (SIV). The battery addresses memory (delayed non-matching to sample,
DNMS; spatial working memory, SWM), attention (intra-/extra-dimensional shift, ED/ID), motivation
(progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task) [CANTAB, Cambridge
Cognition, Cambridge, UK]. As with human neuropsychological batteries, different tasks are thought to depend on
different neural substrates, and therefore performance profiles should assess function in particular brain regions.
Monkeys are tested in transport cages and responding on a touch sensitive computer monitor is maintained by food
reinforcement. Eighteen monkeys have been trained on the SWM (2-5 boxes), PR, and bimanual task. Twelve of
these have also been trained on DNMS (0-64s delay) and 11 tested on ED/ID. Performance on all tasks has been
reliable over a period of years, allowing for assessment of long-term behavioral changes, Increasing delays in the
SWM and DNMS tasks reduces accuracy, as does increasing the number of boxes in the SWM task. The RT task
is sensitive to impairment with dopaminergic or cholinergic antagonists, and PR performance is a function of
reinforcer magnitude. Several tasks have been shown to he sensitive to the effects of SIV infection, including the
bimanual motor, PR, ED/ID and SWM tasks. In summary, sensitivity to neuropharmacological manipulations and
SIV infection, along with stability of performance, validate this battery as a measurement instrument for
characterizing alterations in neuropsychological performance in rhesus monkeys.
ACKNOWLEDGMENTS:
Supported by DA 09111, MH 47680 and MH 19185.
DISCRIMINATING
COGNITIVE IMPAIRMENT
FROM
SUBSTANCE USE IN METHADONE MAINTAINED IVDUS
HIV VERSUS
CHRONIC
D. Dorfman*, L. Handelsman*ˆ, P. Rinaldiˆ, D. Simpson*, B. Stimmel*, K. Williams*, K.
Allran*, J. Kincaid*, P. Enriquez*, J. Schmeidler*, L. Tanners*, and D. Rose*
*Mount Sinai School of Medicine, New York, NY and ˆBronx VA Medical Center, Bronx, NY
The important role of neuropsychological tests for diagnosis, treatment, and research in the nervous system
complications often accompanying HIV infection is largely based on data from non-IVDU groups, mostly gay or
bisexual males. The presumptively high background rate of impairment in IVDUs as well as the cultural and
educational assumptions underlying some neuropsychological tests suggest that a specialized testing strategy is
needed for these patients. We administered standard neuropsychological and reaction time (RT) tests to 131
methadone maintained IVDUs (62 HIV negative, 43 HIV infected asymptomatics, 29 AIDS). Choice RT was
sensitive both to neuropsychological impairment [F(1,108) = 19.59. p < .001] and specifically sensitive to
impairments associated with advancing HIV infection lF(2.108) = 9.53, p < .001]. Simple RT was sensitive to
neuropsychologicai impairment [F(1.108) = 6.39, p < .02] but not specifically sensitive to HIV associated
impairments [F(1.108) = .291, ns]. On the standard tests, mere is an increasing rate of neuropsychological
impairment with advancing HIV infection [F(1.119) = 4.03, p < ,051, however, only tests of memory were
specifically sensitive to these impairments [F(2,105) = 8.361, p < .001]. Further analyses showed that IVDUs,
irrespective of HIV status, have a higher impairment ram than demographically matched healthy controls [F(3.140)
= 5.35, p < .002]. We conclude that IVDUs can be readily screened for HIV associated cognitive impairments by a
battery taking less man to minutes to administer. The significance of our findings with respect to the cognitive
impairments in both HIV infected and uninfected IVDUs will he discussed.
ACKNOWLEDGMENT:
Supported by NIDA grant DA077308.
198
DYNORPHINS MODULATE LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY IN
CORTICAL NEURON/GLIA CULTURES
L.-Y. Kong, G.-H. Jeohn, and J.-S. Hong
Neuropharmacology Section, National Institute of Environmental Health Sciences, National
Institutes of Health, Research Triangle Park, NC
We previously reports that dynorphins inhibit the lipopolysaccharide (LPS)-induced production of nitric oxide RIO)
and proinflammatory cytokines in glial cells from the brain without the participation of -opioid receptors. Because
NO and the proinflammatory cytokines have been implicated in various neuropathological conditions, we
hypothesized that dynorphins would reduce LPS-induced neurotoxicity. Therefore, we examined the effects and
mechanizms of action of dynorphins on the LPS-induced release of lactate dehydrogenase (LDH), an indicator for cell
injury or death, and morphological changes in mouse primary mixed cortical neuron/glia cultures. LPS induced a
concentration-dependent increase in the level of LDH in these cultures. Dynorphin (dyn) A-(1-8) significantly
inhibited the LPS-induced release of LDH and reduced the LPS-induced neuronal losses or morphological changes at
ultralow concentrations of 10-14 to 10-12 M and at a high concentration of 10-6 M. Dyn A-(1-8) suppressed the
LPS-induced production of NO at concentrations of 10-16 to 10-12 M. Ultralow concentrations (10-15 to 10-13 M)
of des-[Tyr1]dyn A-(2-17), a non-opioid peptide which does not bind to -opioid receptors, exhibited the same
inhibitory effect as dyn A-(1-17). [Met5]-enkephalin, -endorpphin, or nociceptin did not affect the LPS-induced
LDH release. These results suggest that dynorphins reduce the LPS-induced neuronal injury in the brain and their
beneficial effect is not mediated by classical opioid receptors or the opioid receptor-like KOR-3 receptor. In
addition, these results indicate that decreasing the level of NO alone is not sufficient to reduce the LPS-induced
neuronal damages, which may provide new insights into the role of NO in the LPS-induced neurotoxicity.
EFFECT OF ACUTE MORPHINE INJECTION IN THE PERIAQUEDUCTAL GRAY
MATTER ON MACROPHAGE FUNCTIONS
R. Gomez-Flores and R. J. Weber
Section of Medical Sciences, Department of Biomedical and Therapeutic Sciences, University
of Illinois College of Medicine at Peoria, Peoria, IL
Opioid action in the periaqueductal gray matter (PAG) is well known to suppress T cell proliferative responses and
NK cell activity. We investigated the effect of acute microinjection of morphine into the PAG on nitric oxide and
tumor necrosis factor- (TNF- ) production, and its effect on phagocytosis of Candida albicans by resident and
activated rat splenic macrophages. Fischer 344N male rats were injected bilaterally into the PAG with 10 nmol of
morphine. Three hours following injection, resident splenic macrophages were obtained, and incubated overnight.
Macrophage monolayers were then incubated for 3 days in the presence or absence of 25 ng/ml of
lipopolysaccharide (LPS). after which supernatants were taken for nitrite (Griess reagent), and TNF- (L929
bioassay) determinations. For the phagocytic activity, resident macrophages were incubated with C. albicans (ratio
yeast to macrophage, 10:1) for 1 hr. and then stained with Giemsa reagent; the phagocytosis of yeasts among
macrophages was determined by visual inspection of at least 100 macrophages. Morphine treatment significantly (P
< 0.01) suppressed nitrite release (39% and 50% reduction compared with untreated control and sham control,
respectively), TNF- production (21% and 28% reduction, respectively), and the phagocytic activity of
macrophages (50% and 60% reduction, respectively). Further studies with acute and chronic injections of morphine
in PAG may provide additional evidence of its effects on macrophage functions.
ACKNOWLEDGMENT:
This work was supported by NIDA Grant DA/Al 08988.
199
IMMUNOSUPPRESSION FOLLOWING PAG MORPHINE INJECTION IS CORRELATED
WITH ACTIVATION OF THE HPA AXIS AND IS NOT BLOCKED BY MIFEPRISTONE
J.-L Suo and R. J. Weber
Section of Medical Science, Department of Biomedical and Therapeutic Sciences, University
of Illinois College of Medicine at Peoria, Peoria, IL
Central nervous system mediated morphine-induced immunosuppression has been hypothesized to be due to
activation of either the hypothalamic-pituitary-adrenal (HPA) axis or the sympathetic nervous system (SNS). We
investigated the effects of morphine injected bilaterally into ventral-caudal periaqueductal gray (PAG) matter of the
mesencephalon on various parameters of immunocompetence. We found that injection of 20 nmol of morphine into
the PAG resulted in a significant suppression of splenic NK cell activity, splenic and thymic T-lymphocyte
proliferation, and peritoneal macrophage function. Furthermore, CD25, CD54, and CD71 activation markers on
splenocytes and thymocytes from morphine treated animals were atso decreased after 24 hours culture with ConA.
No changes in CD3, CD4, and CD8 or NKR-P1 positive cells of spleen and thymus were seen 3 hr after morphine
injection. To assess the effects of morphine on the activation of HPA axis, plasma ACTH and corticosterone
(CSO) levels were determined before and after injection of morphine in jugular catheterized Fischer 344N mate rats.
A temporal increase in ACTH was observed which peaked at 40 minutes (9-fold) following PAG morphine
injection. This was accompanied by a subsequent 2-fold sustained increase in CSO. Prior peripheral injection of
mifepristone (RU 486, 20 mg/kg), a glucocorticoid receptor antagonist. was ineffective in blocking
morphine-mediated suppression of NK cell activity and T cell proliferation, indicating alternative mechanisms
involved in morphine-induced suppression. We have shown that the SNS may play a role in morphine-induced
immunosuppression. In summary, we found that acute microinjection of 20 nmol of morphine bilaterally into
ventral-caudal PAG results in suppression of immune function, which is accompanied by increases of plasma
ACTH and CSO levels but is not blocked by prior administration of RU 486.
ACKNOWLEDGMENT:
This work was supported by NIDA Grant DA/AI 08988
SUPER- AND SUBADDITIVE INTERACTIONS OF MORPHINE AND DELTORPHIN IN
INDUCING IMMUNOSUPPRESSION
J. J. Meissler Jr.*, M. W. Adler, T. J. Rogers*, E. B. Geller, R. J. Tallarida, and
T. K. Eisenstein*
Departments of *Microbiology and Immunology,
School of Medicine, Philadelphia, PA
and Pharmacology, Temple University
We have previously repotted that µ (morphine),
(U50,488H) or 2 (deltorphin) agonists can suppress the
secondary in vitro antibody response of mouse splenocytes to sheep red blood cells in a plaque-forming cell assay.
Treatment of spleen cells with any one of these opioids induces a maximum of 50% to 60% suppression in the
number of plaques at concentrations of 10-7 to 10-11 and the suppressive effects are no longer significant at 10-15.
To try to augment the suppressive effects, combinations of opioid agonists binding at the different receptor types
were used. Morphine (M) and deltorphin (D) were combined in a molar ratio of 3 (M) to 1 (D). The combination
was treated as a new compound and diluted in 100-fold increments. Pooled data from 11 experiments using this
combination showed a dramatic alteration in the dose-response curve. At low concentrations, there was a strong
indication of superadditivity that reverted to subadditivity at high concentrations. Pretreatment of spleen cells with
CTAP, a selective m receptor antagonist, or naltriben (NTB), a selective 2 receptor antagonist, for 2 hours before
addition of the 3(M):1(D) combination returned the dose-response curve to that observed with either agonist atone.
A model is presented to explain the effects of the drug combinations.
200
TIME-DEPENDENT IMMUNOMODULATORY EFFECTS FOLLOWING NATURAL OPIOID
WITHDRAWAL
J. P. West, D. T. Lysle, and L. A. Dykstra
Curriculum in Neurobiology and Department of Psychology, University of North Carolina,
Chapel Hill, NC
Although the consequences of chronic opioid administration and tolerance on immune status have been examined,
few studies have investigated the immunomodulatory effects of opioid withdrawal. The current study utilized the
chronic drinking method of drug administration and a subsequent natural withdrawal episode to investigate the effect
of opioid withdrawal on several in vitro measures of immune status. Male Lewis rats were administered 0.6
mg/ml morphine in their drinking water for 20 days. Following this period, withdrawal was induced either 0, 6.
12, 24 or 48 hours prior to sacrifice and tissue collection. Measures of splenic T- and B-cell proliferation, IFN
production, and natural killer cell activity were performed. Immune measures in rats that drank morphine and did
not experience withdrawal immediately prior to sacrifice were not significantly different from those measures in rats
that drank tap water for 20 days. In rats that underwent natural opioid withdrawal; however, there was a timedependent modulation of Con-A and TSST-1 stimulated splenic T-cell proliferation, Con-A stimulated splenocyte
g-IFN production, and splenic natural killer cell activity. Immune measures were reduced within 12 hr of
withdrawal induction but gradually recovered within 48 hr. Proliferation of splenic B-cells was not significantly
modulated by opioid withdrawal. These data provided evidence to suggest that withdrawal from chronically
administered opioids such as morphine or heroin may lead to alterations in the immune status of drug using
individuals.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA07481, DA00033, and DA 07244.
DELTA OPIOID RECEPTOR LIGANDS MODULATE APOPTOSIS IN CULTURED
LYMPHOCYTES
#
#
K. Linner# *, M. Canty , P. Portoghese*, and W. Heagy *
#
Minneapolis Medical Research Foundation and the *University of Minnesota, Minneapolis,
MN
Apoptosis, a form of programmed cell death characterized by disruption of the nucleus and chromosomal
fragmentation, plays an important role in the homeostasis of both resting and activated lymphocytes. It is mediated,
in part, by i) intracellular proteases, ii) bcl-2-related proteins, and iii) cell surface receptors, including ones for
adhesion molecules, cytokines and members of the tumor necrosis factor receptor superfamily. We have initiated
studies in 3 systems to define the effects of opioids and opioid antagonists on apoplosis. 1) thymocytes from 4-6
week old CD-1 mice were cultured with 0.5 ug/ml concanavalin A (Con A) and apoptosis was measured by DNA
fragmentation or by FITC-Annexin V binding. The addition of the delta receptor antagonist, naltrindole (NTl), to
the Con-A stimulated thymocyte cultures modulated the apoptotic response in a biphasic, dose-dependent manner. 2)
In fetal thymic organ cultures NTI either enhanced or inhibited apoptosis depending on the gestational age of the
thymic lobes. 3) The numbers of apoptotic cells in human Jurkat and NALM 6 cell lines incubated the delta
agonist, DADLE (10-7M), for 48h with and without dexamethasone were reduced, as measured by Hoechst dye and
FITS-Annexin V binding. These studies show that the addition of delta receptor ligands to cultured lymphocytes
results in a shift in the homeostatic processes that regulate apoptosis.
ACKNOWLEDGMENTS:
Supported by NIDA R01DA10166 (WH) and R02DA09724 (KL).
201
RENAL INTERSTITIAL SCARRING (RIS): ROLE OF MORPHINE
P. C. Singhal, N. Franki, K. Reddy, and A. Kaposi
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, N.Y. The Long
Island Campus for Albert Einstein College of Medicine, New York
Renal interstitial scarring (RIS) is an important component of heroin-associated nephropathy (HAN). Kidney
fibroblasts have been demonstrated to play a role in the development of renal scarring in a variety of renal diseases.
We studied the effect of morphine on the proIiferation of rat kidney fibroblasts (NRK-49). Growth arrested
subconfluent NRK cells were incubated with variable concentrations of morphine (10-14 to 10-4 M) for variable periods
(24 to 72 hours). Subsequently, cells were trypsinized and counted (n=4 to 6). [3H]thymidine incorporation studies
were also carried out under identical conditions. To determine the role of early growth associated genes in morphineinduced NRK proliferation, Northern blots were generated from control and morphine treated cells at 10, 30, 60 and
120 min. These blots were probed with cDNA probes specific for c-fos, c-jun and c-myc. Evaluation of NRK
apoptosis was performed after treatment with morphine and subsequent staining with H-33342. The isolated DNA
from control and morphine treated NRK cells was Iabeled with [32P]dCTP and run on gel electrophoresis. Western
blots were prepared from cell lysates of control and morphine treated cells and probed with anti-p53 antibody.
Morphine enhanced (P<0.001) NRK proliferation and mRNA expression of c-fos and c-jun at lower concentrations
in a dose and time dependent manner. Morphine at higher concentrations promoted apoptosis and synthesis of p53.
Morphine treated cells showed Integer multiples of 180 base pair (ladder pattern) confirming apoptosis. These results
indicate morphine may be directly contributing to renal interstitial scarring in patients with heroin-associated
nephropathy.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-06753.
ANERGY AND IMMUNE SUPPRESSION IN INTRAVENOUS HEROIN ADDICTS WITH
HEPATITIS C
F. Tennant
Community Health Projects, Inc. — Research and Education Center, West Covina, CA
Intravenous heroin addicts who are HIV positive are known to have a high rate of anergy and immune suppression.
Heroin addicts in California have a very low rate of HIV positivity but have a high rate of active, hepatitis C
Infection. To determine if addicts with hepatitis C and who are HIV negative demonstrate anergy and susceptibility
to AIDS, tuberculosis and other infections, 156 heroin addicts maintained with methadone at five different locations
in the Los Angeles Basin were selected for study. AlI were HIV negative but had hepatitis C in varying stages. Ages
ranged from 25 to 68 years and subjects had been addicted for periods ranging from 13 to 38 years. All were given
intradermal skin tests with antigen for tuberculosis (PPD - intermediate), candida, mumps, and tetanus. Twenty-four
(24;15.0%) showed no reactivity to any antigen as judged by 5mm or more of induration at 48 and 72 hours postadministration. Eight (8; 33.33%) of these cases demonstrated one or more low, lymphocyte indicators. Seventeen
(17; 11.0%) demonstrated a positive PPD test, and nine of these cases had tested negative in the year prior to this
test indicating that tuberculosis is spreading in the California addict population. This study also suggests that
anergy and infectious disease susceptibility is present in some intravenous heroin addicts who have hepatitis C and
are HIV negative. Identification and improvement of immune suppression in the methadone patient is warranted as a
strategy to contain infectious disease.
202
HEPATITIS C VIRUS INFECTION IN COCAINE USERS--A SILENT EPIDEMIC
H. H. Harsch, J. Ponkiewicz, A. S. Bloom*, J.-K. Cho, L. L. Sperry, and E. A. Stein
Departments of Psychiatry and Pharmacology*, Medical College of Wisconsin, Milwaukee,
WI
About 250 cocaine users were solicited through advertisements for a study requiring otherwise healthy subjects.
These subjects were screened by an extensive phone interview for the presence of other psychoactive drug dependence
or any significant medical or psychiatric condition. Individuals were specifically asked about ever having hepatitis
and their HIV status. Individuals who were dependent on other drugs of abuse, alcohol, or had a significant medical
or psychiatric history were excluded. The remaining 95 volunteers were brought to our clinical research center and
tested for hepatitis B, hepatitis C and HIV. Subsequently, of these 95 assumed healthy subjects, 36 (38%) tested
positive with antibodies to the hepatitis C virus. Only 1 (1%) tested positive with hepatitis B and 2 (2%) with
HIV. The Milwaukee Regional Blood Center has reported a 0.12% incidence hepatitis C viral (HCV) infection
among blood donors in this area. The demographics of this cohort were 73% African-American, 75% male, 75%
never married, 43% employed with a mean age of 36±8 years. The percentage of subjects reporting any lifetime
intravenous drug use among the HCV(+) and the HCV(-) cohorts was 79% vs. 38%. While many vectors involved
in HCV transmission are still unclear, others have reported a high prevalence of HCV infection in cocaine users
both in those with and without a history of intravenous drug use. Other aspects of cocaine use, sharing
paraphernalia for intranasal use, or lifestyle factors may play a role in HCV transmission. Since up to 40% of
HCV infections may progress to cirrhosis, this is an epidemic among a population that is most often uninsured and
receiving little medical care. These subjects also form a pool for the transmission of HCV to the community. This
study, with the finding of a 38% HCV infection rate among well-screened cocaine users, highlights the need for new
public health interventions.
ACKNOWLEDGMENT:
Supported by NIDA Grant DA09465
HEPATITIS B IN INJECTION HEROIN USERS: A FOLLOW-UP
R. McDermott, K. L. Sees, K. Delucchi, H. Robillard, and S. Hall
San Francisco VA Medical Center and University of California, San Francisco
This study is an update of a study on Hepatitis B in injection heroin users presented here last year. We report
findings on 34 subjects, 12 of whom were negative for Hepatitis B. We sought to examine the relationship between
mood, fatigue and hepatitis status in light of our earlier findings that Hepatitis B negative patients demonstrated
higher sexual risk behavior than Hepatitis B positive patients. No drug risk differences between groups was found.
We hypothesized that patients who were positive for Hepatitis might have less energy and feel sicker than their
negative cohort, which might explain their lower sexual risk behavior. All patients were male veterans in
Methadone Maintenance Treatment at the SF-VAMC, who typically have a twenty year or more history of
substance abuse. The mean age of this population was 48. Sixty-eight percent were Caucasian, and 29% were
African-American. Thirty-two percent were married or living with a partner. Twelve percent reported combat history
and 59% reported a history of cocaine use. Sixty-eight percent were living in a home or apartment. We administered
The Profile of Mood States (POMS). the Pleasant Events Scale and three fatigue scales developed by Krupp.
Kobashi, and Haylock to all but two of our original subjects, who were lost to follow-up, and eight new subjects.
Contrary to our expectations. we found that patients who were negative for Hepatitis B reported significantly more
fatigue than patients who were Hepatitis B positive. We tested several possibilities that use of clean needles or no
sex might account for the differences we found, but they had no effect. While it is possible that current blood tests
are not sensitive enough to pick up low levels of infection in those we found to be negative for Hepatitis, we
believe that there may be an as yet undiscovered reason for the behavioral differences we found.
ACKNOWLEDGMENTS:
0121.
Supported by NIDA grants #T32-DA07250, P50-DA09235, and TRDRP #3KT-
203
NUTRITIONAL STATUS
ABSTINENCE
AND HEPATIC FUNCTION DURING DRUG USE AND
L. J. Cheskin, L. Jefferson, K. R. Fontaine*, and D. A. Gorelick
National Institute of Health’s National Institute on Drug Abuse, Division of Intramural
Research, and *Department of Medicine, Johns Hopkins University, Baltimore, MD
While it is widely appreciated that active drug abusers are often undernourished, the epidemiology and clinical
significance of this phenomenon have not been well-studied. In addition, malnutrition and refeeding may be
associated with abnormal hepatic function, but such abnormalities have not been studied in drug abusers. We
addressed these issues by retrospectively abstracting data from the rewards of 301 consecutive subjects admitted to the
NIDA DIR research ward for the period 1994-1996. Data included sociodemographic characteristics, predominant
drug of abuse, nutritional parameters (e.g., weight, weight change, serum cholesterol, albumin, total lymphocyte
count), hepatic parameters (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatitis B
surface antigen); and HIV antibody status. The sample was predominantly male (76%), African-American (87%).
and employed (70%); with an average age of 32.4 ± 5.4 years, and a body mass index (BMI: kg/m2 ) of 23.8 ± 4.2.
The predominant drugs of abuse were cocaine (51.5%) and heroin (42.5%). Upon admission, 12% of the sample
were malnourished. The most prevalent diagnostic indicator of malnutrition was < 80% ideal body weight. Heroin
abusers were more likely to be malnourished at admission (P = .016). There was no association between any other
study variable and malnutrition. In analysis adjusted for length of stay (M = 22 ± 19 days), malnourished patients
gained an average of 3 BMI units (2.9 ± 4.3 kg) over the course of the inpatient stay. Refeeding was associated
with modest increases in AST (19%) and ALT (38%) among those not malnourished at admission. Among the
malnourished, refeeding was negatively associated with AST levels. The magnitude of the associations suggests
that, among the drug abusing population, refeeding does not significantly alter hepatic function.
SUPERVISED TUBERCULOSIS CHEMOPROPHYLAXIS FOR DRUG USERS ENROLLED
IN A METHADONE PROGRAM
J. Shi, S. Henry, P. O’Connor, and P. Selwyn
APT Foundation and Yale University, New Haven, CT
Drug users (DU) are at high risk for Mycobacterium tuberculosis (TB) infection. Previous research revealed newly
detected latent TB infection in 9% DU enrolled in methadone maintenance treatment program (MMTP) in New
Haven, CT. Chemoprophylaxis (chemo) with isoniziad (INH) greatly reduce the risk of developing active disease.
Medication compliance has been identified to be most difficult for DU. In this study, to enhance compliance with
INH, DU enrolled in MMTP who were identified to be tuberculin skin test positive (PPD+) were offered supervised
TB chemo (SC) with INH added to their daily methadone dose. From May 1966 to May 1997. 49 DU went
evaluated. Forty patients were found eligible to initiate INH. of whom, 5% (2/40) refused treatment. Out of the 38
patients (mean age 40 +/- 8 yrs) who consented to INH chemo, 89% (34/38) consented to SC and 11% (4/38)
accepted lNH without supervision (non-SC). So far, among the SC group 38% (13/34) have completed INH
chemo, 41% (14/34) are in progress and 20% (7/34) have discontinued INH without completion. Among the nonSC group, by self report, 50% (2/4) have completed INH chemo and 50% (2/4) have discontinued. The reasons for
incomplete chemo included 13% (5/38) were dicharged from MMTP, 5% (2/38) were incarcerated, 3% (1138) lost to
follow-up although still in MMTP, and 3% (1/38) had elevated liver enzymes related to acute hepatitis B infection.
Although all patients were recommended for monthly follow-up visits for symptom checks and liver function tests
evaluation, only 45% (17/38) returned for one or more visits. There were no INH related toxicity observed. In
summary, supervised TB chemo with INH added to methadone for DU in MMTP is a feasible method of enhancing
INH compliance in DU. INH seemed to be well-tolerated by patients although medical follow-up to assess toxicity
was poor. There were no observed INH related toxicity during this study period.
204
TUBERCULIN REACTIVITY AMONG DRUG USERS VARIES BY YEARS OF INJECTION
BUT NOT BY SPECIFIC DRUG OR ROUTE OF USE
N. Salomon, D. C. Perlman, P. Friedmann, M. P. Perkins, V. Garcia de Soria, L. Ojeda W.
Lugo, and D. C. Des Jarlais
Beth Israel Medical Center, New York, NY
Drug users are al high risk of tuberculous (JB) infection. Identifying subgroups of active drug users with a greater
prevalence of TB infection may be valuable in guiding the development of TB services and in targeting interventions
to disrupt transmission. Participants at a New York City syringe exchange and an inpatient detox program were
offered PPD testing, and were interviewed. From 4/95-8/31/96, 984 completed PPD testing to date. Thirty-four %
were female, 53% nonwhite, 86% US born, 28% homeless, 29% without health insurance. PPD reaction rates were
15% >=10 mm, 3% 5-9 mm, 69% PPD (-). 13% anergic, with a 0.3% rate of active TB. The proportion with PPD
(+) (>= 10mm) increased with age and with years of drug use (both per 10 yr strata, both p < 0.001). PPD (+) rates
were higher among older DUs with longer histories of drug use [ <5 yrs DU, age œ 35 yr, 5% PPD (+); < 5 yr DU,
age > 35 yr, 13% PPD (+); > 5 yr DU, age < 35 yr, 17% PPD (+); > 5yr DU age > 35 yr, 21% PPD (+)]. PPD
(+) rates did not vary by specific drugs used (past 6 months or ever) or by routes of drug use (injection only-14% (+)
PPD, inhalation only-18% (+) PPD, both-12% (+) PPD; p = 0.16). Rates of TB infection increase among older
drug users and are augmented by years of injection drug use but are not markedly affected by the specific drug or
route used, suggesting that the duration of time spent in drug using environments increases TB infection risk.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-09005
TUBERCULOSIS DIRECTLY OBSERVED PREVENTIVE THERAPY FOR ACTIVE DRUG
USERS IN TWO SETTINGS
D. Perlmon, N. Salomon, V. Garcia de Soria, P. Perkins, W. Lugo, L. Ojeda, P. Friedmann,
D. Des Jarlais, and D. Paone
Beth Israel Medical Center, New York, NY
Efficient means of delivering TB preventive therapy to drug users (DUs) are needed. Syringe exchange programs
(SEP) have the potentiaI to deliver health interventions to DUs. We conducted TB screening in DUs both at a New
York City SEP and inpatient detox facility and administered DOPT at the SEP and in an HIV clinic. To date 46
eligible DUs have been recruited for DOPT (17 from SEP, 27 from detox, 2 from a female DU support group) with
twice weekly INH. Incentives were provided weekly based on adherence (31 patients [pts]) only at the HIV clinic.
The mean age was 40 yrs, 39% were female, 80% nonwhile, 47% homeless, 18% without health insurance, 33%
HIV (+). Forty % injected heroin, 15% injected cocaine, 57% used crack, 38% drank alcohol to intoxication. To
date, 10 pts (22%) have completed 6 months (mos) of INH with 80% adherence (# doses taken/# doses
scheduled). Ten (22%) are still in therapy (median 91% adherence, range 28-100%; 60% were 80% adherent).
Twelve (26%) were transferred to care elsewhere (6 to other provider settings, 4 to long term drug Rx. 2
incarcerated). In 1 (2%) INH was discontinued due to adverse reaction after 2 mos. Thirteen (28%) were lost to
follow-up (4 never showed for DOPT despite initially agreeing: 9 lost after 1-6 mos (median, 3). DUs recruited for
DOPT at the SEP (p <0.002) and DUs given DOPT at SEP (p < .002) were less frequently lost than those recruited
from detox or medicated at the HIV clinic, despite the use of incentives only at the HIV clinic. While measures to
improve adherence are needed, SEPs are valuable sites for screening active DUs for TB and may be useful sites to
deliver DOPT to active DUs.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-09005
205
HOW DOES INFORMATION ABOUT “BAD” HEROIN SPREAD AMONG INJECTION DRUG
USERS?
I. Fureman, L. Goehl, D. Metzger, H. Navaline, R. Scotti, and G. Woody
University of Penn/Philadelphia VAMC Center for Studies of Addiction
Revention research and intervention activities require an understanding of bow to effectively communicate with
injection drug users and other marginalized communities al risk for HIV infection. This project aimed to determine
how information is disseminated and interpreted within the injection drug user community. We studied how
information about a batch of “bad” heroin that appeared “on the streets” of Philadelphia on May 9, 1996, flowed
through a sample of drug users. Thirty qualitative interviews were conducted between June and September 1996, as
part of Project LinCS, a CDC funded study to assess community attitudes toward government-sponsored HIV
vaccine trials. Respondents were selected from a cohort of drug users enrolled in Philadelphia’s HIVNET (HlV
Network for Prevention Trials) project. Individuals were chosen from the cohort who represented a variety of ages.
races, neighborhoods and years of heroin use. The data repaid suggest that an active information network exists
within the Philadelphia injection drug user community. Despite their differences, almost all 30 respondents reported
bearing about the “bad’ heroin within one day. Most respondents first heard about the “bad” heroin from local
television news. After first bearing about it, additional information was received from television news by 27 (90%)
from the newspaper by 21 (70%). and from friends by 15 (50%) respondents. Twenty-four (80%) respondents told
others about the “bad” heroin. Overall, the content of the messages conveyed among the respondents was protective
and safety-oriented.
A LONGITUDINAL EVALUATION OF ANABOLIC/ANDROGENlC STEROID ABUSERS
ACROSS ONE OR TWO CYCLES OF USE
P. J. Fudala1, J. S. Calarco1, R. Weinrieb1, K. M. Kampman1, and C. Boardman2
1
University of Pennsylvania, Department of Psychiatry; Department of Veterans Affairs
Medical Center; and the 2Children’s Hospital of Philadelphia, Philadelphia, PA
The illicit use of anabolic/androgenic steroids (AASs) has been mported for individuals seeking to improve their
athletic performance or enhance their physical appearance. While serious adverse medical events seem to be rare,
psychological and psychiatric morbidity may be more common. Still; however, the relationship between AAS use
and changes in affect and behavior is far from clear. The present investigation assessed subjects for up to one year
with a comprehensive behavioral and clinical battery. The study was conducted at the University of Pennsylvania
Treatment Research Center between September 1994 and August 1996. Subjects were studied through one (n=5) or
two (n=2) on/off cycles of AAS use. Drugs were obtained and self-administered by individuals through their usual
mechanisms. Subjects returned to the research clinic at approximately 2-week intervals to complete the assessment
battery. Few clinically relevant changes in physiological parameters or laboratory measures were noted. Although
changes in various behaviorai rating scales (e.g., Beck Depression Inventory, Profile of Mood States questionnaire,
and the Buss-Durkee Hostility Scale) were observed across time, these changes were not clearly related to periods of
reported AAS use. Additional factors such as life events, subjects’ other drug use. and the extended duration of
activity of some of the AAS preparations probably influenced the results. “Off” cycles were associated with a greater
percentage of subject-reported decreased testicular size, appetite frequency of sexual activity, and libido. The results
provide the first reported evaluation of the effects of AASs across and between cycles of use, for periods of up to one
year, when these drugs are administered in a naturalistic pattern of abuse. Overall, the data are not consistent with
readily observable or predictable effects secondary to the use of multiple, high-dose AASs.
206
COCAINE AND THE HEART: MORPHOLOGICAL AND MOLECULAR CORRELATES
M. Mailet*, D. Chairasini*, S. Besse*, C. Latour**, and G. Nahas***
Hospital Lariboisiere, *Hospital Fernand Widal** Paris, France and New York University
Medical Center***New York, NY
Left ventricular hypertrophy and cardiomyopathy in the absence of coronary insufficiency have been reported in
chronic cocaine consumers. The present experiments were designed to study the cardiac morphological and
molecular correlates associated with chronic cocaine administration. Rats fitted with osmotic pumps implanted in
the peritoneum were administered continuously cocaine (10 to 40 mg/kg/day) for 14 to 28 days. Control animals
were aiministered saline. Weight gain and behavior were the same in both groups. Tolerance to the initial
hypertensive effect of the drug was observed after 6 days. Cocaine treated animals presented cardiac morphological
and cytogenetic changes. There was a significant (p<0.01) left ventricular hypertrophy associated with disseminated
ultrastructural lesions of the myofibrils, elongation of the sarcomeres and abnormal mitochondria. Association of
alcohol (20 g/kg in 10% glucose i.p.) for 7 days, resulted in disseminated areas of necrosis. Molecular alterations of
the cardiomyocytes were also observed, with an induction of gene expression for ANF (atrial natriuretic factor) a
shift in myosin heavy chain gene expression and activation of the genes encoding for type I and II collagen.
Protooncogenes fos and MYC were not affected as they are in the neuronal cells of the nucleus acumbens indicating
a possible cocaine tissue specificity. Chronic cocaine intoxication in the rat causes left ventricular hypertrophy,
cardiac ultrastructural lesions and modifications of the cardiomyocyte phenotype. The mechanisms of the
morphological and molecular cardiac aterations, induced by chronic cocaine and administration remain to be
established. A direct intracellular toxicity of the alkaloid might be invoked since cocaine accumulates in tissues
following chronic administration.
CARDIOVASCULAR EFFECTS OF COCAINE
D. Overton, P. Kenny, L. T. Wells, S. Dhother, D. Simms, L. Lamki, B. Barron, L.
Wagner, B. Fang, R. Chen, R. Meisch, L. M. Ratkos, and B. A. Johnson
University of Texas Health Science Center - Houston
Using continuous non-invasive cardiovascular monitoring, eight healthy cocaine addicts receiving intravenous
cocaine (0.325 mg/kg iv or 0.650 mg/kg iv) in a double-blind placebo-controlled experiment demonstrated
significant increases in pulse and mean arterial pressure which peaked about 5 min. post injection and was sustained
for a further 55 min. cocaine administration has no significant effect on oxygen saturation, and no abnormalities of
rhythm or conduction were seen on the electrocardiogram. These doses and method of intravenous cocaine
administration, and our procedures for cardiovascular monitoring, appear relatively safe for laboratory studies of
healthy cocaine addicts with no preexisting cardiovascular disease.
ACKNOWLEDGMENT:
Supported by Advanced Technology Program # 011618 Texas.
207
ACUTE AND CHRONIC TOLERANCE TO CARDIOVASCULAR EFFECTS OF SELFADMINISTERED COCAINE IN RATS
S. R. Tella, M. Rosenberg, C. W. Schindler, and S. R. Goldberg
Department of Pharmacology, Georgetown University Medical Center, Washington, DC, and
Preclinical Pharmacology, NIDA Intramural Research Program, NIH, Baltimore, MD
Cardiovascular effects during chronic, limited access (2 hr/day) cocaine self-administration were studied in SpragueDawley rats implanted with telemetric devices. Following training to lever press for food, rats were tested for
cocaine (1 mg/kg/infusion) self-administration for four weeks, followed by extinction with saline during week 5
and then re-testing of cocaine self-administration during week 6. Th first infusion of cocaine within a given
session produced rapid (< 60 sec) increases in diastolic. systolic and mean pressures and in heart rate (HR). The
subsequent cocaine infusions within the same session produced increases in pressures that were significantly smaller
than that of the first infusion and failed to increase HR. There was an early (<40 min) overall within session
reduction in HR as compared to pie-session base-line measures. These patterns of responses were seen on all days of
testing, however, the mean increases in pressures and HR produced by the first infusions during the daily sessions
of weeks 4 and 6 were significantly smaller as compared to the corresponding increases seen during the first week of
testing. These data indicate that there are two kinds of tolerance to pressor and tachycardiac responses to cocaine.
One is an acute tolerance, which occurs within each session following a single infusion of cocaine, while the other
is a chronic tolerance which occurs over several weeks of cocaine self-administration.
ACKNOWLEDGMENTS:
NIDA.
Supported by NIDA grant DA08830 and by the Intramural Research Program of
CHRONIC COCAINE USE ALTERS RESPIRATORY SINUS ARRHYTHMIA AND HEART
RATE REACTIVITY TO POSTURE CHANGE
P. Suess*, S. Reed*, I. Montoya, S. Porges*, and D. Gorelick
NIH/NIDA, Division of Intramural Research, Baltimore, MD and *University of Maryland,
College Park, MD
While cocaine has prominent acute cardiovascular effects (tachycardia, increased blood pressure and reduced
respiratory sinus arrhythmia [RSA]), little is known about chronic changes in the neural regulation of
cardiovascular functioning as a result of cocaine dependence. We assessed cardiac functioning in 40 chronic cocaine
users with cocaine dependence (DSM-IIIR) and 19 control subjects who reported no substance abuse other than
tobacco. RSA, a component of heart rate variability reflecting vagal (parasympathetic) control of the heart, and
heart rate were calculated from ECG recordings obtained during supine, sitting, and standing positions for 10
minutes each. We hypothesized that chronic cocaine use would alter normal cardiac reactivity to posture change via
the baroreceptor reflex. In comparison to non-users, cocaine users bad larger decreases in RSA and increase heart
rate when changing position from sitting to standing. Similar findings resulted when 24 outpatient cocaine users
and 16 drug-free residential cocaine users were analyzed separately. Both cocaine using groups responded to the
standing challenge with larger RSA decreases than nonusers. Outpatient cocaine users responded with greater bean
rate increases than nonusers. These results suggest chronic alterations in the neural control of cardiac function in
chronic cocaine users, even when drug-free.
208
ELECTROPHYSIOLOGICAL EVIDENCE OF COCAINE EFFECTS ON CARDIAC
CONDUCTION IN HUMANS
R. A. Nelson, D. A. Gorelick, and R. C. Ziegelstein*
NIH-NIDA Division of Intramural Research and *Johns Hopkins Bayview Medical Center,
Baltimore, MD
Cocaine is well known to produce acute serious cardiac consequences. Less well understood are cocaine’s
subclinical effects, including actions on cardiac electrical conduction. We evaluated this using 12-lead, signalaveraged (high resolution) electrocardiogram (ECG) Marquette MacVu) data obtained a mean [SD] of 7.7 [5.3] days
into monitored abstinence on a closed research ward from 27 prescreened (medical history, physical examination,
routine clinical laboratory tests, standard 12-lead ECG) healthy male IV/smoked cocaine users (19 AtricanAmerican, 8 white; age 33.9 [4.5] years; 11.4 [6.2] years of cocaine use, using 18.6 [6.3] days/month). The
cocaine users had a longer filtered QRS duration (mean [SE] = 114.5 [9.5] msec) and shorter root-mean square
voltage in the terminal 40 msec (32.2 [12.7]µV) compared to published values for sex-matched normal controls
(Timmermans et al., 1994), with the differences trending in the direction of threshold values used to diagnose a late
ventricular potential. Six subjects subsequently received each of 3 IV cocaine doses (10, 25, 50 mg) at least 2 days
apart with serial recording of standard 12-lead ECGs Cocaine administration was associated with significant dosedependent increases in QTc interval, with no significant changes in PR interval or QRS duration. At the 50 mg
dose, QTc interval increased from 396 [2] msec (mean [SE]) at baseline to 437 [7] msec 4 minutes after cocaine
injection and 412 [4] msec after 41 minutes. While the clinical significance of these findings in otherwise healthy
individuals is unknown, they suggest that cocaine may produce specific acute and subacute changes in cardiac
electrical conduction.
REFERENCE:
Timmermans C., et al., Pacing and Clin Eletrophysiol 17(3 Pt 1):303-311, 1994.
ACKNOWLEDGMENT:
Supported by NIDA intramural funds.
POTENTIALLY ADVERSE CARDlOVASCULAR CHANGES ASSOCIATED WITH
EXPERIMENTAL COCAINE ADMINISTRATION
T. F. Newton, P. Bridge*, D. Leiderman*, M. Goldman, T. Richter, J. Lindholm, G.
Bortzokis, and W. Ling
UCLA and the WLA VA Medical Center, and * NIDA/MDD
We studied acute effects of cocaine administered IV at Img/sec in order to determine whether pretreatment with
putative therapeutic medications alters subjective or physiologic effects of cocaine. Cocaine-dependent subjects were
carefully screened to exclude those with preexisting medical disease or substance dependence other than cocaine. The
laboratory is equipped as an ICU with crash cart, nurse and ACLS trained physician in attendance. After each saline
or cocaine infusion, pulse, blood pressure, and EKG morphology are monitored on a beat by beat basis, and the
results are confirmed using manual sphygmomanometry. To date, 102 cocaine administrations have been performed
in 28 subjects (mean age 41, range 3147, including 26 unique subjects and 2 subjects who participated in two
protocols). Of these 102 cocaine administrations, subjects in 9 developed changes in pulse or blood pressure which
prompted us to drop the subject from the protocol; no subject developed an adverse reaction which produced
morbidity. Because these 9 subjects were dropped from the protocol, 9 of 28 subjects were unable to complete the
study. For example, one subject developed a diastolic blood pressure of 120 to 130 (mmHg); another had a rapid
rise in systolic blood pressure to above 200 for about 1 minute. Two subjects developed excessive premature atrial
contractions (PACs), both after the 20mg cocaine dose. One subject developed unexplaned EKG changes suggestive
of right ventricular hypertrophy (or artifact). In all cases the vital signs returned to normal within an hour without
morbidity. Age, amount or duration of cocaine or other drug use did not predict outcome. Our experience
demonstrates that idiopathic and potentially adverse alterations in vital signs occur after approximately 9% of
cocaine administrations, in about one third of subjects studied. Close monitoring and the availability of appropriate
medical personnel are required even after relatively low doses.
ACKNOWLEDGMENT:
Supported by a grant from NIDA establishing the WLA VA MDRU (Dr. Ling).
209
ERYTHROCYTHEMIA (“BLOOD DOPING”) DUE TO SPLENIC CONTRACTION AFTER
INTRAVENOUS COCAINE
A. J. Siegel1 , M. B. Sholar2 , M. J. Kaufman2,3 , P. F. Renshaw3 , T. J. Kukes 3 , J. C.
McDonald 4, and J. H. Mendelson2
Department of Medicine’, Alcohol and Drug Abuse Research Center’, Brain Imaging Center’,
Pharmacy Department’, McLean Hospital--Harvard Medical School, Belmont, MA
Cocaine is among the most dangerous drugs of abuse due to the risk for acute thrombotic events. Erythrocythemia
(“blood doping”) has been previously found in human subjects following intranasal cocaine administration. We
therefore measured sequential hematologic parameters after a moderate dose of cocaine was administered to healthy
human subjects by intravenous (i.v.) route. Fourteen healthy male volunteers with reported sporadic prior cocaine
use Participated after informed consent. Vital signs and electrocardiographs were continuously monitored before and
for 180 minutes after administration of iv. cocaine (0.40 mg/kg, n=7) or placebo (n=7). There was a significant
increase in hematocrit, hemoglobin concentration, and red blood cell (RBC) mass 10 minutes after i.v. cocaine
which persisted for 20 minutes (p=0.001). The white blood cell and platelet counts showed no increase after
cocaine challenge. Splenic volume as assessed by magnetic resonance imaging decreased by 27.0 ± 2.5% (mean ±
S.D.) 10 min. after cocaine administration, and returned to baseline within 40 min. Infusion of RBCs from splenic
contraction into the general circulation may be the mechanism for the increase in RBC mass. These data
demonstrate that acute erythrocythemia (“blood doping”) occurs following a moderate dose of i.v. cocaine in healthy
humans which may alter blood viscosity and contribute to medical risk for acute thrombotic events.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA00064, DA04059 and DA09448.
A NOVEL PARADIGM TO INVESTIGATE TITRATION OF DRUG DOSE IN RATS
REINFORCED BY INTRAVENOUS COCAINE OR HEROIN
W. J. Lynch, L. P. LoBounty*, and M. E. Carroll
Department of Psychiatry, University of Minnesota, Minneapolis, MN and Department of
Psychology*, Macalester College, St. Paul, MN
The purpose of the present experiment was to investigate dose-regulation in rats self-administering heroin or cocaine
when both dose size and interdose interval were under the subjects’ control. This paradigm allowed the subjects to
increase and decrease their dose in discrete steps throughout the session. Twenty Wistar rats were assigned to one of
two drug groups that were given access to either cocaine (n=10) or heroin (n=10) during daily 5 hr sessions. Drug
dose was determined by altering the duration of the infusion from 0 to 25 sec. The duration of infusion depended on
which lever was pressed. A response on the lever with a stimulus signaling an increase in dose size increased the
infusion duration by 3 sec, and a response on lever with a stimulus signaling a decrease in dose size, decreased the
infusion duration by 3 sec. At the beginning of each session, infusions durations started at 12 sec. When a
maximum duration of 25 sec or a minimum duration of 0 sec was reached, that duration remained in effect until the
other lever was pressed. Significant correlation coefficients were obtained for interdose interval (IDI) and infusion
duration (dose) for both groups. Furthermore, daily and hourly drug intake for cocaine and heroin groups were
relatively constant. These findings indicate that subjects regulated hourly and daily drug intake by adjusting
magnitude of dose and interdose interval throughout drug self-administration sessions.
ACKNOWLEDGMENT:
Supported by NIDA Grant R37 DA03240.
210
SECOND-ORDER SCHEDULES OF ORAL COCAINE SELF-ADMINISTRATION IN
RHESUS MONKEYS
M. J. Macenski and R. A. Meisch
Department of Psychiatry and Behavioral Sciences, University of Texas - Houston Health
Science Center, Houston, TX
Three rhesus monkeys were allowed access to cocaine under second-order, fixed-ratio, reinforcement schedules.
Under this arrangement, stimulus lights which were either explicitly paired with reinforcer delivery or never paired
with reinforcer delivery were presented at different frequencies during the overall ratio. The overall fixed-ratio value
was varied from 64 to 256. The number of stimulus presentations during the ratio was varied from 0 to 256. All
fixed-ratio and stimulus presentation frequency values were tested under reinforcer paired and reinforcer nonpaired
stimulus conditions. Cocaine self-administration and cocaine intake were reduced as overall fixed-ratio value was
increased. There were no systematic differences between the paired and nonpaired conditions. There were no
systematic dilferences among stimulus presentation frequencies. The former finding is consistent with previous
literature. The lack of any systematic effects of the pairing operation and stimulus presentation frequency may be
due to the monkeys previous extended history of fixed-ratio cocaine-maintained responding.
ACKNOWLEDGMENTS:
Supported by NIDA grants F32 DA05552, RO1 DA04972, and K05 DA00159.
REINFORCED AND EXTINGUISHED BEHAVIOR USING TWO PROGRESSIVE-RATIO
SCHEDULES OF COCAINE DELIVERY
D. Stafford, M. C. LeSage, and J. R. Glowa
Department of Pharmacology and Therapeutics. Louisiana State University Medical Center in
Shreveport, LA
Ptogressive-ratio (PR) schedules of drug delivery have been used by an increasing number of investigators in the
area of drug self-administration. These schedules are popular partly because subjects’ performance is thought to
reflect the reinforcing efficacy of the drug dose that maintains responding, and PR-maintained behavior has been used
frequently as a baseline against which the effects of various pretreatments are assessed. Recent research has indicated
that specific procedural variations may improve the quality and usefulness of the data collected: Woolverton (1995)
and Rowlett et al. (1996) described innovative PR schedules of drug delivery in which the response requirements did
not increase from one ratio to the next (as is typical), but instead increased across “blocks” of ratios within each
session. The current studies were undertaken to further evaluate the similarities and differences between
performances generated by conventional PR schedules (1-trial PR program) and one with blocks of ratios (5-trial PR
program) in rhesus monkeys. Performance was examined across a range of unit doses of cocaine and also during
extinction (i.e., saline substitution). In both procedures the average number of ratios completed increased across
small to mid-sized unit doses, and often decreased at the largest unit doses tested. The peak of the unit-dose-effect
function occurred at a lower dose (10 ug/kg/inj) for the 5-trial program than for the l-trial program (10-56
ug/kg/inj), and overall intake of drug during the 5-trial program was much greater than intake during the 1-trial
program. Patterns of extinction were also different across the two PR schedules. Subjects whose behavior was
relatively insensitive to extinction on the 1-trial program displayed more rapid and complete decreases in responding
on the 5-trial program. In addition to improving our understanding of PR schedules of drug-maintained behavior,
these data may offer suggestions for future research in the area of behavioral economics. REFERENCES:
Available upon request.
ACKNOWLEDGMENT:
Supported by NIDA grant RO1 DA09820-01 (J.R. Glowa, Principal
Investigator).
211
REINSTATEMENT OF COCAINE SELF-ADMINISTRATION BY STRESSORS FOLLOWWG
CHRONIC EXTINCTION
J. R. Mantsch and N. E. Goeders
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center,
Shreveport, LA
The ability of electric footshock (EFS) or a conditioned stimulus paired with the delivery of EFS to reinstate
responding previously reinforced by cocaine was investigated following chronic extinction. Six adult male Wistar
rats were trained to self-administer cocaine (0.5 mg/kg/inf) under a fixed-ratio 4 schedule of reinforcement with a 90second limited-bold during daily 2-hour sessions. Once stable responding was observed, self-administration was
extinguished by presenting no programmed consequences of lever-pressing. Following 2 or 4 weeks of extinction,
the ability of EFS (0.6 mA, 0.5 msec duration. every 15 sec for 15 min), a pair of stimuli (10 sec tone and light)
previously paired with the delivery of EFS (3 consecutive pulses. 0.5 msec duration, 0.6 mA intensity, 0.5 msec
interval) under a random interval 5-min schedule during daily 1-hour sessions, or a neutral stimulus (tone and light
not paired with EFS) to reinstate responding was investigated. After 4 weeks of extinction, no significant
reinstatement was observed when EFS was presented for 15 min immediately prior to the subsequent extinction
session. Likewise, the presentation of the conditioned stressors or neutral stimuli failed to reinstate responding
when these stimuli were presented either immediately prior to or during (i.e., 60 min after the start of) extinction
sessions. However, reinstatement was observed following 2 weeks of extinction when EFS (15 min) or the
conditioned stressor were presented immediately prior to the next extinction session.
ACKNOWLEDGMENT:
Abuse.
Supported by USPHS grant DA-06013 from the National Institute on Drug
ACTH AND CORTISOL IN COCAINE SELF-ADMINISTRATION IN RHESUS MONKEYS
J. H. Broadbear1, C. D. Winger, T. J. Cicero2, and J. H. Woods
Departments of Pharmacology and Psychology1, University of Michigan, Ann Arbor, MI and
Department of Psychiatry2 , Washington University, St. Louis, MO
There is a substantial body of work strongly suggesting positive relationships between plasma glucocorticoid levels
and cocaine self-administration (SA) behavior in rats (eg., Piazza; Goeders). This study investigated whether
cortisol feedback is important in a primate model of cocaine SA, as well as whether there would be any differences
between the cortisol response evoked by contingently and non-contingently administered cocaine. Four male rhesus
monkeys (Macaca mulatta), each with a surgically-implanted venous catheter, were used in this study. Cocaine
(0.01, 0.03, 0.1 and 0.3 mg/kg/inj) or saline was available on a fixed-ratio 30 time-out 600-s (FR 30 TO 600)
schedule. Non-contingent tests involved infusions automatically given in a pattern identical to the SA session from
the previous day. Venous blood was sampled before, during and after a.m. 130 min SA sessions and plasma
cortisol and ACTH levels were measured by RIA. A positive correlation was found between amount of cocaine
taken and plasma cortisol levels, although under these conditions there was no difference in the cortisol response to
behaviorally contingent and non-contingent cocaine administration. Etomidate (0.1, 0.3 and 1.0 mg/kg), an
intravenous sedative-hypnotic previously shown to block cortisol responses to ACTH stimulation, was infused
prior to the SA session. Etomidate was shown to block the increase in cortisol observed with 0.1 and 0.3
mg/kg/inj cocaine and produce an accumulation in ACTH, although the amount of cocaine injected during the
session was not changed. Thus, although there is a positive correlation between cocaine intake and plasma cortisol,
blocking cortisol production does not appear to reduce SA behavior.
ACKNOWLEDGMENT:
This work was supported in part by USPHS Research Grant DA 09161.
212
CORTICOTROPIN-RELEASING FACTOR RECEPTOR BLOCKADE ATTENUATES THE
REWARDING PROPERTIES OF COCAINE IN RATS
S. C. Heinrichs, A. Klaassen, G. F. Koob † , G. Schulteis, and S. Ahmed †
Neurocrine Biosciences, Inc., San Diego CA and † The Scripps Research Institute, La Jolla,
CA
The behavioral profile of corticotropin-reIeasing factor (CRF) in mediating anxiogenic-like and aversive responses
to stressors may be particularly relevant for dependence and withdrawal in drug-experienced organisms. Moreover,
stressful aspects of drug exposure in the drug naive organism may also induce CRF system activation, In the
present studies, the dependence of aversive properties of cocaine on activation of endogenous CRF systems has been
evaluated in rats using taste conditioning and runway self-administration paradigms. Systemic cocaine
administration (20 mg/kg i.p.) produced a conditioned saccharin aversion which was dose-dependently potentiated by
central administration of the CRF receptor antagonist. D-phe CRF (12-41). In addition, acquisition of intravenous
cocaine self-administration (0.75 mg/kg/inj i.v.) produced goal-box avoidance and conditioned place avoidance
responses which were significantly accelerated by CRF antagonist treatment in self-administering, but nor cocainenaive subjects. In contrast, CRF receptor stimulation using CRF itself abolished cocaine-induced increases in goal
lafencies in the runway paradigm. This generalized involvement of CRF systems in cocaine-related
motivational/associative states is consistent with the comprehensive role of CRF in mediating emotional responses
to non-drug stressors and suggests the utility of CRF receptor antagonists in counteracting the acquisition of
cocaine use.
ACKNOWLEDGMENTS:
Supported by MDA grants DA09503 to SCH, DA04398 and DA08467 to GFK
and SA and NIDDK grant DK26741 to GFK.
COCAINE PREEXPOSURE FAILS TO SENSITIZE TASTE AVERSION LEARNING
H. F. Diamond and A. L. Riley
American University, Washington, DC
Previously, we have reported that animals given massed or spaced preexposure co cocaine (either intraperitoneal or
subcutaneous) did not display sensitized aversions to cocaine during subsequent conditioning (see Diamond and
Riley, Soc. Neurosci. Abstr. 21:1953; 1995; Diamond and Riley, Soc. Neurosci. Abstr. 22:1583; 1996). In fact,
preexposed subjects were retarded in the acquisition of cocaine-induced taste aversions. The present series of
studies further investigated the effects of cocaine preexposure by examining such preexposure under conditions
which typically produce sensitization to the motoric effects of cocaine, i.e., multiple intraperitoneal injections
(10) of low doses (10 mg/kg) of cocaine or a single intraperitoneal injection of a high dose of cocaine (40 mg/kg).
Following preexposure under these conditions, subjects were given a novel saccharin solution to drink followed
by a subcutaneous injection of cocaine (32 mg/kg) to assess the effects of preexposure on aversion conditioning.
Under all preexposure conditions, there was no evidence of sensitized aversions to cocaine (relative to subjects
preexposed to vehicle and subsequently injected with cocaine during conditioning). As in our previous work (see
above), cocaine preexposure (single or multiple injections) attenuated cocaine-induced taste aversions. These data
suggest that preexposure to cocaine attenuates or weakens its aversive properties which in turn results in
weakened cocaine-induced taste aversions. Such an attenuation may contribute to the sensitization of the rewarding
effects of cocaine with chronic exposure.
ACKNOWLEDGMENT:
Supported by a grant from the Mellon Foundation
213
LiCL-INDUCED CONDITIONED TASTE AVERSIONS:
LEW/N AND F344/N RAT STRAINS
A COMPARISON BETWEEN
A. L. Riley, H. F. Diamond, and J. R. Glowa*
American University, Washington, DC and *Louisiana State University, Shreveport, LA
Previously, we have reported that cocaine-induced taste aversions were differentially acquired by Lewis and Fischer
rat strains (Glowa et. al., Psychopharmacology 114:229-232; 1994). Specifically, doses of cocaine that had no
effect in the Fischer strain produced robust aversions in the Lewis strain, suggesting that the two strains differ in
their relative sensitivities to the aversive effects of cocaine. The present study extended this analysis by examining
LiCl-induoed aversions in the two strains. Specifically, 24 Lewis and 24 Fischer rats were adapted to water
restriction and then allowed limited access to a novel saccharin solution. Different groups within the two strains
were then injected with various doses of the emetic LiCl (0.3, 0.6 and 1.2 mEq, 0.15 M) or with the LiCl vehicle.
These pairings were repeated every fourth day for a total of four trials. For both strains, LiCl-induced aversions were
dose-dependent with the higher doses of LiCl producing greater suppression of consumption. There were significant
differences between the strains in their sensitivity to LiCl. Specifically, at the intermediate dose (0.6 mEq) Lewis
rats acquired aversions at a faster rate and to a greater degree than Fischer rats. There were no differences between
strains following injections of the vehicle or the highest dose of LiCl. Lewis and Fischer rats appear differentially
sensitive to the aversive effects of LiCl, suggesting that differences between these strains occur for effects other
than the reinforcing effects of drugs and for drugs other than drugs of abuse.
ACKNOWLEDGMENT:
Supported by a grant from the Mellon Foundation to ALR.
ENHANCED EXTRACELLULAR ASPARTATE (ASP) RESPONSE TO COCAINE IN
BEHAVIORALLY SENSITIZED RATS
S. E. Robinson, P. M. Kunko, M. J. Wallace, Q. Mo, and J. A. Smith
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA
The effect of behavioral sensitization to cocaine was determined on ASP and glutamate (GLU) in male SpragueDawley rats. Seven days after guide cannula implantation, a concentric microdialysis probe was inserted into the
nucleus accumbens (NAcc) core. After a 4 hr equilibration, samples were collected in 10-min fractions for 2 hr to
establish baseline values in the awake rat. Cocaine (15 mg/kg) or saline was injected i.p. and fractions collected for
2 hr. Videotapes of the rats were scored by observers blind to treatment. Rats receiving cocaine for the first
microdialysis procedure were divided into 2 groups receiving 5 additional daily cocaine or saline injections in home
cages; rats receiving saline for the first microdialysis procedure were divided into 2 groups receiving 6 additional
cocaine injections (the first on the day of microdialysis) or 5 additional daily saline injections in home cages. A
second microdialysis procedure was performed in which rats were challenged with cocaine or saline 48 hrs after the
last injection. To exclude an effect of repeated microdialysis on extracellular ASP or GLU, another group of rats
was exposed to elevated K+ (70 mM) via the microdialysis probe, followed by a second exposure 1 week later.
Kruskal-Wallis and Mann-Whitney U tests revealed behavioral sensitization of rats receiving 6 injections of cocaine
(Z=-2.107, p < 0.05). Two-way repeated measures ANOVA of the areas under the curve revealed a significant
interaction of treament and repeated measure such that rats receiving 6 injections of cocaine exhibited increased
extracelluIar ASP when challenged with cocaine (p < 0.05). GLU was nof significantly increased. No difference
was observed in the effect of high K+ on extracellular ASP and GLU between the first and second exposures.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA05274 and grant DA07027.
214
CONCURRENT-SCHEDULE PERFORMANCE UNDER LONG VI SCHEDULES OF
COCAINE OR FOOD AVAILABILITY
K. Aling and W. L. Woolverton
University of Mississippi Medical Center, Jackson, MS
Concurrent schedule respouding maintained by cocaine urder short variable-interval (VI) schedules has been shown
to conform to the generalized matching equation. That is, drug maintained behavior is apportioned in accordance
with relative frequency of reinforcement. The purpose of the present experiment was to examine the ability of the
generalized matching equation to account for choice under long VI schedule of cocaine or food presentation. One
group of rhesus monkeys (N=4) was prepared with indwelling i.v. catheters and allowed to respond under concurrent
VI schedules of cocaine delivery (0.025, 0.05 or 0.1 mg/kg/inj) with an average inter-reinforcer interval of 30 min.
In a second group of monkeys (N=4), a comparable experiment was conducted with responding maintained by
differing magnitudes of food (1, 2, or 4 banana-flavored pellets). For both groups, the same reinforcer followed
responding on either lever, the only difference between the options being the schedule of reinforcement. Although
results from the two groups were similar, the behavior of the cocaine group more closely fit the predictions of the
generalized matching equation. Specifically, goodness of tit was better for the cocaine group (0.83 versus 0.78),
them was a greater tendency toward under-matching in the food group (0.51 versus 0.70), and response bias was
greater for the food group (0.79 versus 0.99). This finding suggests that under the conditions studied, the generalized
matching equation predicted choice maintained by drug somewhat better than food-maintained choice The results
expand the applicability of the generalized matching actuation to choice maintained by long VI schedules of drug
injection.
ACKNOWLEDGMENT:
Supported by NIDA Grant DA-08731.
MOTIVATIONAL EFFECTS OF COMBINING STIMULI INDEPENDENTLY ASSOCIATED
WITH FOOD AND COCAINE
L. V. Panlilio, S. J. Weiss*, and C. W. Schindler
Division of Intramural Research, NIDA-ARC, Baltimore, MD and *American University,
Washington, DC
In previous experiments, the compounding of two discriminative stimuli associated with the same reinforcer
increased rats’ responding approximately three-fold, regardless of whether the reinforcer was food, water, cocaine, or
shock-avoidance. Compounding a discriminative stimulus associated with food with one associated with water
increased responding two-fold. Compounding an appetitive discriminative stimulus (associated with food) with an
aversive one (associate with shock avoidance) did not increase responding. In the present experiment, compounding a
discriminative stimulus associated with food with one associated with cocaine increased responding two-fold. These
results support the hypothesis that 1) the motivational effects of stimuli associated with reinforcers from opposite
classes (appetitive and aversive) are mutually inhibitory, 2) the effects of stimuli associated with reinforcers from
within the same incentive class are mutually enhancing, and 3) the effects of combining stimuli associated with two
different reinforcers from within the same class are not as strong as strong as those of combining two stimuli
associated with the same reinforcer. These results also suggest that discriminative stimuli associated with a non-drug
reinforcers may increase the motivation to self-administer cocaine when encountered in combination with drugrelated stimuli.
ACKNOWLEDGMENT:
Supported by NIDA/DIR.
215
CONDITIONED SUPPRESSION OF OPERANT RESPONDING WITH COCAINE IN RATS
C. W. Schindler, E. B. Thorndike, and S. R. Goldberg
Preclinical Pharmacology Laboratory. NIH/NIDA DIR, Baltimore, MD
In the current study, the conditioned suppression procedure was used to study drug conditioning. Conditioned
suppression involves the pairing of a drug injection with a discrete, environmental stimulus. That stimulus-drug
pairing is presented during ongoing operant performance and conditioning is measured as a disruption in that
performance. Rats were trained to nose-poke on a food-reinforcement schedule. A 5-min tone-light compound
stimulus was then presented 30 min into the session. Two min after the onset of the stimulus, either saline or
cocaine (1.0 or 5.6 mg/kg, i.v.) were administered to separate groups of rats. For a fourth group, the stimulus was
presented and the 5.6 mg/kg dose of cocaine was injected in an unpaired fashion. After four training days, a test was
given where the tone-light stimulus was presented alone. No disruption of responding during the stimulus was
observed for the saline and unpaired groups. When the stimulus was paired with 5.6 mg/kg cocaine. however, it
produced a nearly 50% reduction in responding and even the stimulus paired with 1.0 mg/kg group produced some
suppression of responding. In preliminary studies, the 5.6 mg/kg dose alone clearly disrupted responding, while the
1.0 mg/kg dose produced small increases in response rates. The conditioned suppression observed with the stimulus
paired with 5.6 mg/kg cocaine extinguished over 5 days of stimulus alone presentations. Thus, the conditioned
suppression procedure may be a useful model for studying the conditioned effects of drugs of abuse, even
psychomotor stimulants, although it is unclear whether response-rate increases can be conditioned to discrete stimuli
in this manner.
ACKNOWLEDGMENT:
Supported by NIDA Intramural Research Funds.
NORADRENERGIC INVOLVEMENT IN THE DISCRIMINATIVE STIMULUS EFFECTS OF
COCAINE IN RATS
P. M. Callahan and K. A. Cunningham
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston
TX
Noradrenergic involvement in the cocaine-saline discrimination was assessed in rats (N=24) trained to discriminate
cocaine (10 mg/kg) from saline using a two-lever, water-reinforced FR20 procedure. Results indicated that the alpha2 agonist clonidine (0.01-0.06 mg/kg) and the beta-1,2 antagonist (-)-propranolol (4-16 mg/kg) produced a
maximum 50-60% cocaine-lever responding, whereas the NE reuptake inhibitor nisoxetine (8 mg/kg), the alpha-1
antagonist prazosin (0.2 mg/kg) and the alpha-2 antagonist idazoxan (2-8 mg/kg) engendered primarily saline-lever
responding. Coadministration of a ftxed dose of nisoxetine (8 mg/kg) or idazoxan (4 mg/kg) plus cocaine (0.625-5
mg/kg) produced a “supra-additive” enhancement of the cocaine dose-response curve, whereas (-)-propranolol (8 and
16 mg/kg) plus cocaine engendered a modest “additive” effect. Conversely, prazosin (0.03-1 mg/kg) or clonidine
(0.06 mg/kg) resulted in a 70% reduction in cocaine-lever responding when combined with a dose of cocaine (5
mg/kg) that produced >80% drug-lever responding when given alone. These results support previous evidence
demonstrating a role of NE systems in mediating the discriminative stimulus effects of cocaine.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA00260 and DA06511.
216
POTENTIATION OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF COCAINE BY
CYMSERINE
E. B. Thorndike, N. H. Greig*, Q.-S. Yu*, G. Carmona, M. Shooib, S. R. Goldberg, and
C. W. Schindler
Preclinical Pharmacology, NIH, NIDA Intramural Research Baltimore, MD and * NIA
Gerontology Research Center, Baltimore, MD
Butyrylcholinesterase (BChE) is a primary cocaine metabolizing enzyme in both humans and animals. The present
study examined the effect that cyrmserine, a BChE inhibitor, has on the discriminative stimulus properties of
cocaine. Sprague Dawley rats (N = 9) were trained in a 2-lever drug discrimination paradigm to discriminate cocaine
(10 mg/kg. i.p., given 10 min pre-session) from its vehicle (saline). Responding was maintains by a fixed-ratio
10 (FR 10) schedule of food reinforcement. The subjects were trained 5 days per week, 15’ per day, using a double
alternation schedule (2 days vehicle followed by 2 days cocaine). Once subjects met criteria (=>90% appropriate
responding and less than 10 incorrect responses on the first trial) for 8 consecutive sessions they were switched to a
single alternation schedule with a maximum of 2 test days per week. Before test sessions, during which both levers
were active, the animals were created with saline or cocaine (0.3, 1, 3, 10, 20 mg/kg) alone or cymserine (30
mg/kg, i.p.) followed 40 min later by saline or cocaine (0.3. 1, 3, 10, 20 mg/kg, i.p.). A time course was also
examined where cocaine 10 mg/kg was given 60, 90, 120, 150, and 180 min pre-session or 40 min following
cymserine 10 mg/kg. Cymserine 30 mg/kg shifted the cocaine dose effect function to the left. Cymserine 10 mg/kg
increased the duration of the cocaine discriminative stimulus properties.
ACKNOWLEDGMENT:
Supported by NIDA intramural Research Funds.
GENETIC ANALYSIS OF COCAINE-INDUCED PLACE PREFERENCE IN SMXA RI
INBRED STRAINS OF MICE
T. Suzuki, H. Ikeda, M. Misawa, and M. Nishimura*
Department of Pharmacology, Hoshi University, Tokyo, Japan and *Institute for
Experimental Animals, Hamamatsu University School of Medicine, Hamamatsu, Japan
It is well known that genetic factors play an important role in drug responses. Genetic factors associated with drug
responses can be determined using many inbred strains or recombinant inbred (RI) strains of mice. SMXA RI
strains of mice were derived from two distinct inbred strains, A/J and SM/J strains. The SMXA Rl strains consist
of 26 substrains: one of the greatest number of substrains among many RI strains of mice. The SDP of 158
markers in SMXA Rl strains of mice has been established. The present study was designed to determine the
chromosomes and their loci associated with cocaine-induced place preference using conditioned place preference
paradigm. First, cocaine (8 mg/kg, s.c.)-induced place preference was examined in genetically distinct A/J and SM/J
strains of mice. In A/J mice, cocaine produced a significant place preference, but in SM/J mice, cocaine produced
neither significant place preference nor place aversion. The strain difference observed here suggests that genetic
factors may play an important role in modulating the cocaine-induced place preference. Secondly, the cocaineinduced place preference was determined in 26 SMXA Rl strains of mice. In SMXA RI mice, cocaine-induced place
preference was found to be distributed unimodally. Quantitative trait loci analysis using these data indicated that 7
loci on 4 chromosomes, especially D9Mit16 located 61 cM on chromosome 9, are involved in the expression of
rewarding effect of cocaine.
217
RATE OF RISE IN BRAIN CONCENTRATION DETERMINES REINFORCING STRENGTH
OF COCAINE IN ONLY 63% OF TESTED RATS
G. Zernig
Suchtforschungslabor, Universitätsklinik für Psychiatric, Graz, Austria
One of the central dogmas in addiction research maintains that the reinforcing strength and, thus, the abuse liability
of a drug are determined by the rate of rise of the drug’s brain concentration after administration (Jaffe 1990). In
order to test this hypothesis, intravenous cocaine (0.083 - 2.25 mg/kg-1 injection-1) was made available to LongEvans rats in a self-administration paradigm (FR1 TO 150 s) at two injection speeds (injection interval 6 s or 150 s)
that were tailored to yield the same peak brain cocaine concentrations but a 25-fold difference in the initial rate of
rise in brain concentrations, using the pharmacokinetic data by Pan et. al., (1991). Accordingly, in vivo
microdialysis experiments showed that the peak nucleus accumbens dopamine overflow was essentially identical for
both injection speeds. The lower initial rate of rise in the brain cocaine concentration resulted in a decreased
reinforcing strength of cocaine in only 5 of 8 tested rats. In one of these 5 animals, response rates were decreased at
the lower injection speed at both the peak and the ascending part of the cocaine dose-response curve. Three animals
showed decreased rates of responding at the lower injection speed only at the lowest cocaine dose that maintained
responding at the higher injection speed (i.e., the threshold dose). One animal showed decreased responding only for
the cocaine dose, that maintained peak rates of responding at the higher injection speed. These data suggest that the
initial rate of rise in the brain concentration of a drug of abuse controls behavior to a much lesser degree than
previously thought.
References: Jaffe, J. R., 1990, Drug addiction and drug abuse, In: A. Goodman Gilman, A., Rall, T. W., Nies,
A. S., and Taylor, P., eds. The pharmacological basis of therapeutics. New York: Pergamon Press, 1990, pp. 522573. Pan, H. T., Menacherry, S., Justice, J., Jr., Differences in the pharmacokinetics of cocaine in naive and
cocaine- experienced rats. J. Neurochem. 56,1299-1306, 1991
REPEATED DOSING WITH ORAL COCAINE IN HUMANS: PHARMACODYNAMIC AND
PHARMACOKINETIC EFFECTS
S. L., Walsh, R. Jufer, E. Cone, and G. E. Bigelow
Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences
Johns Hopkins University School Of Medicine, Baltimore, MD
This inpatient study examined the effects of repeated oral cocaine dosing in human cocaine abusers. During each of
a possible 16 sessions, five identical doses were given at 1 hr intervals; subjective. objective, and physiological
measures, including plasma and urine, were collected before, during and for up to 24 hr after dosing. Doses were
administered in ascending order over consecutive sessions, beginning at 100 mg/capsule and increasing by 25
mg/capsule/session for a maximum of 400 mg/capsule with intermittent placebo sessions. Preliminary results
(n=4) indicated that the lowest doses (100-150 mg) were not reliably detected by all volunteers; ratings of magnitude
of drug effect and euphoria (“high,” “good effects”) showed dose-related and sustained elevations at doses 175 mg.
Similarly, heart rate and blood pressure were not appreciably altered by the lowest doses, while doses >150 mg
reliably produced dose-related cardiovascular responses. In contrast, pupil diameter was increased by even the lowest
doses of cocaine. Preliminary pharmacokinetic data indicated that clinically significant plasma concentrations of
cocaine (i.e., 500-1000 ng/ml) proportional to dose were achieved by the oral route of administration and that
plasma cocaine concentrations showed cumulative increases with successive hourly oral doses. These data indicate
that orally administered cocaine produces effects qualitatively similar to those produced by other routes of
administration. However, the onset of oral cocaine action is slower, and thus oral cocaine may be more safely
tolerated in controlled studies of chronic cocaine exposure and withdrawal in humans compared to other routes of
administration associated with faster cocaine delivery.
ACKNOWLEDGMENTS:
Supported by USPHS/NIH/NIDA grants R29 DA 10029 and KO5 DA 00050.
218
HOW DEPENDABLE IS THE IP ROUTE? PHARMACOKINETIC (PK) AND
PHARMACODYNAMIC (PD) EVIDENCE FOR COCAINE AND MIDAZOLAM
C. E. Lau, F. Ma, Y. Wang, and J. L. Falk
Department of Psychology, Rutgers University, New Brunswick, NJ
Cocaine (coc) or midazolam (mid) by the IP route decreased the reinforcement rate (RR) of a differential
reinforcement of low rate (DRL 45-s) performance in 3-h sessions. However, the effects of these Iwo drugs on RR
as the PD measure were not always consistent for a given dose. Two groups of rats were used to investigate the
dependability of the IP route: 10 and 20 mg/kg coc (N=8); 3 mg/kg mid (N=4). Each dose was given twice and
separated by 3-5 days. Drug effects on RR were reproducible for the respective two injections except for 10 of the
40 injections, for which RR was variable or remained at baseline level. Furthermore, this diminished effect occurred
randomly following either the fit or second injection. Hence, the differences could not be attributed to
sensitization or tolerance. Inasmuch as PD often can be predicted from PK, parallel PK were conducted for coc
(N=4) and mid (N=6) to study the relation between drug concentration-time profile (CTP) and performance. Withinsubject variability of cot and mid CTPs for a given dose was as evident as those for the PD. One of the extreme
occasions was that coc CTP was just at the detection limit following IP 20 mg/kg cocaine. These results confirmed
that the retarded serum coc or mid CTP accounted for the diminished performance. However, the mechanism(s)
involved in the undependable effect of the IP route on CTPs remains to be clarified, especially as no difficulty
occurred for caffeine. A reproducible CTP is essential before other mechanisms accounting for the change can be
inferred.
ACKNOWLEDGMENTS:
00142.
Supported by NIDA grant R01 DA-05305 and Research Scientist Award K05 DA-
CONCURRENT PHARMACOKINETICS OF COCAINE AND ADRENOCORTICOTROPIC
HORMONE IN MEN
M. B. Sholar, J. H. Mendelson, N. K. Mello, J. W. Sholar, M. J. Kaufman*, J. M. Levin*,
P. F. Renshaw,* and B. M. Cohen*
Alcohol and Drug Abuse Research Center and *Brain imaging Center, McLean Hospital—
Harvard Medical School, Belmont, MA
Acute cocaine administration increases ACTH, and this may influence cocaine’s reinforcing effects. The goal of this
study was to quantify the covariance between plasma cocaine levels and ACTH. Eighteen healthy male occasional
cocaine users participated in a double-blind study, intravenous cocaine (0.2 mg/kg, 0.4 mg/kg) or placebo was
infused over 1 min. and samples for cocaine and ACTH analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60,
80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 ± 14.6 ng/ml and 231.5 ± 20.1 ng/ml.
ACTH increases were significantly correlated (p<0.0001) with increases in plasma cocaine levels (r=.78 r2=.62,
r=.67 r2=.44). Pharmacokinetic analysis showed that the tmax for cocaine (8.0 ± 1.0 min.) and ACTH (8.7 ± 0.7
min.) were almost identical. Area under the curve was calculated using the trapezoidal rule, the area under the curve
(AUC) for 0.2 mg/kg was 6463 ± 1070 ng•min/ml, AUC for 0.4 mg/kg was 15603 ± 1010 ng•min/ml. The AUC
for ACTH after 0.2 mg/kg cocaine was 1873 ± 188.3 pmol•min/L and after 0.4 mg/kg cocaine was 1966 ± 101.3
pmol•min/L. The mean half-life (t 1/2) for cocaine was 46.7 ± 4.0 min and t 1/2 for ACTH was 37.2 ± 3.7 min.
Cardiovascular and subjective effect measures were correlated with increases in plasma cocaine levels and ACTH.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA00064, DA00101, DA09448 and DA04059.
219
THE EFFECTS OF BUTYRYLCHOLINESTERASE ON PLASMA COCAINE
CONCENTRATION
C. N. Carmona 1 , N. H. Greig*, H. Holloway*, R. Jufer 1 , E. J. Cone 1 , S. R. Goldberg 1 , D. A.
Gorelick,1 and C. W. Schindler1
NIH/NIDA Division of Intramural Research, Baltimore, MD and * NIH/NIA Gerontology
Research Center, Baltimore, MD
Studies have shown that butyrylcholinesterase (BChE, E.C.3.1.1.8) is a major enzyme responsible for the
metabolism of cocaine for humans. More recently, we have demonstrated that, when administered as a pretreatment,
horse-serum derived BChE (HS-BChE) significantly reduces cocaine-induced locomotor activity in the rat. To
determine whether or not this result may have been due to alterations in cocaine metabolism, an in vitro study was
performed with rat plasma spiked with HS-BChE. Specifically, cocaine was added to rat plasma with and without
exogenous HS-BChE and cocaine concentrations together with metabotites, were quantitated. To further elucidate
and characterize the action of BChE on cocaine, the concentration-dependent action of HS-BChE on the timedependent metabolism of cocaine in vivo was analyzed. Four groups of 6 rats were unplanted with arterial catheters
for blood sampling and venous catheters for the administration of HS-BChE. HS-BChE was administered (i.v) 30min prior to a cocaine (17.0 mg/kg i.p) challenge. Rats received one of the following: saline(i.v)+cocaine, HSBChE (50 IU)=cocaine, HS-BChE (500 IU)=cocaine, and HS-BChE (5000 IU)+cocaine. Plasma cocaine
concentrations were not affected by saline, 50 IU or 500 IU HS-BChE. Rats receiving 5000 IU of HS-BChE
showed a marked increase in cocaine metabolism, while cocaine’s disappearance dropped from 26.7-min in control
animals to 13.2-min in animals receiving 5000 IU HS-BChE. When compared to controls, the highest dose of HSBChE (5000 IU) produced a clear increase in EME production. Our data suggest the HS-BChE pretreatment alters
the metabolism of cocaine in a way that further reduces cocaine’s half-life in plasma and that HS-BChE also shifts
the metabolic profile for cocaine towards more EME production.
ACKNOWLEDGMENT:
Supported By NIDA/IRP.
INHIBITION OF CYTOCHROME P450 2D6 MODIFIES CODEINE METABOLISM AND
ABUSE LIABILITY
E. M. Sellers, K. Kathiramalainathan, H. L. Kaplan, U. E. Busto, M. K. Romach, and R. F.
Tyndale
Departments of Pharmacology, Medicine and Psychiatry, University of Toronto and Addiction
Research Foundation and Women’s College Hospital, Toronto, Canada
Codeine is an opioid drug that is a widely abused drug worldwide. The genetically polymorphic human drug
metabolizing enzyme cytochrome P450 2D6 (CYP2D6) catalyzes the O-demethylation of codeine to morphine.
Morphine and its metabolites are more active than codeine and contribute substantially to the analgesic effects of
codeine. We conducted a study to determine the importance of O-demethylation to codeine’s reinforcing properties.
Twelve extensive metabolizers received 3 doses of codeine (60/120/180 mg) and placebo to determine the best liked
dose (BLD). The BLD was repeated after quinidine (QD) placebo; QD 50 mg; and QD 50 mg q.i.d. for 4 days. QD
is a potent CYP2D6 inhibitor in vivo. The mean urinary O-demelhylation metabolic ratios for codeine increased
from 0.25 0.33 (placebo) to 0.82 0.36 (single QD) and 1.0 0.55 (chronic QD) (p < 0.01). After QD, mean peak
plasma morphine levels decreased by 71% (single dose) and 91% (chronic) (p < 0.001) confirming inhibition of
codeine O-demethylation by QD. The acute QD treatment, in particular, decreased the subjective and physiological
effects of codeine on most measures. The results indicate that CYP2D6 activity contributes importantly to codeine
abuse liability.
ACKNOWLEDGMENTS:
Foundation.
Supported in part by NIDA grant DA06889 and the Addiction Research
220
PHARMACOKINETICS OF INTRAVENOUS HEROIN IN MORPHINE-MAINTAINED
HUMANS
E. D. Collins, S. D. Comer, R. B. MacArthur, and M. W. Fischman
New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia
University, New York, NY
The pharmacokinetics of intravenous heroin were evaluated in seven heroin-dependent individuals (six men, one
woman), maintained on divided daily doses of oral morphine. The research volunteers were participating in a 2.5week study of heroin self-administration in which they received a dose of intravenous heroin (pbo, 6.25, 12.5, 25,
and 50 mg) in the morning. Blood (5-6 mL) was taken at times 0, 2, 4, 10, 20, 40, and 60 minutes through an
indwelling intravenous catheter in the arm opposite the heroin administration arm. The blood was collected in
vacuum tubes containing NaF and K oxalate and immediately placed on ice before centrifuging for isolation and
subsequent freezing of plasma. Heroin (H), 6-monoacetyl morphine (MAM), and morphine (M) were measured in
plasma using liquid/liquid extraction, derivitization of the MAM and M, followed by capillary GC-MS in the
positive chemical ionization mode with simultaneous ion monitoring. Internal standards consisted of deuterated
labeled H, MAM, and M. Plasma concentration-time curves were analyzed using a one-compartment model and
AUC was determined by the trapezoidal method. For both H and MAM, AUC and Cpmax increased dosedependently. The plasma half-life for H ranged from 10 to 14 minutes and for MAM from 24 to 31 minutes, for the
dose levels studied. Tmax for H occurred between 2.0 and 3.3 minutes after injection and for MAM between 2.0 and
3.0 minutes after injection.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-09236 and grant DA-00317.
SENSITIVE GC-MS METHOD FOR DETERMINATION OF BUPRENORPHINE AND
NORBUPRENORPHINE IN RAT PLASMA
T.-B. Tzeng, Y. Xue, M. Borenstein, and A. Cowan*
School of Pharmacy and *School of Medicine, Temple University,
Philadelphia, PA
A sensitive, specific, and robust capillary CC-MS method has been developed and validated for simultaneous
determination of buprenorphine (BUP) and its active metabolite, norbuprenorphine (NBUP), in rat plasma by using
levallorphan as the internal standard (IS). Sample preparation involved a clean-up procedure by a C8 cartridge and a
reaction with pentafluoropropionic anhydride, the derivatizing agent. Separation was carried out by an HP-I fused
silica capillary column (12 m x 0.2 mm I.D.) using helium as the carrier gas. Oven temperature was 150 °C for
2.5 min initially, increased at 15 °C/min to 280 °C for 8 min. Injection temperature was 150 °C. Selected ion
monitor mode was used in the electron impact mass detection set at 300 °C. The retention times for BUP
(m/z=524), NBUP (m/z=648) and IS (m/z=403) were 15, 12 and 8 min, respectively, with baseline separation. No
interference from blank plasma was observed. With a sample size of 0.1 ml rat plasma, excellent linearity was
found between 0.5 to 30 ng/ml with limit of detection of 0.2 ng/ml and limit of quantitation of 0.5 ng/ml for both
BUP and NBUP, respectively. Assay validation was performed at concentrations of about 1, 7 and 27 ng/ml,
representing low, medium and high concentrations. Intra-day assay precisions were <11% for BUP and <12% for
NBUP, and accuracies were within 10% for nominal concentrations. Inter-day assay precisions were <13% for BUP
and <15% for NBUP, and accuracies were within 10% for nominal concentrations. The absolute recoveries for both
entities were near-quantitative and no concentration-dependence was found. This method will be applied to the
pharmacokinetic/pharmacodynamic studies of BUP and NBUP in rats and extended for the analysis of human plasma
matrix.
ACKNOWLEDGMENT:
Supported in part by Temple University Research Incentive Fund.
221
GENETICALLY DEFICIENT CYPZD6 METABOLISM PROVIDES PROTECTION AGAINST
ORAL OPIATE DEPENDENCE
R. F. Tyndale, K. P. Droll, and E. M. Sellers
Addiction Research Foundation, Departments of Pharmacology, Medicine and Psychiatry,
University of Toronto, and Women’s College Hospital, Toronto, Canada
Oral opiates (e.g. codeine, oxycodone, and hydrocodone) are metabolized by cytochrome CYP2D6 to metabolites of
increased psychoactivity (e.g. morphine, oxymorphone, and hydromorphone). CYP2D6 is genetically polymorphic,
4-10% of Caucasians being homozygous for deficient alleles (poor metabolizers, PMs) with no CYP2D6 activity.
We tested if the failure to activate oral opiates was a protection factor in opiate dependence, by genotyping
(CYP2D6*3 and *4 defective mutant alleles) Caucasians (n = 452) who met or didn’t meet DSM criteria for oral
opiate dependence. In opiate (± smoking) dependent subjects (n = 89) we found no PMs. In contrast, the PM
frequency in never- and multi-drug dependent controls were 4% and 6.5%, respectively. This under-representation of
PMs (Fisher’s, p = 0.05) in people dependent on oral opiates suggests that CYP2D6 defective genotype is a
pharmacogenetic protection factor for oral opiate dependence (estimated odds ratio 7). This is the first demonstration
of differences in geneticaily determined P450 metabolism influencing risk for substance dependents, suggesting that
these differences may influence the risk for dependence of other substrate drugs, and may occur with other genetically
variable P450s.
ACKNOWLEDGMENTS:
Foundation.
Supported in part by NIDA grant # DA06889 and the Addiction Research
OPIOID DISCRIMINATION IN FEMALE VS. MALE RATS
P. J. Kruzich, J. S. Boyer, and R. M. Craft
Department of Psychology, Washington State University, Pullman, WA
Eight female and eight male rats were trained to discriminate the opioid (5 ,7 8 )-(-)-N-methyl-[7-(1pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl] benzeneacetamide (U69,593,0.13 mg/kg s.c.) from vehicle. Female tats took
significantly longer to acquire the discrimination than males did (66.9±27.1 vs. 44.1±17.9 sessions, respectively),
and the ED50 for U69,593 substitution was significantly higher in females than in males (0.074 vs. 0.025 mg/kg).
The time course of U69,593 substitution also differed between females and males: peak and offset occurred earlier
in females than in males. Another opioid agonist, bremazocine, substituted for U69,593 but the ED50 for
bremazocine substitution was significantly higher in females than in males (0.0039 vs. 0.0006 mg/kg). The /µ
opioid agonist ethylketazocine substituted for U69,593 in all males and 5 of 7 females. The µ agonist morphine
and the agonist BW373U86 did not substitute for U69,593 in either sex. U69,593 also produced significantly
less mine output -- but equivalent antinociception -- in females compared to males (e.g., 5.92±1.71 vs. 14.83±2.05
ml urine/kg body weight in females vs. males, respectively, after 1.0 mg/kg U69,593). Sex differences in
acquisition and time course of the U69,593 discrimination. and in the potency of U69,593 to produce discriminative
stimulus and diuretic effects suggests differential U69,593 pharmacokinetics in female and male rats. However, the
fact that no sex differences were observed for U69,593’s response rate-decreasing or antinociceptive effects argues
against a simple pharmacokinetic explanation.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 10284
222
EFFICACY OF SWEAT PATCHES TO MONITOR COCAINE AND OPIATE USE DURING
TREATMENT
M. A. Huestis, E. J. Cone, C. J. Wong, K. Silverman, and K. L. Preston
Intramural Research Program, NIDA, NIH, Baltimore, MD
improved methods for monitoring illicit drug use are needed in clinical treatment trials. A new technique, sweat
patch analysis. was used to determine cocaine and opiate use in methadone maintenance patients enrolled in a
voucher-based contingency management trial. The results of thrice weekly urine drug tests (EMIT immunoassay
cutoffs; 300 ng/mL) from 44 human subjects were compared to results of 355 sweat patches that were applied for 7
days. Sweat was analyzed for cocaine and heroin and metabolites by an ELISA immunoassay (cutoffs 10 ng/mL)
and confirmed in a subset of samples by GC/MS (cutoffs 5 ng/mL). If any of three urine specimens were positive,
drug use was assumed. if all three urine specimens were negative, drug abstinence was assumed. If either of two
duplicate sweat patches worn by the subject was positive by the ELISA test, the sweat test result was judged to be
positive. The sweat ELISA results for cocaine and opiates were 77.7 and 78.6% as accurate as compared to urine
results. Sensitivities and specificities were 97.6 and 60.5% for sweat cocaine analysis and 68.8 and 86.1% for
opiate analysis as compared to urine cocaine and opiate detection. In 75 cases (21.1%). the sweat was positive for
cocaine or metabolites by the ELISA assay, but the three weekly urines at the 30 ng/mL cutoff were negative;
however, in 36 of these 75 cases (48%) only one of the two patches applied to the patient was positive. GC/MS
analysis of the sweat was available in 43 of these 75 cases and confirmed the presence of cocaine and analytes in 40
or 93% of the specimens. Additional controlled drug administration studies are needed to determine if the increased
detection of cocaine by sweat analysis is due to greater sensitivity of sweat testing over urine analysis or to
analytical variability or environmental contamination of the sweat patch. The accuracy, sensitivity and specificity
of sweat ELISA results as compared to GC/MS results were 93.1. 93.5, and 90.5% for cocaine and 89.5, 96.7,
72.2% for opiates. Cocaine was detected in 99% of positive sweat patches with a mean GC/MS concentration of
990.6 ng/mL (range 0 to 26,490). In contrast, the mean benzoylecgonine and ecgonine methyl ester concentrations
were 133.7 (range 0 to 2150) and 116 ng/mL (range 0 to 774), respectively. Fewer of the positive sweat patches
were positive ( 5 ng/mL) for benzoylecgonine (78.2%) and ecgonine methyl ester (73.0%). Lower mean opiate
concentrations were found in sweat: heroin 23.9 ng/mL (range 0 to 195) 6-acetyl-morphine (6AM) 21.2 ng/mL
(range 0 to 181). morphine 20.8 ng/mL (range 0 to 112), and codeine 22.3 ng/mL (range 0 to 360). Heroin was
detected in one fourth of all opiate positive sweat patches, while 6AM, morphine and codeine were detected in more
than three fourths of all positives. Analysis of sweat patches may provide a more sensitive method for objectively
monitoring drug use and provides an alternative method for evaluating behavioral interventions in drug treatment
programs.
DETECTION OF FENFLURAMINE AND PHENTERMlNE IN HAIR AND NAILS
D. E. Lewis, C. M. Moore, and J. B. Leikin
U.S. Drug Testing Laboratories, Des Plaines, IL and Poison Control Center, Rush-St. Lukes
Presbyterian Hospital, Chicago, IL
Fenfluramine and phentermine are widely prescribed in a combination known as fen/phen for use in weight loss.
The determination of these drugs in human biological samples may be useful for medical reasons and for the
insurance industry. Both hair and nails provide a longer historical record of drug use than either urine or blood, the
more common samples tested for drug determination. An additional advantage to these specimens is the ease and
non-invasiveness of collection. The determination of fenfluramine and phentermine in hair and nails taken from
users of the fen/phen drug combination is described for the first time. The specimens were powdered in an
amalgamator using stainless steel ball-bearings to provide milling action. The powdered substances were hydrolyzed
overnight the drugs were extracted and analyzed using GC/MS in electron impact selected ion storage mode. The
analytical method was linear over the range 0.05 - 5 ng/mg of hair. The limit of detection was 0.05 ng/mg of hair,
sufficient for the determination of fenfluramine and phentermine in both hair and nails. The described procedure has
applications in the medical and insurance fields.
223
NALTREXONE-DERIVED pA2 ANALYSIS OF THE ANTINOCICEPTIVE EFFECTS OF
OPIOIDS IN RATS
H. A. Appanaitis 1 , R. M. Allen2 , E. A. Walker l , and L. A. Dykstra 1,2
1
Department of Psychology and
Carolina, Chapel Hill, NC
2
Curriculum in Neurobiology, University of North
Effects of the µ-selective opioid antagonist naltrexone (NTX) were assessed alone and in combination with
morphine, levorphanol and butorphanol in Sprague-Dawley rats using a warm water tail-withdrawal procedure. In
this procedure, the lower 8 cm of each rats tail is placed in 40°, 52°, and 55° C water, and the latency to remove the
tail from the water is measured. Morphine, levorphanol, and butorphanol (n=5) dose-dependently increased tail
withdrawal latency from both 52° and 55° C water, when combined with morphine, NTX (0.03-0.3 mg/kg)
produced dose-dependent rightward shifts in the morphine dose-effect curve. Similarly, when combined with
levorphanol, NTX (0.03-0.3 mg/kg) produced dose-dependent rightward shifts in the levorphanol doze-effect curve.
NIX (0.03-0.3 mg/kg) produced rightward shifts in the butorphanol dose-effect curve, however these shifts were not
dose-dependent Apparent pA2 values for naltrexone as an antagonist of morphine and levorphanol were similar in
both 52° C and 55° C water. Apparent pA2 values for naltrexone in combination with butorphanol could not be
calculated however a pKB analysis showed butorphanol to be more sensitive to NTX antagonism than either
morphine or levorphanol. These results indicate that both morphine and levorphanol’s antinociceptive effects are mu
mediated, whereas butorphanol’s antinociceptive effects are not.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA00033, DA02749, and DA07244
ORPHANIN FQ BLOCKS THE ANTINOCICEPTION INDUCED BY OPIOID AGONISTS ON
THE COLD-WATER TAIL-FLICK TEST
X. H. Chen, E. B. Geller, and M. W. Adler
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA
Recent studies have shown that orphanin FQ (OFQ)/nociceptin, a 17-amino-acid peptide, is an endogenous agonist
whose receptor is similar in sequence to mu, delta and kappa opioid receptors (-75% homology). It was reported
that OFQ can block antinociceptive effects induced by opioid receptor agonists in the radiant beat tail-flick test and
warm water tail-withdrawal test. The present studies were designed to see the effect of OFQ on antinociception
induced by opioid receptor agonists In the cold water tail-flick (CWT) test. Adult male SD rats were used. OFQ
was diluted with phosphate-buffered saline (vehicle). The results showed that intracerebroventricular (icv) injection
of OFQ at doses of 50 fmol to 10 nmol did not induce a significant change in the CWT test. In rats given
subcutaneous (sc) injections of saline or morphine (8 mg/kg), icv injection of OFQ (10 nmol) 15 min later
produced a significant reversal of sc morphine antinociception (p<0.01, ANOVA followed by Duncan’s test),
compared to the corresponding saline control group. Vehicle (t=+15 min, icv) was totally ineffective against sc
morphine antinociception (p>0.01), compared to the corresponding saline control group. When the kappa opioid
receptor agonist spiradoline (80 mg/kg, sc) was used instead of morphine, similar results were observed. In another
series of experiments, we found that intracerebroventricular (icv) injection of OFQ (10 nmol) reversed the
antinociception induced by icv injection of the specific mu opioid agonist PL017 (2 µg). delta opioid agonist
DPDPE (100 µg) and kappa opioid agonist dynorphin (10 nmol), respectively. These results indicate that OFQ
may be an endogeneous anti-opioid peptide in the brain of rats.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 00376.
224
ORPHANIN FQ PEPTIDES IN VITRO BIOTRANSFORMATION IN HUMAN BLOOD
J. Yu, B. T Chait, and M. J. Kreek
The Rockefeller University, New York, NY
Orphanin FQ (OFQ)/nociceptin is a newly isolated and sequenced non-opioid neuropeptide of 17 amino acid residues
related in sequence to dynorphin A (1-17). In vitro biotransformation of this peptide in human (n=5) blood, incubated
at 37°C, was studied. The major and several minor biotransformation products were detected and identified using
matrix-assisted laser desorption/ionization mass spectrometry. Cleavage at peptide linkage Phe(1)-Gly(2) was the
predominant biotransfomation pathway with OFQ (2-17) as the major product. Cleavages at basic amino acid
residues, e.g. Arg(8)-Lys(9), Arg(12)-Lys(13), were observed, to form OFQ (1-8), OFQ (1-9), OFQ (1-11), OFQ (112) and OFQ (1-13), although these were not major biotransformation pathways under these in vitro experiment
conditions. Other minor biotransformation products included OFQ (3-17), OFQ (4-17), OFQ (5-17), OFQ (1-10),
OFQ (1-14), OFQ (2-8), OFQ (2-9), OFQ (3-10), OFQ (2-12) and OPQ (4-12). In vitro biotransformation of the
major processed product OEQ (2-17), was also studied. Processing studies were carried out in freshly-drawn human
(n=5) blood incubated at 37°C for various time periods. In these studies, no major biotransformation pathways were
detected, although a variety of minor biotransformation products were detected and identified, e.g. OFQ (3-17), OFQ
(4-17), OFQ (5-17), OFQ (2-8), OFQ (2-9), OFQ (2-12), OFQ (4-12), OFQ (7-12), and OFQ (8-12).
ACKNOWLEDGMENTS:
Supported by NIH-NIDA Research Center Grant P50-DA05130 (MJK); NIHNIDA Research Scientist Award K05 DA00049 (MJK), and RR 00862 (BTC).
PHARMACOLOGICAL CHARACTERIZATION OF THE MIXED OPIOID AGONISTANTAGONIST CYCLAZOCINE
J. P. McLaughlin and J. M. Bidlack
University of Rochester, Department of Pharmacology and Physiology, Rochester, NY
The affinity, selectivity and antinociceptive properties of cyclazocine for the multiple opioid receptors was
characterized. In competition binding assays with bovine striatal membranes, cyclazocine showed little opioid
selectivity, binding to all three receptors with a K1 value of 1 nM or less. In behavioral analgesic assays,
cyclazocine failed to produce maximal antinociception in the mouse 55°C warm-water tail-flick assay at i.c.v. doses
up to 100 nmol. However, cyclazocine produced maximal antinociception in the mouse writhing assay, producing a
50% antinociceptive response with a dose (and 95% C.L.) of 4.2 (2.1-8.1) nmol when administered i.c.v., nearly
five times more efficacious the kappa agonist U50,488, which had a D50 value of 20 (11-33) nmol. The
antinociceptive effect lasted no more than 2 hr, and was significantly reduced by the administration of selective
opioid antagonists for all three opioid receptors, although this reduction was most pronounced with the kappa
antagonist, nor-BNI. An i.c.v. dose of 0.3-nmol cyclazocine significantly antagonized the antinociceptive effect of
morphine in the tail-flick test. Doses of cyclazocine ten-fold higher produced antagonism of antinociception induced
by the delta-selective agonist DPDPE and the kappa-selective agonist U50,488. Taken together, these data suggest
that low doses of cyclazocine produced both agonist effects mediated by the kappa receptor and antagonistic effects to
mu opioid-induced antinociception as previously demonstrated. However, at slightly higher doses, cyclazocine
further demonstrated both agonist and antagonist activity at all three opioid receptors.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA01674, DA03742 and DA07232.
225
BEHAVIORAL EFFECTS OF BUTORPHANOL AFTER CLOCINNAMOX ADMINISTRATION IN RHESUS MONKEYS
J. A. Vivian1, B. van Bemmel2, J. W. Lewis3, and J. H. Woods1
University of Michigan Medical School, Ann Arbor, MI, 2 Free University, Amsterdam, the
NETHERLANDS and 3 University of Bristol, Bristol, UK
Butorphanol has approximately equal affinity for mu and kappa, opioid receptor sites (KiDAMGO: 0.50 nM, KiU69593:
0.68 nM), yet its behavioral effects are consistent solely with a mu mechanism of action. Using food-reinforced
drug discrimination and diuresis assays in rhesus monkeys, the present study investigated the effects of butorphanol
alone, and in the presence of either me reversible opioid antagonist quadazocine or the mu receptor insurmountable
antagonist clocinnamox. Alone, butorphanol (0.001 - 0.1 mg/kg s.c.) generalized to fentanyl, but not to
ethylketocyclazocine (EKC) in fentanyl-and EKC-trained monkeys, respectively; butorphanol did not alter urine
output. In the presence of quadazocine (0.1 and 1 mg/kg s.c.). butorphanol’s discriminative stimulus, ratesuppressive, and diuretic effects wee unchanged, although its potency was decreased. After the administration of
clocinnamox (0.1 mg/kg s.c.), butorphanol generalized to EKC, and produced a 300% increase in urine output.
These kappa agonist-like effects were observed 24-72 hr after clocinnamox administration, and a return to mu
agonist-like effects were observed 1-2 wk after clocinnamox administration. These results demonstrate butorphanol’s
in vivo agonist activity al mu and kappa opioid receptors; further, the use of irreversible antagonists such as
clocinnamox may provide a novel technique in the study of mixed agonists such as butorphanol.
ACKNOWLEDGMENTS:
Supported by USPHS grams DA00254, DA07268, and DA05773.
EFFECTS OF CLOCINNAMOX IN COMBINATION WITH ETORPHINE IN A PRIMATE
TITRATION PROCEDURE
R. M. Allen2 , E. A. Walker 1 , R. C. Pitts 1 , and L. A. Dykstra 1,2
1
Department of Psychology and
Chapel Hill, NC
2
Curriculum in Neurobiology, University of North Carolina,
Effects of the irreversible, µ-selective opioid antagonist clocinnamox (C-CAM) were assessed alone and in
combination with etorphine in squirrel monkeys responding under a shock-titration procedure. In this procedure,
shock intensity increased every 15 s from 0.01 mA to 2.0 mA in 30 increments. Five lever presses during any
given 15 s shock period produced a 15 s shock-free period after which shock resumed at the next lower intensity.
When given alone, etorphine (n=3) dose-dependently increased the intensity below which the monkeys maintained
shock 50% of the time (median shock level, MSL) and decreased response rates (RR). When combined with
etorphine, C-CAM (0.03-0.1 mg/kg) produced dose-dependent rightward shifts in the etorphine dose-effect curves for
MSL and RR as early as 4 hours after administration. Etorphine failed to produce maximal effects on MSL or RR
in the presence of the highest dose of C-CAM tested (0.1 mg/kg). Etorphine’s effects returned to within 1/4 log
unit of control values 3 days after administration of 0.03 mg/kg C-CAM whereas etorphine's effects returned to
within 1/4 log unit of control values 10 days after administration 0.1 mg/kg C-CAM. When compared to prior
research on the effects of C-CAM on other opioids, these results indicate that etorphine is a higher efficacy µ-opioid
agonist in this procedure.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA00033, DA02749, and DA07244.
226
BIOTRANSFORMATION AND DURATION OF ACTION OF DYNORPHIN A(2-17) IN
RHESUS MONKEYS
E. R. Butelman, J. Yu, B. T. Chait, J. H. Woods*, and M. J. Kreek
Rockefeller Univ., NY, NY and *Dept. of Pharmacology, Univ. of Michigan, Ann Arbor, MI
The non-opioid peptide dynorphin A(2-17) [DYN A(2-17)] is active when administered systemically or centrally, in
tests of antinociception, and in reducing the expression of morphine withdrawal signs in rodents. The mechanism of
these effects is unknown at present. By using the technique of matrix-assisted laser desorption/ionization mass
spectrometry (MALDI MS), we have previously found that the endogenous opioid peptide DYN A(1-17) is
biotransformed in rhesus monkey blood in vitro and in vivo into DYN A(2-17) (Yu et al., 1996; J Pharmacol Exp
Ther 279:507-514). One aim of the present experiments was to study the biotransformation of DYN A(2-17) in
rhesus monkey blood, using MALDI MS. Freshly drawn rhesus monkey blood (n=3) was incubated at 37°C.
Dynorphin A(2-17) (0.59 mg/ml) was added to the blood and aliquots were removed at various times after addition
(0-120 min). Two identifiable pathways of biotransformation were detected. Firstly, a sequential cleavage of the Nterminal glycine residues, to yield DYN A(3-17) and DYN A(4-17). The second pathway involved the cleavage
between arginine residues in positions 6 and 7, which yielded DYN A(7-17). In all subjects, intact DYN A(2-17)
was still detected afler 60 min incubation. Dynorphin A(1-17) and A(2-17) (0.32-3.2 mg/kg) were administered i.v.
to rhesus monkeys (n=4) in the warm waler (50°C) tail withdrawal assay, a test of thermal antinociception. DYN
A(1-17) was only slightly effective at the highest dose studied. In contrast, DYN A(2-17) produced dose-dependent
antinociception with an apparently higher peak effect, up to 30 min after administration. These studies show that
intravenously administered DYN A(2-17) produced thermal antinociception in primates.
ACKNOWLEDGMENTS:
Supported by NIH grants DA 11113 (ERB), DA 00254 (JHW), DA 05130 and
DA 00049 (MJK) and RR 00862 (BTC).
CHANGES lN CNS-DERIVED TNF
COMPONENT TO PERSISTENT PAIN
IN
THE
DEVELOPMENT
OF
A
CENTRAL
#
#
W. C. Covey*, P. R. Knight , and R. N. Spengler*
*Department of Pathology, SUNY at Buffalo, Buffalo and ''Dept. Anesthesiology, SUNY at
Buffalo, Buffalo, NY
Changes in CNS levels of proinflammatory cytokines such as TNF- have been associated with the development of
certain types of persistent pain. Additionally, many persistent pain syndromes having a central component are
believed to involve abnormal sympathetic activity. Changes in TNF levels are associated with modifications in
adrenergic responsiveness, and TNF is an important endogenous modulator of CNS NE release. We have previously
demonstrated an interactive relationship between TNF- production and
adrenergic regulation of NE release in the
CNS. Thus, we hypothesize that TNF- may exert its effects in the development of persistent pain by its actions at
central
adrenergic receptors. The present study examines pain-associated changes in central TNF production in a
neuropathic pain model. Rats underwent unilateral ligature placement around the sciatic nerve, and at t=2,4,6 and 8
days post-surgery, paw-withdrawal latency was measured as an index of hyperalgesia. Additionally, several regions
of the CNS were harvested and assayed for TNF content. The results demonstrate that alterations in TNFexpression occur in regions of the brain associated with adrenergic function during the induction of neurolpathic
pain, and that increases in cylokine levels coincide with the period of peak hyperalgesia. Based on previous results
adrenergic responsiveness
from our laboratory, we speculate that persistent increases in TNF levels will shift
from inhibition to facilitation. Elucidating the interaction between proinflammatory cytokines and adrenergic
responses in the CNS in a model of centrally-miediated pain will contribute to our understanding of the mechanisms
involved in me pathogenesis of such chronic pain syndromes.
Key words: TNF, Pain, Adrenergic, CNS.
227
HYPERALCESIA IN METHADONE-MAINTAINED PATIENTS
P. Compton, W. Ling, and C. Choruvastra
UCLA School of Nursing, West Los Angeles VA Medical Center, Pizarro Treatment Center,
Los Angeles, CA
It is increasingly evident that pain and opioid addiction a not urelated phenomena. Preclinical data indicate that
rats made tolerant to the antinociceptive effects of opioids are also hyperalgesic to painful stimuli theorized to be
due to NMDA receptor-mediated responses. Consistenl with this finding, we previously demonstrated that
methadone-maintained heroin addicts evidence significantly less tolerance for cold-pressor pain than drug-free exaddicts1. In this extension of that work, pain tolerance was compared between samples of methadone-maintained
subjects (n=35) and normal controls (n = 42) matched on gender and race. Methadone-maintained subjects were on a
stable dose. of methadone; pain tolerance was measured within two hours of being dosed. Mean pain tolerance (each
sb underwent 3 cold-pressor trials separated by at least 48 hours) was significantly lower for the methadonemaintained group. Degree of hyperalgesia was unrelated to absolute methadone dose.
References:
1
Compton M. Cold-pressor pain tolerance in opiate and cocaine abusers: Correlates of drug type and use status. J Pain
Symptom Manage 1994; 9462-473.
ACKNOWLEDGMENTS:
Supported in part by NIDA grants R03DA09866 and P50DA06082.
SUBJECTIVE, PSYCHOMOTOR, AND ANALGESIC EFFECTS OF CODEINE AND
MORPHINE IN HEALTHY VOLUNTEERS
D. J. Walker, J. L. Galinkin, D. W. Coalson, J. M. Klafta, P. A. Klock, C. J. Young, and
J. P. Zacny
Department of Anesthesia and Critical Care, The Pritzker School of Medicine, The
University of Chicago, Chicago, IL
Oral codeine and morphine are commonly prescribed for pain relief in medical settings. The abuse liability of these
drugs and their effects on cognitive/psychomotor performance in nondrug-abusing volunteers have not been well
characterized. The purpose of the present study was to characterize the effects of two oral doses of codeine and
morphine on mood, psychomotor performance, physiological measures, and pain in healthy volunteers. A
randomized, double-blind, placebo-controlled crossover design was conducted with twelve healthy, nondrug-abusing
volunteers. Each session began with 15 minutes of baseline testing; then subjects ingested a solution that
contained codeine 60 or 120 mg, morphine 20 or 40 mg, or placebo. Testing continued for 5.5 hours after drug
ingestion, and dependent measures included subjective effects, cognitive/psychomotor performance, physiological
measures, and ratings of pain intensity induced by a cold-pressor test (nondominant forearm in 2°C water for 90
seconds). Subjects reported weak to mild drug effects with codeine and morphine, including increased scores on the
Pentobarbital-Chlorpromazine-Alcohol Group scale of the Addiction Research Center Inventory. Both drugs
increased ratings of “dry mouth” on the Opiate Adjective Checklist and ratings of “coasting,” “heavy/sluggish,” and
“nauseous” on a Visual Analog Scale. Neither drug impaired cognitive/psychomotor performance as measured by
the Digit-Symbol Substitution Test and tests of logical reasoning. auditory reaction time, eye-hand coordination,
and short- and long-term memory. Both drugs produced miosis, which was dose-related and analgesia which was
dose-related for morphine but not for codeine. Some subjects liked the drug effects; others did not. These results
suggest that codeine and morphine, at the doses tested, are effective analgesics that do not impair performance and
produce mild subjective effects.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-08573
228
EFFECTS OF SEVOFLURANE AND NITROUS OXIDE ON THE PAIN RESPONSE AND
OTHER BEHAVIORS IN HEALTHY VOLUNTEERS
D. J. Janiszewski, J. L. Galinkin, J. P. Zacny, D. W. Coalson, C. J. Young, J. M. Klafta,
P. A. Klock, and J. L. Apfelbaum
Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL
The present study examined the effects of sevoflurane (S) and nitrous oxide (N), by themselves and in combination,
on the pain response, psychomotor performance, and sedation in healthy volunteers. Isoflurane, a volatile inhaled
general anesthetic, has been shown to antagonize the analgesic effect of N in rats (Goto et al., 1996). In addition, N
has been shown to oppose the depression of isoflurane on the CNS (Yli-Hankala, et al, 1993). However, other
effects of N, such as psychomotor impairment, are potentiated by isoflurane in humans (Zacny et al., 1996). Based
on these findings, we hypothesized that S, a volatile inhaled general anesthetic, would antagonize the analgesic
effects of N and that N would antagonize the sedation caused by S. Finally, we predicted that N would potentiate
the psychomotor impairment caused by S. Nine subjects (7 males, 2 females, mean age 25 years) participated in
this IRB-approved, randomized, crossover experiment. Subjects, over the course of three sessions, inhaled 0, 0.2, or
0.4% end-tidal S for a 68 min inhalation period. Each inhalation was divided into four 17-min blocks. During
either the second or fourth block, 30% end-tidal N was added. During these two blocks, psychomotor performance
(as assessed by the Digit Symbol Substitution Test), pain responses (as assessed by use of a 2-min cold water test),
and sedation (as assessed by subjects’ visual analog scale ratings) were evaluated. N produced analgesia but S did
not antagonize this effect. There was a main effect of S on subjects’ ratings of sleepiness and these ratings either
decreased or remained the same when N was added to S. Lastly, S potentiated the psychomotor-impairing effects of
N. Since the drugs differed in their sedation profiles, the potentiatied psychomotor impairment of S by N suggests
that the impairment induced by N and the impairment induced by volatile anesthetics are mediated by different
neurochemical mechanisms of action.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-08391.
DEVELOPMENTAL PCP EXPOSURE PRODUCES LONG-LASTING DECREASED
LOCOMOTOR RESPONSES TO PCP AND MK-801
F. M. Scalzo
Department of Pediatrics, University of Arkansas for Medical Sciences
Children’s Hospital Research Institute, Little Rock, AR
and Arkansas
Previous studies from our laboratory have shown that subchronic developmental exposure to phencyclidine (PCP)
on postnatal days (PND) 24-37 (but not PNDs 4-17) results in allerations in the behavioral response to a
pharmacological challenge with PCP or the NMDA antagonist, MK-801, 10 and 20 days after cessation of
treatment. The present studies were designed to determine the persistence of these effects. Rats were dosed with
saline or 7.5 mg/kg PCP on PNDs 24-37. Ten and 20 days, and 61 and 68 days (PND 105) post-dosing,
locomotor activity was measured for one hr following a challenge with either saline, 2.5 mg/kg PCP, or 0.1 mg/kg
MK-801. Activity was measured via an automated system. PCP treatment resulted in decreased locomotor
responses to both PCP and MK-801 challenges for up to 68 days post-dosing. The locomotor response to a saline
challenge was not affected by pretreatment with PCP. These results suggest that subchronic exposure to PCP
results in long-lasting decreases in the locomotor response to both PCP and MK-801. The mechanism(s) mediating
this change in responsiveness are unclear but might involve alterations in NMDA systems or treatment-induced
alterations in PCP metabolism during development.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-08240 and DA-06319.
229
CHRONIC PHENCYCLIDINE ADMINISTRATION INDUCES APOPTOSIS IN THE RAT
OLFACTORY TUBERCLE AND PIRIFORM CORTEX
M. Phillips, C. Wang, and K. M. Johnson
Department of Pharmacology and Toxicology, Univ. of Texas Medical Branch, Galveston,
TX
Acute or chronic low-dose administration of phencyclidine (PCP) and other NMDA receptor antagonists causes
neurotoxicity evidenced by vacuolization, hsp70 induction, and increased GFAP in rat retrosplenial/cingulate cortex
as well as in other corticolimbic brain regions. A variety of drugs, including both typical and atypical
antipsychotics, have been shown to protect the affected brain regions from neurotoxicity produced by NMDA
receptor antagonists. Although the vacuolization, hsp70 induction, and increased GFAP produced by NMDA
receptor antagonists are believed to occur primarily via a necrotic mechanism, we wished to investigate the
possibility that chronic PCP administration in rats induced apoptosis as well. We administered 20 mg/kg PCP i.p.
once a day for 5 consecutive days to adult female Sprague Dawley rats, a pattern that closely resembles the binge
pattern of administration by drug abusers. Seventy-two hours following the last PCP injection, the rats were
administered 3.2 mg/kg PCP and locomotor activity was monitored for 90 min. Immediately afterwards, the rats
were anesthetized and perfusion fixed for immunochemical assessment of terminal dUTP nick-end labeling
(TUNEL) as a marker of apoptosis. Behavioral analysis revealed that chronic PCP treatment produced a robust
sensitization to PCP challenge. Other experiments revealed that a 1 hr. Pretreatment with 10 mg/kg clozapine (an
atypical antipsychotic) blocked the development of sensitization. A single 20 mg/kg injection of PCP produced no
TUNEL staining of nuclei in any rat brain region observed including the retrosplenial/cingulate cortex. However,
chronic PCP administration caused a regionally-specific, substantial increase in the number of positively TUNELstained nuclei in the olfactory tubercle and piriform cortex that was verified as apoptotic by electron microscopy.
Clozapine prevented the PCP production of positively TUNEL-stained nuclei in the olfactory tubercle and piriform
cortex.
ACKNOWLEDGMENTS:
Supported by DA 02073 and T32 DA 07287.
FACTORS AFFECTING ACQUISITION OF ORAL PCP SELF-ADMINISTRATION IN
RHESUS MONKEYS
V. C. Campbell, S. S. Thompson, and M. E. Carroll
Department of Psychiatry, University of Minnesota, Minneapolis, MN
The effects of drug dose and a nondrug alternative reinforcer on rates of acquisition of oral PCP self-administration
in drug naive rhesus monkeys were examined. Acquisition was studied using 3 separate groups of 6-7 monkeys, One
group received a low PCP dose (0.0375 mg/delivery) and the other two groups received a high PCP dose (0.15
mg/delivery). One of the high dose groups had concurrent access to a saccharin solution (0.03% wt/vol) and water
during the intersession (17.5-hr) period. Food satiated monkeys were initially given access to water under a fixedratio (FR) 1 schedule during daily 3-hr sessions. Water was then replaced with PCP during the session. The
monkeys were then reduced to 85% of their free-feeding body weight and were fed before the session, and the FR
value was increased from 1 to 2.4 and 8. Food was then given post-session and water and PCP were available under
concurrent FR 8 schedules. Acquisition was considered to occur if PCP intake exceeded water intake. Monkeys
receiving the low PCP dose maintained higher response rates and lower drug intake per session than monkeys
receiving the high PCP dose. Monkeys receiving the high PCP dose maintained higher response rates and drug
intake than monkeys receiving the high PCP dose with saccharin during intersession. When all 3 groups were given
concurrent access to PCP and water, PCP intake was greater than water intake although the magnitude of this effect
was greater in the group of monkeys receiving the high PCP dose. PCP maintained higher response rates than water
when saccharin was replaced by water during intersession in the high PCP dose group. Within-group data revealed
that a higher percentage of monkeys acquired PCP reinforcement in the group given assess to the high PCP dose
than the other two groups. These data suggest that drug dose and presence of alternative nondrug reinforcers affect
acquisition of drug self-administration in nonhuman primates.
ACKNOWLEDGMENT: Supported by NIDA R01 DA02486.
230
MEDICATIONS DEVELOPMENT FOR DRUG ABUSE: A DRUG CLASS-SPECIFIC
PHARMACOKINETIC ANTAGONIST FOR PHENCYCLIDINE
J. S. Hardin, W. D. Wessinger, and S. M. Owens
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas
for Medical Sciences, Little Rock, AR
Use of phencyclidine (PCP) and other arylcyclohexylamines in humans can result in severe toxicity or even death.
We have developed an anti-PCP monoclonal antibody Fab fragment which acts as a pharmacokinetic antagonist to
reverse these effects. The aim of this study was to determine if the anti-PCP Fab fragment was effective against
structural analogs of PCP. To test our hypothesis we chose two analogs, 1-[1-(2-thienyl)-cyclohexyl]piperidine
(TCP) and N-ethyl-1-phenylcyclobexylamine (PCE) because these drugs are more potent than PCP and they have
also been reported to be drugs of abuse. For the studies, each male Sprague-Dawley rat received seven treatments in
a repeated-measures, mixed-sequence design (n=4). The behavioral parameters ‘distance traveled’ and ‘total
movement were used to assess the ability of the Fab fragment to inhibit drug-induced effects in the animals. PCP,
TCP, and PCE were each administered as i.v. 3 mg/kg doses. The Fab was given i.v. as a 1.0 mole equivalent dose
30 min after drug administration. The Fab was equally effective al antagonizing the locomotor effects of PCP,
TCP, and PCE (RM ANOVA followed by Student-Newman-Keuls, P < 0.05). For example, the average distance
traveled induced by PCP (417 m), TCP (541 m), and PCE (691 m) was decreased after Fab treatment to 76 m, 107
m, and 125 m, respectively. As a control, we determined that the Fab did not antagonize the locomotor effects of
methamphetamine. We conclude that the anti-PCP Fab can antagonize several potent arylcyclohexylamines, and
these data suggest that monoclonal antibodies can be developed for treating classes of drugs. as well as individual
drugs.
Supported by NIDA grant DA07610, Research Scientist Development Award K02
ACKNOWLEDGMENTS:
DA00110 to S.M.O., and a NIDA predoctoral fellowship T32 DA07260 to J.S.H.
ANTIBODY-BASED MEDICATIONS DEVELOPMENT FOR PHENCYCLIDINE (PCP)
ABUSE: OPTIMIZATION OF ANTI-PCP FAB RENAL CLEARANCE
J. W. Proksch and S. M. Owens
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas
for Medical Sciences, Little Rock, AR
We have previously shown that a high-affinity monoclonal antibody fragment (Fab) against PCP is very effective in
reversing PCP-induced behavioral effects and in rapidly redistributing PCP out of the CNS. The purpose of these
studies was to optimize conditions for use of an antibody-based medication for PCP abuse. Although the Fab-PCP
complex can be eliminated via the kidney, the details of this process are not well understood. To study the effect of
fluid loading on anti-PCP Fab elimination, male Sprague-Dawley rats (n=4) received PCP (1 mg/kg i.v.) followed
10 min later by a 1 mol-eq anti-PCP Fab dose, with or without lactated ringer’s (21 ml/kg i.v.). Urine output was
higher following fluid loading over the First 3 hr (P<.05). however anti-PCP Fab elimination did not differ from
controls at any time point. The total amount of anti-PCP Fab appearing in the urine was 55.7±6.1% of the antiPCP Fab dose compared to 64.1±10.3% without fluid loading. To study the effect of urinary alkalinization on PCP
and anti-PCP Fab co-elimination, rats (n=1) received NaHCO3 at 8 min after PCP administration (8 mEq/kg + 2
mEq/kg every 45 min for 3 hr) followed 2 min later by 1 mol-eq anti-PCP Fab. Urine alkalinization did not affect
the amount of Fab being excreted (69.1 4.1%) or the co-elimination of PCP (41.4±7.2%). To study the effect of
Fab dose on anti-PCP Fab elimination, rats (n=3-4) received PCP (0.1, 0.3, 1.0 and 3.0 mg/kg) followed 10 min
later by a mol-eq Fab dose (21-617 mg/kg). Elimination of Fab following the 21 mg/kg dose (50.0±4.1%) was
statistically lower than that of the 62 mg/kg (65.4±10.3%) and 617 mg/kg (66.0±6.7%) doses (P<.05), but not the
206 mg/kg dose (57.4±5.12). In summary, anti-PCP Fab treatment significantly improves PCP excretion,
presumably through elimination of an intact PCP-Fab complex which is unaffected by anti-PCP Fab dose, fluid
loading and urinary alkalinization.
Supported by NIDA grant DA07610, RSDA KO2 DA0110 (S.M.O.) and NRSA
ACKNOWLEDGMENTS:
F31 DA05795 (J.W.P.).
231
REINFORCING AND DISCRIMINATIVE STIMULUS EFFECTS OF MEMANTINE, A LOW
AFFINITY NMDA CHANNEL BLOCKER
K. L. Nicholson, H. E. Jones, L. Hua and R. L. Balster
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA
Memantine (MEM) is currently in use in Europe for the treatment of various neurological disorders. It is a low
affinity channel blocker of NMDA receptors whose rapid binding kinetics are thought to limit its phencyclidine
(PCP)-like side effects. MEM and its analog, amantadine (AMA), which has also been demonstrated to have some
NMDA antagonist activity. were evaluated for PCP-like behavioral effects. The discriminative stimulus properties of
MEM and AMA were tested in monkeys and rats trained to discriminate PCP from saline using a standard two-lever
chug discrimination paradigm. In monkeys, MEM produced complete substitution. AMA occasioned little or no
responding on the PCP-associated lever. In rats, MEM resulted in full substitution for PCP, but only at response
rate suppressing doses. AMA was without PCP-like effects in rats. IV self-administration of MEM and AMA was
tested under a fixed ratio schedule of reinforcement in monkeys trained to lever press for infusions of PCP. MEM
served as a reinforcer in all subjects at one or more doses tested. Results with AMA were inconsistent. Overall,
MEM was shown to produce PCP-like discriminative stimulus effects in rats and monkeys while AMA did not.
MEM also served as a positive reinforcer in rhesus monkeys, while AMA served as a weak reinforcer in only some
subjects. Both AMA and MEM are reported to serve as NMDA antagonists, yet clear differences exist in their
behavioral effects with MEM acting more like a PCP-like antagonist. In addition, despite the rapid channel kinetics
of MEM’s NMDA receptor blockade it may have some PCP-like abuse potential in humans at doses above the
normal therapeutic levels.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-01442 and DA-07027.
NMDA RECEPTOR ANTAGONIST MEMANTINE DOES NOT ALTER “BINGE” COCAINE
INDUCED ELEVATION OF DYNORPHIN mRNA
V. P. Yuferov, Y. Zhou, S. D. Schlussman, C. E. Maggos, A. Ho, R. Spangler, and M. J.
Kreek
The Rockefeller University, New York, NY
The noncompetitive NMDA receptor antagonist MK 801 has been reported to attenuate the increase in striatal
dynorphin peptide levels induced by repeated cocaine administrations. We have examined the effect of another
noncompetitive NMDA receptor antagonist, memantine (1-amino-3,5-methyladamantane), which is clinically
used for the treatment of dementia and Parkinson’s disease, on preprodynorphin (Dyn) mRNA levels in the rat brain
after one day “binge” pattern cocaine administration (three 15 mg/kg injections i.p. with 1h interval). To minimize
the effects of stress, mate Fischer rats were injected with saline for 6 days prior to the test day. On the seventh day,
all rats received injections of either saline (1mg/kg, i.p.) or memantine (10 or 20 mg/kg, i.p.) 30 min prior to start
of the “binge” administration of cocaine or saline in four treatment groups: a) saline/saline; b) memantine/saline; c)
saline/cocaine and d) memantine/cocaine. Rats were sacrificed 30 min after the final injection and the amount of Dyn
mRNA were determined for selected brain regions by a solution hybridization RNase protection assay. Data were
analyzed using analyses of variance with repeated measures followed by Newman-Keuls post hoc tests. Dyn mRNA
levels were increased in the caudate putamen of rats following “binge” cocaine administration (p<0.05). Memantine,
at 10 or 20 mg/kg. did not alter the cocaine-induced increase in Dyn mRNA levels in this brain region. There were
no significant differences in the Dyn mRNA levels in the caudate putamen between memantine/saline and
saline/saline rat groups, although memantine injections alone led to a dose dependent increase in circulating levels
of corticosterone and a marked behavioral effect.
ACKNOWLEDGMENTS:
Supported by NIDA P50-DA 05130 and DA 00049.
232
EFFECTS OF TOLUENE ON RECOMBINANT NMDA RECEPTORS
S. L. Cruz1, T. Mirshashi2, R. L. Balster2, and J. J. Woodward2
1
Department of Pharmacology and Toxicology CINVESTAV, IPN, Mexico 2 Department of
Pharmacology and Toxicology, Medical College of VA/Virginia Commonweallh University,
Richmond, VA
Toluene is a widely used industrial solvent and a drug of abuse. Previous studies have shown that toluene depresses
neuronal activity and causes behavioral effects similar to those observed for ethanol. In this study the oocyte
expression system was used to tesl the hypothesis that toluene, like ethanol, inhibits the function of NMDA
receptors. Oocytes injected with mRNA for the NR1 subunit and that of various NR2 subunits were maintained in
L-15 media for up to 7 days prior to recording. Drug solutions were prepared by mixing toluene with emulphor
(ethoxylated castor oil) at a 1: 1 ratio (v: v) and diluting this mixture to the appropriate concentration with bariumcontaining Ringer solution (Ba-NFR). NMDA-induced currents were measured in BA-NFR at a holding potential of
-80 mV using two-electrode voltage-clamp. Emulphor up to 0.1% had no significant effects on the resting
membrane potential or on NMDA-induced currents. In contrast, toluene-containing solutions dose-dependently
inhibited NMDA-induced currents in oocytes expressing the NR1/2A, NR1/2B or the NR1/2C subunit
combinations. The inhibition was rapid, almost complete and reversible although some channel rundown occurred at
higher concetrations. The NR1/2B combination was the most sensitive with an IC50 value of 0.17 ± 0.02 mM.
The NR1/2A and NR1/2C receptors were 8 and 12-fold less sensitive with lC50 values of 1.4 ± 0.17 mM and 2.1 ±
0.27 mM, respectively. These results suggest that the effects of toluene on neuronal activity may be mediated in
part by inhibition of NMDA receptors.
ACKNOWLEDGMENTS:
DA03112.
Supported by NIDA/lNVEST fellowship to SLC and by grants AA09986 and
TOLUENE ALTERS RAT VTA DOPAMINE (DA) AND NON-DA NEURONS THROUGH A
DOSE-DEPENDENT MECHANISM
A. C. Riegel and E. D. French
Department of Pharmacology, School of Medicine, University of Arizona, Tucson, AZ
Inhalant abuse is a prevalent form of substance abuse best categorized as the intentional inhalation of organic
solvent containing products consumed for their psychotropic effects. The present study was designed to assess the
effects of toluene on the activity of VTA DA and non -DA neurons, using extracellular recordings in ketamine
anesthetized rats breathing acute concentrations of toluene (11,500 ppm) similar to those consumed by inhalant
abusers (10,000-20,000 ppm). lnhalation elicited two dissimilar dose-dependent patterns of response in DA neurons.
The first pattern (n=28) was a biphasic response consisting of a low dose stimulation (+221% ± 72% at 1-8
minutes) followed by high dose attenuation (-162% ± 6.3% at 8-17 minutes). The second pattern (n=28) was
composed of an inhibition of firing (reaching -97% ± 2.9% in 1-17 minutes). In contrast, non-DA neurons (n=8)
displayed only uniform inhibitions (reaching -80% at 1-8 min) during inhalation. Blood samples taken at the same
time as recordings and analyzed by GC/FID indicated comparable blood toluene concentrations (4-79 µg/ml at 1-14
min) for both DA patterns of response. It was also determined that olfactory sensation did not play a role in the
observed toluene induced changes in DA cell firing. Thus, toluene at concentration’s relevant to those found in
human abusers profoundly alters the activity of mesolimbic dopamine neurons. a system known to be involved in
the reinforcing properties associated with drugs of abuse.
ACKNOWLEDGMENT:
Supported in part by NIDA grant # DA09025.
233
PHENCYCLIDINE- AND DIAZEPAM-LIKE DISCRIMINATIVE STIMULUS EFFECTS OF
ABUSED INHALANTS IN MICE
S. E. Bowen, J. L. Wiley, H. E. Jones, and R. L. Balster
Department of Pharmacology and Toxicology, Medical College of Virginia,
Virginia Commonwealth University, Richmond, VA
Previous research has found that the abused solvents, 1,1,1-trichloroethane (TCE) and toluene share pharmacological
properties with CNS depressant drugs, including anxiolytic effects and ethanol-like discriminative stimulus effects.
In the present studies, mice were trained to discriminate between diazepam (DZ; 2.5 mg/kg) and vehicle or between
phencyclidine (PCP; 2.0 mg/kg) and saline. Stimulus generalization was examined after 20-min inhalation
exposures to TCE (4.000-16,000 ppm), toluene (1,000-6,000 ppm), methoxyflurane (500-4,000 ppm) and flurothyl
(300-900 ppm). In the DZ-trained mice, methoxyflurane fully substituted for DZ at 2,000 ppm and severely reduced
responding at 4,000 ppm. TCE produced partial substitution. Flurothyl and toluene produced no appreciable DZlever responding at any concentration. Concentration-related increases in PCP-lever responding were observed for
toluene with maximal levels of 70% PCP-lever responding occurring at 6,000 ppm. Methoxflurane and TCE did
not substitute for PCP. Although DZ and PCP both produce CNS depressant effects, they do so by different
mechanisms (GABA vs. NMDA). The present results suggest that the mechanisms of action through which TCE,
methoxyflurane, and toluene produce their CNS depressant effects may also differ.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-05670, DA-03112, and DA-01442.
NEUROTOXICITY PROFILE OF DEXTROMETHORPHAN AND THE 3-AMINO ANALOG
AHN649: CORTICAL EEG AND BEHAVIORAL STUDIES IN THE RAT
F. C. Tortella, A. J. Williams, A. H. Newman*, and X.-C. Lu
Division of Neuroscience, Walter Reed Army Institute of Research, Washington, DC and
* NIDA Addiction Res. Ctr., Baltimore, MD
The [+]-methyl morphinan dextromethorphan (DM) exhibits a broad spectrum of CNS pharmacology relative to
potential chical therapeutics, including antitussive, anticonvulsant and neuroprotective properties. While
generally considered safe, a major concern exists regarding possible adverse effects of high doses of DM including
the potential for drug abuse and the induction of toxic psychotic reactions. Since DM is rapidly metabolized to
dextrorphan, a drug possessing PCP-like properties which, in part, likely contribute to its CNS toxicity, a series of
DM analogs have been synthesized which are less likely to metabolize to dextrorphan (or do so at a reduced rate).
One such analog is the anticonvulsant and neuroprotective 3-amino-17-methyl morphinan, AHN649. This study
examined the potential neurotoxicity of DM and AHN649 in the rat. Male S.D. rats (300-350 g) implanted with
cortical electrodes and a jugular vein cannula were injected i.v. (1 min infusion) with DM (12.5-37.5 mg/kg, n=25)
or AHN649 (10-100 mg/kg, n=35). Low doses of DM (12.5-25 mg/kg) produced EEG seizures (ED50 = 19 [14-28]
mg/kg). Typically, EEG seizure activity commenced immediately postinjection (within 1 min) and was
accompanied by clonic behavior followed by postictal depression. Sedation was evident in non-seizing animals
given DM (ED50 = 30 [13-66] mg/kg). DM-induced lethality was immediate, occurring within 30-60 sec of the
start of the i.v. infusion (LD50 = 27 [24-31] mg/kg). In contrast, AHN649 failed to induce seizures or clonus at
doses up to 100 mg/kg. However, a mild sedation accompanied by EEG slowing was evident at the 20-80 mg/kg
dose range (ED50 = 25 [13-45] mg/kg). Higher doses (60-100 mg/kg) of AHN649 were also lethal (LD50 = 79 [62100] mg/kg). For both drugs, lethality appeared to be cardiorespiratory and not related to CNS neurotoxicity.
These results indicate that while i.v. DM may be predisposed to serious CNS neurotoxicity, AHN649-induced
neurotoxicily may be minimal. Furthermore, based upon unpublished “in vivo neuroprotection” data, AHN649
appears relatively safe and may exhibit an improved therapeutic index over DM.
234
EFFECTS OF SIGMA LIGANDS ON COCAINE-INDUCED CONVULSIONS
R. R. Matsumoto 1 , W. D. Bowen2 , and B. R. de Costa 2
1
Dept. of Pharmacology and Toxicology, University of Oklahoma Health Sciences Center,
Oklahoma City, OK and 2Lab. of Med. Chem., NIDDK/NIH, Bethesda, MD
The ability of sigma ligands to alter cocaine-induced convulsions was tested in Swiss Webster mice. Mice were
pretreated for 15 min with vehicle or a sigma ligand (up to 30 mg/kg, i.p.), then challenged with a convulsive dose
of cocaine (60 mg/kg, i.p.). Convulsions were observed in 100% of mice preheated with vehicle (saline, 50%
DMSO). The following sigma ligands which are thought to act, at least in part, as antagonists or partial agonists
significantly attenuated cocaine-induced seizures (50% or better protection at the most effective dose): BD1008,
BD1018, BD1047, BD1060, BD1061, BD1063, BD1067, LR132, LR172, LR176, haloperidol, reduced baloperidol.
At the highest dose tested in this preliminary study, BMY14802 protected 40% of animals, while rimcazole was
anticonvulsive in only 20% of mice. In contrast, the putative sigma receptor agonists, DTG and BD1052, worsened
the severity of the cocaine-indured seizures, with DTG (30 mg/kg, i.p.) ultimately producing death in all animals
tested. The pattern of results suggests the involvement of sigma-1 receptors in these effects. Further studies are
underway to evaluate the effects of sigma ligands on other cocaine-induced behaviors.
THE NEUROTOXIC EFFECT OF IBOGA ALKALOIDS MAY BE MEDIATED BY SIGMA-Z
RECEPTORS
B. J. Vilner*, Cl. K. Bandarage#, M. E. Kuehne#, C. M. Bertha*, and W. D. Bowen*
*Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD and #Department of Chemistry,
University of Vermont, Burlington, VT
Ibogaine suppresses drug self-administration and is being investigated as a possible treatment for drug abuse.
However, at high doses in rats, it produces neurotoxicity in the cerebellum (O’Hearn and Molliver 1993). We have
shown that sigma-2 receptor ligands cause dose-dependent morphological changes and cell death upon chronic
exposure in culture (Vilner et al. 1995). Ibogaine and some of its congeners have been demonstrated to have
moderate sigma-2 affinity (Bowen et al. 1995; see Williams et al., this volume). Thus, we investigated the cellular
effects of iboga alkaloids in vitro. Human SK-N-SH neuroblastoma cells were cultured in the presence of 3 - 30
uM of the sigma-2-active iboga alkaloids ibogaine, (±)-ibogamine, and (±)-4-(2-methoxyethyl)-desethylibogamine.
These compounds produced dose- and time-dependent morphological changes which were characterized by loss of
processes, cell rounding, detachment and ultimately cell death. However, noribogaine (NI) and (±)-4-(2methoxyethyl)-18-carbomethoxydesethylibogamine (MC), which are weak or inactive at sigma-2 sites, showed little
or no toxicity at comparable times and doses. Similar results were observed with primary cultures of rat cerebellar
granule cells using ibogaine vs. NI. These results are consistent with me reported lack of toxicity of NI and MC in
vivo (Glick et al. 1996a,b). The sigma-2-active alkaloids produced a rise in [Ca++]i in SK-N-SH neuroblastoma
cells, which may possibly be linked to me neurotoxicity, whereas the inactive compounds had no effect on [Ca++]i.
Although sigma-inactive and lacking in effect on [Ca++]i, (±)-coronaridine did produce morphological changes and
cell death. However, the morphological changes were distinct from those produced by the sigma-active iboga
alkaloids (ie. appearance of abundant intracellular granules, which did not occur with the other ibogaine analogs),
suggesting action via a mechanism unrelated to sigma receptors. In conclusion, sigma-2 sites may play a role in
the neurotoxic and tremorigenic effects of iboga alkaloids, but are unlikely to be involved in their anti-addiction
properties since both NI and MC are active at suppressing drug self-administration despite low sigma-2 affinity
Reference list is available from senior author upon request.
(Glick et al. 1996a,b).
235
COMPARATIVE IN VIVO NEUROBIOLOGICAL EFFECTS OF IBOGAINE AND MK-801 IN
RATS
S. F. Ali, R. B. Rothman*, and M. H. Baumann*
Neurochem. Lab., Div. Neurotox., NCTR, Jefferson, AR and *CPS, NIDA/NIH, IRP,
Baltimore, MD
Ibogaine (IBO) is a naturally-occurring indole alkaloid with putative anti-addictive properties. While IBO interacts
with multiple targets in the brain, recent evidence suggests the drug acts as an NMDA antagonist similar to MK801. The purpose of the present work was to compare neuroendocrine and neurochemical effects of IBO and MK801 in vivo. Male rats (n=6-8) received either IBO (10 & 100 mg/kg, ip). MK-801 (0.1 & 1 mg/kg, ip). or saline.
Groups of rats were decapitated 30 and 60 min after injection; trunk blood was collected for analysis of
corticosterone and prolactin by RIA, whereas brains were harvested for analysis of DA, 5-HT and their metabolites
by HPLC-EC. IBO and MK-801 caused comparable elevations in circulating corticosterone, but only IBO increased
prolactin. IBO produced marked dose-dependent reductions in DA with concurrent increases in the metabolites,
DOPAC and HVA. The prolile of IBO-induced effects on DA function was consistently observed in the cortex,
striatum, and olfactory tubercle. MK-801, on the other hand, ten&d to increase DA and its metabolites. Neither
drug consistently affected 5-HT systems. The present findings show that the effects of IBO on neuroendocrine
secretion and DA neurotransmission are not mimicked by MK-801. Thus, the in vivo actions of IBO can not be
explained simply on the basis of antagonism at NMDA receptors.
ACKNOWLEDGMENT:
Generously supported by NIDA lntramural Research Program.
STRUCTURE-ACTIVITY STUDIES FOR BINDING OF IBOGA ALKALOIDS TO SIGMA
RECEPTORS
W. Williams * , U. K. Bandarage#, M. E. Kuehne#, C. M. Bertha*, and W. D. Bowen*
*Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD and #Department of Chemistry,
University of Vermont, Burlington, VT
We have previously shown that ibogaine and some of its natural congeners are selective ligands for sigma-2
receptors with moderate affinity, Ki = 137 - 201 nM (Bowen et al., Eur J Pharmacol 279, R1-R3, 1995). Sigma-2
affinity was unaffected by the position of the aromatic methoxy group (ibogaine vs. tabemanthine) or the absence of
an aromatic methoxy group altogether ((±)-ibogamine). However, neither a free phenolic hydroxyl moiety
(noribogaine) nor an 18-carbomethoxy group ((±)-coronaridine) were tolerated. Here we investigate additional
ibogaine analogs to further determine the effect of substitution on the aromatic ring and at the 18-position, and to
assess the effect of substitution on the 4-ethyl side-chain. All novel analogs tested had low affinity for sigma-1
sites (Ki = 4.5 uM - 28.6 uM). A 12-O-tert butyl group was tolerated equally as well (Ki = 247 nM) at the sigma-2
site as the 12-methoxy group in ibogaine. (±)-4-(2-Hydroxyethyl)-desethylibogamine had sigma-2 Ki = 209 nM.
(±)-4-(2-Methoxyethyl)-desethylibogamine ((±)-4-MDI) exhibited sigma-2 Ki = 42.8 nM. Thus, methoxy
substitution of the 4-ethyl side chain enhances while hydroxylation slightly decreases sigma-2 affinity. (±)-4-(2Methoxyethyl)-18-carbomethoxydesethylibogamine was practically inactive at sigma-2 sites (Ki = 7.5 uM). (±)-4(2-Methoxyethyl)-18-hydroxymethyldesethylibogamine exhibited sigma-2 Ki = 1 .0 uM. These data confirm the
detrimental effect of substitution at the 18-position. Optical resolution of (±)-4MDI revealed 22-fold
enantioselectivity, with (-)-4-MDI being the most active isomer (Ki = 30.6 nM vs. 662 nM for (+)4MDI). (-)-4MDI, with high affinity and 150-fold selectivity for sigma-2 sites over sigma-1 sites. may prove to be a useful tool
for the study of sigma-2 receptor function. This study shows that sigma-2 binding affinity is quite sensitive to
modifications of the indole ring, 4-ethyl side-chain, and 18 position on the saturated ring system.
236
IN VIVO IBOGAINE BLOCKADE AND IN VITRO PKC ACTION OF COCAINE
A. Chakrabarti, S. F. Ali, and E. S. Onaivi
Department of Pharmacology and Pyschiatry, Vanderbilt University School of Medicine,
Nashville, TN; Neurobehavioral Research Institute, Antioch, TN; and National Center for
Toxicology Research/FDA, Jefferson, AR
Ibogaine may have anti-addiction potential against alcohol, psychostimulant and opiate abuse, but its mechanism
its mechanism of action is incompletely understood. Protein kinase C (PKC) plays a key role in a number of
cellular and neuronal functions. For the in vivo studies, we first determined the acute and subacute effects of
ibogaine (1-5 mg/kg) in mice using the plus-maze test. Acutely, increasing doses of ibogaine produced a reduced
aversion to the open arms. The sub-acute administration provoked a variable response which was characterized by
fluctuation in aversive and anti-aversive behavior of the animals to the open arms of the plus-maze during the 14day treatment period. A separate group of mice received 1.0 mg/kg cocaine for 14-days and upon abrupt cessation
from cocaine treatment, ibogaine 2.5 mg/kg was administered to a subgroup of these mice. Ibogaine reversed the
withdrawal aversions produced by the abrupt cessation from cocaine administration. For the in vitro studies. the
expression and activity of PKC isoforms and Ca2+ levels were examined following incubation of PC12 cells with
cocaine. We report that cocaine disrupts signal transduction in PC12 cells by altering the expression and activity of
PKC isoforms and Ca2+ levels. The data obtained suggest 1) that the PC12 cells may be useful in studying the
neurobiology of abused drugs like cocaine in vitro. 2) that if anxiety is a factor in drug-dependency, then the antiaddictive property of ibogaine in vivo may be associated with modifying the CNS neurotransmission that may be
involved in anxiety and 3) cocaine differentially altered the expression of PKC isoforms accompanied by increased
levels of Ca2+ total PKC activity. It remains to be de&mined if ibogaine will block the effects of cocaine on
the expression of PKC isozymes and activity.
Supported by NIH/NHLBI-K01-HL03319.
ACKNOWLEDGMENT:
BEHAVIORAL PROFILE OF CONSTITUENTS IN AYAHUASCA,
PSYCHOACTIVE PLANT MIXTURE
AN AMAZONIAN
C. Freedland and R. S. Mansbach
Connecticut College, New London, CT. and Pfizer Central Research, Groton, CT
Ayahuasca is a psychoactive plant mixture originating in the Peruvian upper Amazon, typically composed of a
combination of the banisteriopsis vine and the hallucinogenic pIant psychotria viridis. Ayahuasca has long been
used by aboriginal populations for its putative spiritual and medicinal benefits, but more recently it has become the
basis of religious ceremonies in urban South America and elsewhere. Although the presumed primary chemical
constituents of ayahuasca have been identified, little is known about their basic pharmacology and potentiaI
synergistic effects in the central nervous system. Two major constituents of ayahuasca, harmine and
dimethyltryptamine (DMT), were selected for detailed study in mice using the functional observational battery
(FOB), a standard neurobehavioral test battery, and the acoustic startle response. The data from these studies was
used as reference data for studies involving the interaction of DMT and banisteriopsis extract preparation. In the
FOB, DMT (5-32 mg/kg) altered posture, increased ease of removal, increased gait score, decreased mobility, and
decreased arousal. Harmine (5-32 mg/kg) dose-dependentIy decreased arousal levels, impaired mobility and gait,
increased ease of removal, reactivity to being handIed and gait score, and induced clonic and tonic involuntary
movements. In the acoustic startIe procedure, harmine produced decrease in startIe amplitude but had no effect on
prepulse inhibition, a measure of sensorimotor gating. DMT had no effect in either startle measure. In the FOB a
harmine (5-32 mg/kg)/DMT (32 mg/kg) combination exacerbated the effects of harmine alone. The effects of the
banisteriopsis extract preparation were consistent with the effects of harmine alone. The combination of extract and
DMT (32 mg/kg) increased the effects of the extract alone. In PPI the extract decreased startle amplitudes whereas
the combination increased amplitudes. These data will form the basis for a better understanding of the acute
psychoactive effects of ayahuasca in man, and assist in elucidating the cellular basis for its claimed medicinal
benefits, as well as its potential hazards.
237
GENES ENCODING MARIJUANA RECEPTORS
E. S. Onaivi, P. H. Reggio, and A. Chakrabarti
Dept. of Pharmacology and Psychiatry, Vanderbilt University School of Medicine,
Nashville, TN, and Neurohehavioral Research Institute, Antioch, TN and Kennesaw State
College, Marietta, GA
There has been some controversy about the medicinal use of marijuana. Cannabinoids are the constituents of the
marijuana plant (cannabis sativa). Recent advances include the cloning of the cDNA encoding the rat, human,
mouse and fish CNS (CB1, CB1A) and the peripheral (CB2) cannabinoid receptors (Cnrs ). Putative endogenous
cannabis-like ligands in the brain, including anadamide and an antagonist, SR141716, that hinds the Cnrs have
been identified. We cloned, sequenced, constructed the helical structure and localized the murine CB1 Cnr gene to
chromosome 4. There is extensive nucleotide and protein sequence homology between the mammalian Cnr, CB1
that are distinct from Cnr CB2. The chromosomal location of the human and mouse CB1 genes adds a new marker
to the region of the human 6q genes of mouse-human homology. The Northern blot analysis data using the CB1
cDNA probe indicate that the CB1 gene is not only differentially expressed in the naïve mouse strains but also
following anandamide administration. The neurobehavioralchanges following the administration of anandamide or
9
-THC to the mouse strains may be associated to the differential expression of the brain Cnrs. The identity of the
differentially expressed genes using the differential display polymerase chain reaction (DDPCR) in the brain
following treatment of mice with anandamide remains to be determined. We concluded that it is unlikely that the
CB1 Cnr mediates all the cannabimimetic actions of cannabinoid or after smoking marijuana. An understanding of
the in vivo role of cannabinoids and their receptors may require the careful analysis of targeted gene mutations in
mice.
ACKNOWLEDGMENT:
Supported by NIH/NHLBI-K01-HL03319.
SYNTHESIS AND EVALUATION OF ARACHIDONYLPHOSPHONATES AS CANNABINOID
RECEPTOR LIGANDS
H. H. Seltzman, M. J. Roche, B. F. Thomas, S. R. Fernando*, and R. G. Pertwee*
Research Triangle Institute, Research Triangle Park, NC, USA and *University of Aberdeen,
Foresterhill, Aberdeen, Scotland, UK
Analogs based on the endogenous cannabinoid ligand arachidonylethanotamide (anandamide) are a new class of
compounds that can serve as probes of the cannabinoid receptors (CB) and the neurochemical system it represents as
well as the enzymes responsible for the synthesis and breakdown of anandamide. Deutsch and coworkers have
shown that methyl arachidonylfluorophosphonate (MAFP) inhibits anandamide amidase/synthase with an IC50 in
the nM range and binds to the CB1 receptor more strongly than anandamide. This binding precludes subsequent
binding of the highly active non-classical cannabinoid CP 55,940. We have found MAFP itself to exhibit no effect
on the twitch response yet it behaves as an irreversible antagonist of cannabinoid-induced inhibition of electricallyevoked contractions of the myenteric plexus-longitudinal muscle preparation of the guinea-pig small intestine (GPI)
at a concentration of 1 µM. While blocking the inhibitory effects of the cannabinoid agonists CP55,940,
WIN55,212-2, delta-9-THC, nabilone and R-(+)-methandamide, the twitch inhibition of nor-morphine and clonidine
and the ability of acetylcholine to induce contractions were not affected, demonstrating a level of cannabinoid
specificity. We have also found that substituting the pentyl terminus of anandamide with the 1,1-dimethylheptyl
(DMH) group enhances binding to the rat brain receptor preparation by two orders of magnitude, suggesting that
combining the DMH-arachidonyl structure with the methyl fiuorophosphonate moiety could result in a high
affinity, cannabinoid selective, irreversible antagonist for the CB1 receptor the current work presents a previously
unpublished synthesis of MAFP and its application towards the synthesis of methyl 1,1-DMHarachidonylfluorophosphonate.
ACKNOWLEDGMENTS:
Supported by Wellcome Trust grant 039538 and NIDA grants DA9158 and
DA10063-02.
238
EFFECTS OF SR141716A ON DIAZEPAM SUBSTITUTION FOR
DISCRIMINATION
9
-THC IN RAT DRUG
J. L. Wiley and B. R. Martin
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA
Diazepam (DZP) produces consistent partial substitution for 9-tertahydrocannabinol (THC) in rats trained to
discriminate this cannabinoid from vehicle. In order to determine whether this effect might be related to DZP action
at cannabinoid receptors, we examined the effects of SR141716A, an antagonist of brain cannabinoid (CB1)
receptors, on DZP substitution for itself or for THC. Rats were trained to discriminate either THC (n=7) or DZP
(n=7) from vehicle in a two-lever drug discrimination procedure for food reinforcement. As in previous studies,
DZP partially substituted for THC. In contrast, THC did not substitute for DZP in any rats. Hence, crossgeneralization of these two drugs was asymmetrical. When tested in combination with DZP, SR141716A did not
block the partial substitution of DZP for THC nor did it antagonize the discriminative stimulus effects of DZP in
DZP-trained rats. These results suggest that the partial overlap in the discriminative stimulus effects of THC and
DZP is not mediated by DZP action at CB1 receptors, However, the fact that DZP produced partial substitution for
THC is consistent with a GAB Aergic component to cannabinoid drug discrimination.
ACKNOWLEDGMENT:
Research supported by NIDA grant DA-03672.
ABSTINENCE SYMPTOMS FOLLOWING ORAL THC ADMINISTRATION IN MEN AND
WOMEN
M. Haney, A. S. Ward, S. D. Comer, R. W. Foltin, and M. W. Fischman
NYS Psychiatric Institute and College of Physicians and Surgeons of Columbia University,
NY, NY
Tolerance and withdrawal after the frequent administration of high doses (210 mg/day) of 9-tetrahydrocannabinol
(THC) have been reported (Jones and Benowitz, 1976), yet little is known about the effects of lower THC doses,
which are more relevant to the effects of chronic marijuana use. In this 20-day residential study, we measured a range
of behaviors (food intake, performance tasks, subjective effects, social interaction) in male and female marijuana
smokers both during THC administration (20, 30 mg qid) and for 4 days after THC administration. Each day, daily
marijuana smokers (4M, 4F) worked on 5 psychomotor tasks during the day (1000 - 1700), and in the evening
engaged in private or social recreational activities (1700 - 2330); visual analog, subjective-effects measures were
completed 10 times/day. Food and beverages were available ad libitum. Placebo THC (qid) was administered on days
2-3, 8-11, and 16-19. THC was administered on days 4-7 (20 mg qid) and on days 12-15 (30 mg qid). Capsules were
given at 1000, 1400,1800, and 2200. THC increased ratings of “High.” “Good Drug Effect,” “Willingness to Take
Dose Again” and “Trouble Sleeping” compared to baseline (days 2-3). THC also increased food intake by 35-45%,
and decreased social interaction compared to baseline; these effects tended to be dose-dependent in men but not in
women. Tolerance developed to the effects of THC on mood but not on food intake or social behavior. Abstinence
from THC increased ratings of “Anxious,” and “Restless,” decreased food intake by 20-30%, and increased social
interaction compared to baseline. Mood changes were most pronounced during abstinence from the higher THC
dose. Thus tolerance and dependence develop following exposure to lower THC doses and less chronic dosing than
have been previously utilized. These data suggest tolerance and dependence to THC may play a role in maintaining
chronic marijuana use.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA03476-11 and the Aaron Diamond Fellowship
Foundation.
239
EFFECT OF A BRIEF MOTIVATIONAL GROUP THERAPY ON READINESS TO CHANGE
SCORES IN SUBSTANCE ABUSERS
N. C. Bernardy, I. Hogan, and R. Sinha
Department of Psychiatry, School of Medicine, Yale University, New Haven, CT
The motivation of a client to change behavior is an important determinant of engagement and retention in substance
abuse treatment. Our goal was to study the readiness for change in alcohol and other drug abusers evaluated for
substance abuse at an outpatient clinic. Clients participated in a 3 session Self Assessment Treatment Group that
gave them a chance to explore their substance use behaviors in an educational and supportive manner while
allowing them to “self assess” their behaviors and desires to change over the 3 week period. 43 clients completed
the SOCRATES, an alcohol and drug specific readiness to change questionnaire, at treatment entry and at the end of
the 3 group sessions. Findings indicated that marijuana abusers, as compared to those clients abusing alcohol,
showed the most significant change across the 3 sessions in their readiness to address substance abuse problems.
Clients did not differ in stages of change scores al treatment entry, but marijuana abusers showed significantly
higher scores on the action and maintenance subscales of the SOCRATES at the end of treatment which reflected
readiness to address their drug use behavior. These findings suggest that a brief motivational and educational selfassessment group can be an effective intervention to engage and retain marijuana abusers in outpatient treatment.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-07238.
TEST-RETEST RELIABILITY OF THE ALCOHOL AND DRUG SECTIONS OF
SCHEDULES FOR CLINICAL ASSESSMENT IN NEUROPSYCHIATRY (SCAN)*
B. Ulug, A. Gögüs, G. Özgen, C. Kilic, A. Ulusphin, A. Sagaduyu, B. Gürsoy, O. Terbas,
C. Easton, E. Meza, D. Mager, and T. Babor
Hacettepe University Department of Pyschiatry, Ankara, Turkey
This report presents the results of a test-retest reliability study of the alcohol and drug sections of the Schedules for
Clinical Assessment in Neuropsychiatry (SCAN), investigating the diagnosis of alcohol and drug dependence and
abuse, disorders via a within-site design. Reliability for the past 12 months, prior to past 12 months, and lifetime
back were evaluated across ICD-10, SMI-III-R and DSM-IV diagnostic at sites located in both Ankara Turkey and
Farmington. Connecticut, USA. The study also tested the diagnostic concordance in a relatively heterogeneous
group of treatment and community subjects in both countries. The subjects were recruited from the general
population, special treatment settings and from general medical settings. A total of 287 subjects were recruited. The
two sites were comparable across most demographic variables and inpatient treatment status. The test-retest
administration of the interview were separated by intervals ranging from 3 to 20 days for the Farmington site with
an average of 7.25, and by intervals ranging from 3 to 10 days for the Ankara site with an average of 5.95 days. In
the study, kappa a measure of agreement corrected for chance was used as a measure of reliability. The results show
that the alcohol and drug sections of SCAN version 1.0 reliably identifies patterns of dysfunctional use, abuse and
dependent for alcohol and other drugs during the past 12 months, prior to past 12 months and the individual’s
lifetime. Although there were some methodological limitations, the present report supports the usefulness of semistructured interviews in attaining diagnoses of abuse and dependence when administered by clinicians from different
mental health disciplines and diverse cultural origins.
ACKNOWLEDGMENT:
Funded by the WHO/NIH Joint project (PI: T.B. Üstün).
240
POSTER SESSION III
ROLE OF OPIOID SYSTEM IN ETHANOL-INDUCED PLACE PREFERENCE UNDER
CONDITIONED FEAR
S. Matsuzawa* ,**, T. Suzuki*, M. Misawa*, and H. Nagase***
*Department of Pharmacology, School of Pharmacy, Hoshi University, **Kyorin
Pharmaceutical Co. Ltd., ***Toray Industries, Inc., Japan
Psychological stress (PS) is considered an important motivating factor in the continued ethanol (ET) intake, and
may be related to the rewarding effect of ET. It has hitherto been suggested that both PS and ET modulate
endogenous opioid system. The present study attempted to establish ET-induced place preference using conditioned
fear stress (CFS) as PS, and to clarify the role of endogenous opioid system in rewarding effect of ET using the
conditioned place preference paradigm. Male Sprague-Dawley rats were subjected to CFS (at 24 hours after electric
foot shock exposure), and then ET (300 mg/kg) or saline was injected i.p. For conditioning, animals were
immediately confined to one compartment after ET injection and to the other compartment after saline injection.
This conditioning session was repeated twice (for 8 days). After the conditioning, test session was Performed on day
9. ET treatment with CFS, but not without CFS, significanlly induced a place preference. In addition, the
development of ET-induced place preference in ET-treated rats that were subjected to another CFS immediately
before the test session was clearly enhanced. Pretreatment with nonselective opioid receptor antagonist naloxone (3
mg/kg, s.c.) or selective delta opioid receptor antagonist NTI (3 mg/kg, s.c.) significantly antagonized the ETinduced place preference. These results indicate that PS may play an important role in the development of rewarding
effect of ET and that the rewarding effect of ET under PS may be partially mediated by endogenous opioid system.
THE EFFECTS OF NALTREXONE NALTRINDOLE AND BETA-FUNALTREXAMINE ON
ALCOHOL CONSUMPTION IN THE RAT
M. F. Stromberg, L. Volpicelli, M. Casale, J. R. Volpicelli, and C. P. O’Brien
University of Pennsylvania, Center For Studies of Addiction, Philadelphia, PA
There is considerable evidence from both preclinicai and clinical investigations suggesting a link between
endogenous opioids and the motivation to consume alcohol. While both naltrexone (ntx), a nonselective opioid
antagonist, and naltrindole (nti), a selective antagonist, have been demonstrated to reduce ethanol consumption.
the contribution of specific opioid receptor subtype remains unclear. These experiments were designed to compare
the effects of ntx, nti and beta-funaltrexamine ( -fna), a µ selective antagonist, on alcohol consumption in
nondeprived Wistar tats provided with daily 1 hour access to a 6% alcohol solution. In Experiment 1, ntx at doses
of 0.1, 0.25, 0.5, 1.0, 3.0 and 10.0 mg/kg significantly reduced alcohol consumption compared to saline control.
At higher doses, e.g. 10.0 mg/kg, ntx antagonizes as well as µ receptors. However, between doses of 0.5 and
10.0 mg/kg the dose response curve for ntx was flat suggesting that ntx may reduce ethanol consumption by
antagonizing only µ receptors. In Experiment 2, nti at doses of 5.0 and 20.0 mg/kg did nor alter ethanol
consumption. In Experimenl 3, a single dose of -fna. 20.0 mg/kg, significantly reduced ethanol consumption for
two days, while a dose of 5.0 mg/kg did not. These data suggest that alcohol consumption may be primarily
modulated by µ receptors. The failure to replicate the reduction in alcohol consumption following administration
of
antagonist may be due to the use of alcohol preferring rats in those experiments compared to the use of
genetically heterogeneous Wistar rats in the present experiments.
241
NALTREXONE DOES NOT BLOCK THE ACUTE BEHAVIORAL EFFECTS OF
PENTOBARBITAL IN HUMANS
C. R. Rush, D. L. Armstrong, J. A. Ali, and P. J. Pazzaglia
University of Mississippi Medical Center, Jackson, MS
Naltrexone, an opioid antagonist is used as an adjunct in the management of alcohol abuse and dependence. The
mechanism by which naltrexone exerts its clinical effect is unknown, but it has been shown to block some of
alcohol’s acute “pleasurable” subject-rated drug effects. The aim of the present study was to determine if this effect
is specific to alcohol, or whether naltrexone also blocks the acute “pleasurabIe” subject-rated drug effects of other
commonly abused sedatives. To accomplish this aim, 8 volunteers (5 females, 3 males) received pentobarbital (0,
150 and 300 mg), alone and in combination with naltrexone (0, 50 and 100 mg). Pentobarbital, a barbiturate
hypnotic, was chosen because it is a commonly abused sedative that produces “pleasurable” subject-rated drug
effects. Subjects received one of 9 possible dose combinations under double-blind conditions during each of 9
experimental sessions. Order of drug administration was mixed, and at least 48 hours separated all sessions.
Subjects ingested naltrexone 60 minutes after pentobarbital. The timing of pentobarbital and naltrexone
administration was arranged to have the peak behavioral effects of pentobarbital occur across peak plasma levels of
naltrexone. Drug effecrs were assessed before drug administration and periodically afterwards for 5 hours using a
battery of subject-rated drug-effect questionnaires and performance measures previously shown to be sensitive to the
acute effects of sedative drugs. Pentobarbital alone (i.e., in combination with placebo naltrexone) produced
prototypical sedative-like subject-rated drug effects (e.g., increased ratings of “Drug Effect”, “Like Drug”. “Good
Effects”, “Drunk”, “High” and Sedation) and impaired performance as a function of dose. Naltrexone alone (i.e., in
combination with placebo pentobarbital) did not affect these measures. Naltrexone generally did not alter the
subject-rated or performance- impairing effects of pentobarbital to a statistically significant degree. These findings
suggest naltrexone’s ability to attenuate “pleasurable” sedative-induced subject-rated drug effects may be specific to
alcohol. Supported by a gram from the Alcoholic Beverage Medical Research Foundation.
EFFECTS OF PIMOZIDE ON SUBJECTIVE RESPONSES TO ETHANOL IN HUMANS
H. de Wit and K. Lucas
Department of Psychiatry, The University of Chicago, Chicago, IL
Evidence from studies with laboratory animals suggests that dopamine is involved in the reinforcing and stimulantlike effects of several drugs of abuse, including low doses of ethanol (Imperato and Di Chiara, 1986). Because
reinforcing effects of drugs are often closely associated with their subjective effects, it might be expected that
dopamine may also be involved in the subjective feelings of euphoria that humans report with drugs of abuse and
alcohol. Surprisingly, few studies have explored the neurochemical mechanisms underlying the euphorigenic
effects of drugs or alcohol in humans. In the present study, 14 normal healthy volunteers consumed a beverage
containing a low dose of ethanol (0.25 g/kg) or placebo, 4 hours after raking a capsule containing the dopamine
antagonist pimozide (4 mg) or placebo. Subjective ratings of drug effects were measured for 4 hours after ethanol
administration. Subjects reported feeling the effects of this low dose of ethanol and reported significant increases in
ratings of drug “liking”. Pimozide administered alone decreased ratings of liking and increased ratings of feeling
“down,” indicating that the dose was centralIy active. However, when the two drugs were given in combination
pimozide did not attenuate the effects of ethanol. These results do not support the idea that dopamine mediates the
euphorigenic effects of a low dose of ethanol in healthy volunteers.
ACKNOWLEDGMENTS:
Supported by DA-02812 and MO1RR00055.
242
EVALUATION OF GENDER EFFECTS ON SCHEDULE-INDUCED ALCOHOL
CONSUMPTION IN CYNOMOLCUS MONKEYS
S. Angeli-Cade, M. A. Kautz, and K. A. Grant
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake
Forest University, Winston-Salem, NC
Schedule-induced pulydipsia (SIP) has been used to induce excessive drinking in laboratory animals and has been
suggested as a possible factor in human excessive alcohol consumption. In an initial investigation of gender
influences on susceptibility to schedule-induced ethanol consumption, several parameters of drinking were studied in
6 cynomolgus monkeys (2 males and 4 females). The monkeys had daily sessions under a fixed-time (FT) 180 s
schedule of food (1 g pellets) presentation with 4% (w/v) ethanol available from a drinking apparatus that contained
an in-line flow meter interfaced to a computer system. Sessions ended after 1.0 g/kg ethanol intakes were reached.
A gender difference was found in mean session volume ingested (males =146±6ml, females =72±3ml), but this
difference was nullified when body weight was factored in the measure. Gender differences were also found in mean
number of drinking bouts (males =16±1, females =14±1) and mean volume ingested per bout which remained
significant when body weight was factored in the measure (males=1.32±0.04 ml/bout/kg, females = 2.03±0.2
ml/bout/kg). There was no ditference in the pattern of drinking during the FT (IOC values: males and females =
-0.24) or the mean length of the session (males and females= 48 min). In addition, 3 monkeys (1 male, 2 females)
were tested under FT values of 120, 180, 240 and 300 s. Number of bouts and volume ingested was bitonic in
relation to schedule, with peak values found under FT 180-240 s. These preliminary results indicate that male and
female cynomolgus monkeys show similar adjunctive behavior with a difference in the microstructure of
consumption and that SIP is useful for inducing equivalent alcohol consumption across genders.
ACKNOWLEDGMENTS:
Supported by RO1AA10254 and T32 AA07565.
CHARACTERISATION OF CHANGES IN MOOD DURING ACUTE AND PROTRACTED
ALCOHOL WITHDRAWAL
J. M. White and R. E. Humeniuk
Dept. Pharmacology, University of Adelaide, South Australia
The alcohol withdrawal syndrome in humans includes mood and psychiatric disturbances, especially anxiety and
depression. Symptoms are reported to be most severe in the first five days following the last drink but have also
been reported to persist for weeks and months following cessation of drinking. Most reports on the intensity ad
time course of these withdrawal symptoms are primarily cross-sectional in nature, employ non-standardised methods
of assessment and have a narrow symptom focus. There is a need to characterise the intensity and duration of these
symptoms since persistent mental health disturbances may result in relapse drinking. This study employed three
standardized questionnaires: the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory (STAT) and the
Profile Of Mood States (POMS). Questionnaires were administered to 25 subjects presenting to an in-patient unit
for treatment of alcohol withdrawal. Subjects experiencing withdrawal received standard clinical treatment.
including monitoring of withdrawal severity using the CIWA-Ar with diazepam dosing when scores were greater
than 10. Questionnaire administration occurred on days 2 and 5 (acute withdrawal phase) and days 14, 42 and 70
(protracted withdrawal phase) following cessation of drinking. Subjects’ scores were compared with questionnaire
norms, and data were analysed using a mixed model analysis of variance. Withdrawal subjects experienced
significant anxiety and depression during the acute phase, which persisted for at least two weeks following the last
drink. Data from days 42 and 70 indicated that some subjects still exprienced anxiety and depression. although
means were not significantly different from normal scores. Fatigue-inertia and confusion-bewilderment were also
most severe during the acute phase, and persisted for at least two weeks following the last drink. Further research
will examine the relationship between withdrawal severity and relapse to alcohol use.
243
EFFECTS OF ALCOHOL ON MOOD, EQUILIBRIUM, AND SIMULATED DRIVING
A. Liguori, J. Robinson, and S. I. Dworkin
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake
Forest University, Winston-Salem, NC
This study compared the effects of alcohol on simple versus complex behavior in 18 adult humans. Subjects
received doses of 0.0, 0.5, and 0.8 g/kg ethanol in a randomized double-blind design. Forty minutes after finishing
drinking, subjects completed a 60-minute battery of tests including 1) a sensory organization test of posturography
(EquiTest), 2) latency to apply brake following appearance of a barrier in a driving simulator (brake reaction time),
3) visual analog subjective effects scales (VAS), 4) the Profile of Mood States (POMS), 5) critical flicker fusion
(CFF), and 6) choice reaction time (CRT). Alcohol reduced composite equilibrium scores in a dose-related fashion
(0.0 g/kg=78, 0.5 g/kg=72, 0.8 g/kg=60; p<.0001). Following the high dose but not the low dose. subjects’
EquiTest vestibular and somatosensory scores were lower and visual preference scores were higher than scores with
the placebo (p <.001). indicating increased reliance on visual information rather than on input from the vestibular or
somatosensory system to maintain balance. Brake reaction time increased with increasing alcohol doses (0.0
g/kg=.59 sec, 0.5 g/kg=.63 sec, 0.8 g/kg=.71 sec; p<.0001). Alcohol increased VAS “dizzy”, “high”, and “drug
effect” ratings in a dose-related fashion. VAS “drowsy” scores increased comparably with both doses. POMS,
CFF, and CRT scores with alcohol did not differ significantly from scores with the placebo beverage. These data
suggest that ethanol doses that neither influence certain mood states nor impair simple psychomotor tasks
nonetheless do impair equilibrium and complex psychomotor tasks (e.g., driving).
ACKNOWLEDGMENT:
Supported by a gift from R. J. Reynolds Tobacco Company.
PROSPECTIVE ASSESSEMENT OF DSM-IV ALCOHOL DISORDERS AMONG 14-17 YR
OLDS IN MUNICH GERMANY
C. B. Nelson and H. U. Wittchen
Max-Planck Institute for Psychiatry, Department of Clinical Psychology and Epidemiology,
Munich, Germany
Background: General population surveys of substance and psychiatric disoders among adults show that alcohol
disorders are among the most prevalent in the community. In addition, these studies indicate the prevalence of
alcohol abuse and dependence is highest among the youngest age groups and that the peak incidence of first onset
occurs in the late teens. Despite these findings, relatively little information is available on the distribution,
determinants and development of DSM-defined alcohol disorders among adolescents. The objective of this work is
to compare follow-up with baseline information to examine patterns of disorder incidence, persistence and remission
in a population of 14-17 year old adolescents. Methods: Baseline cross-sectional interviews assessing DSM-IV
substance disorders were conducted during the spring of 1995 in a random sample of 14-24 year olds from Munich,
Germany. Follow-up interviews were conducted among all 14-17 year olds approximately 20 months later (response
rate=91%, n=1220). Baseline and follow-up assessments were made using a version of the WHO-CIDI modified for
DSM-IV. Results: At baseline, DSM-IV alcohol abuse (men: 15.1%, women: 4.5%) was considerably more
prevalent than dependence (men: 10.0%; women: 2.5%) with few cases among respondents younger than 16 years
of age and peak first onset at 16-17 years of age. Exploratory analysis of retrospectively assessed diagnostic
stability show: a temporal progression to abuse and then dependence, that nearly half of past abuse diagnoses are in
remission, that abuse remission is more common than progression to dependence, and that dependence is highly
persistent, especially among women. Follow-up of the 14-17 year old sub-sample found similar results although
diagnostic remission was more frequent in this young age group. Conclusions: Alcohol disorders are frequent in
adolescents and young adults being characterized by transient abuse and less prevalent but persistent dependence
syndromes. These findings are discussed with regards to the clinical validity of DSM-IV criteria in adolescents and
young adults.
244
A COMPARISON OF A SELF-ADMINISTERED ASI WITH THE STANDARD ASI
INTERVIEW
J. S. Cacciola, A. T. McClellan, A. J. Alterman, and F. D. Mulvaney
Center for the Studies of Addiction - University of Pennsylvania/Philadelphia VA Medical
Center, Philadelphia, PA
The present investigation examined the concurrent validity of a self-administered version of the Addiction Severity
Index (SA-ASI). One hundred and five men (75% black, 25% white; 44 ± 7 years old) were recruited for
participation upon admission to outpatient treatment for opiate dependence (methadone maintenance, n=51) or
alcohol/cocaine dependence (abstinence oriented rehabilitation, n=54) at the Philadelphia VA Medical Center.
Participants completed either a standard ASI interview or SA-ASI, and 1 to 5 days later completed the alternate
version of the ASI. Results indicated that the SA-ASI and standard ASI Composite Scores were significantly and
highly correlated; Medical .41, Employment .95, Alcohol .76, Drug .77, Legal .65, Family/Social .93 Psychiatric
.71. In general, more clearly specified and operationalized behaviors and experiences bad higher levels of agreement
whereas agreement for items more open to subjective interpretation was not as good. This was true for both current
and lifetime information, Much of me information collected during a standard ASI interview can bc validly obtained
in a self-administered formal. Further work is needed to refine items and to determine under what circumstances and
with what populations a SA-ASI can yield valid data.
ACKNOWLEDGMENT:
Supported by NIDA grant P-50-DA-05186.
AGE AT ONSET IN ALCOHOLISM:
SIBLING COMPETITION
INFLUENCE OF GENES ENVIRONMENT AND
E. O. Johnson1, M. B. M. van den Bree2, and R. W. Pickens2
1
Depart. of Psychiatry, Henry Ford Health Sciences Center, Detroit MI and
IRP/ARC, Baltimore MD
2
NIH/NIDA -
Background: Age at onset has been important to understanding disease throughout medicine. Contrasting early
versus late. age at onset has also played a prominent role in the study of alcoholism: early onset indicating a more
genetically influenced case or subtype. However, genetic influence on milestones in me development of alcoholism
has not been examined other than first drink. This study investigated the relative genetic and environmental
influence on age at first intoxication and first alcohol problem. Also examined was the genetic influence shared
between age at onset and alcohol dependence. Methods: The sample consisted of 118 male twin pairs ascertained
through 16 public and private alcohol and drug abuse treatment programs in Minnesota from 1982-88.
Distributions of age at onset for this sample and heritability of alcohol dependence were shown to be comparable to
general population estimates. StructuraI equation modeling was used to identify the types of influence (genetic,
environmentaI, and gene-environment interactions) necessary to explain variation in age at onset and estimate the
level of influence attributable to those factors. Results: Distinct etiologies for age at first intoxication and age at
first problem were found. First intoxication was influenced equally by common and unique environment. First
problem was predominantly additive genetic in origin, although moderate sibling competition was also evidenced.
Contrary to expectations, genetic influence on age at first problem appeared consistent across me range of onset
ages. Also, age at first problem and alcohol dependence shared only a small amount of genetic variance and no
environmental variance. Conclusions: These findings highlight the complex etiology of alcoholism. Not only
is the disorder likely to be multifactorial in origin, hut it may be that distinct sets of genes and environmental
factors influence different aspects of alcoholism’s development.
245
SIBLING RISK FOR SUBSTANCE USE AND DEPENDENCE: COMPARISON OF ILLICIT
DRUGS, TOBACCO AND ALCOHOL
A. E. Gupman1, E. O. Johnson2, and R. W. Pickens1
1
National Institute on Drug Abuse, Baltimore, MD and
Detroit, MI
2
Henry Ford Health Sciences Center,
Sibling risk for drug use and dependence was estimated in a population based sample of multiple household
respondents to the 1991, 1992, and 1993 National Household Survey on Drug Abuse. From a total of 87.915
respondents, 835 pairs of individuals from the same household were identified as being likely sibs (same sex, age
difference < 10 years, both indicating a sib living in the household both reporting living with same biological
parent). The sample included 438 male and 397 female pairs: mean age older sib 21.1 years, younger sib 16.4
years. Risk to younger sib was estimated from older sib drug status after controlling for group differences in race,
sex, and younger sib age. Comparisons were made for ever used, problem use, and DSM-IIIR dependence on
alcohol, tobacco (cigarettes), marijuana, and all illicit drugs except marijuana. Significant sibling influences were
seen with all drugs (p<.0006). Younger sib was more likely to be affected when the older sib used drugs, had drug
problems, or was drug dependent than when the older sib did not. Sibling risk was lowest for tobacco use (Odds
Ratio (OR)=3.9) and any illicit drug use (OR = 3.2), and higher for alcohol use (OR=4.4) and marijuana use
(OR=8.1). Sibling risk for tobacco and alcohol showed little increase as severity of problem increased from use to
problem use to dependence (for tobacco, 3.9, 2.5, and 3.4; and alcohol, 4.4, 3.1, and 4.4, respectively). However,
sibling risk for marijuana and any illicit drug except marijuana increased with increases in problem severity (far
marijuana, 8.1, 9.6 and 112.4; for any illicit drug except marijuana, 3.2, 20.6, and dependence not calculated due to
small N, respectively). The results suggest the sibling risk of drug use may be greater for illicit man for licit drugs
and increase more with severity of drug problem.
INTERGENERATIONAL TRANSMISSION OF DRUG USE PATTERNS AND NORMS
H. R. While
Center of Alcohol Studies, Rutgers University, Piscataway, NJ
The purpose of this study was to assess the association between parents’ licit and illicit drug use patterns and
attitudes and their offspring’s use both in adolescence (Time 1) and in adulthood (Time 4). Parental behaviors and
attitudes were assessed from parent self-reports as well as offspring perceptions. We used data from the Rutgers
Health and Human Development Project, a four-wave, prospective study of substance use behaviors in a
nontreatment sample (N=1201). Correlational analyses indicated that offspring perceptions of mothers’ and fathers’
use of alcohol and, especially, cigarettes were consistent with parent self-reports. Thus. these results suggest that
adolescent perceptions of their parents use can be used with relative confidence in lieu of parent self-reports.
Regression analyses indicated that higher levels of parent drinking, cigarette smoking, and marijuana use predicted
higher levels of offspring use in adolescence and adulthood and that parent drug use as compared to attitudes was a
better predictor of offspring use in adolescence and especially in adulthood. Overall, parental modeling of licit and
illicit drug use behaviors did not strongly influence offsprings’ use. Hence, we will need to consider other aspects
of the parent-child relationship in future research on the intergenerational transmission of drug use.
ACKNOWLEDGMENT:
Supported by NIDA grant DA/AA-03395.
246
DIRECT AND INDIRECT EFFECTS OF TEMPERAMENT ON SUBSTANCE USE IN
ADOLESCENT CHILDREN OF DRUG ABUSERS
A. M. Seracini, M. M. Weissman, T. A. Wills*, E. V. Nunes, G. McAvay, and R. B.
Goldstein
Columbia University College of Physicians and Surgeons and *Albert Einstein College of
Medicine, New York, NY
Children of drug abusers (CDA’s) are at risk for substance abuse. This study examined the relationships among
temperament, coping behavior and early substance use in 99 adolescent children of opiate dependent parents. Based
on prior research, it was hypothesized that 1) difficult affective temperament, and the temperament dimensions of
high activity, low positive mood and rigidity (measured by the DOTS-R) would be associated with more frequent
substance use in adolescent children of opiate addicts; 2) that difficult affective temperament, high activity, low
positive mood and rigidity would be associated with maladaptive coping styles (avoidant coping, aggressive coping,
and helplessness/ behavioral disengagement) in CDAs; and 3) that maladaptive coping would mediate the
relationship between temperament and substance use. Data based on self-report, were analyzed using simple and
multiple regression. As predicted, the temperament dimension of high activity was significantly related to
anger/aggression coping and overall avoidant coping, as well as to alcohol use. Rigidity was related to overall
avoidant coping, alcohol use and overall substance use (cigarettes, alcohol and marijuana). Anger coping and
overall avoidant coping were related to overall substance use. The findings provide evidence that anger coping
mediates the relationship between high activity and overall substance use in this population.
ACKNOWLEDGMENTS: Dr. Seracini is an Aaron Diamond Fellow; this research was supported by NIDA
RO1-DA07201 and the Aaron Diamond Foundation.
EFFECTS OF DRUG ABUSE ON THE FAMILY: FAMILY MEMBERS, THE PROBLEMS,
AND TREATMENT OUTCOMES
K. C. Kirby, D. S. Fesringer, K. Garvey, M. Firely, A. Follis, D. B. Marlowe, R. J. Lamb,
and M. Y. Iguchi
Allegheny University of the Health Sciences, Philadelphia, PA
Little research has examined the effects of drug abuse on the family and significant others (FSOs) of drug users.
We recruited 52 FSOs through an advertisement offering help for people worried about the drug use of a family
member or close friend. All subjects completed two social adjustment scales (SAS); one for themselves and one for
the drug abuser. They also completed a Significant Others Needs Survey (SONS) which identified problems
experienced due to the drug abuser. Thirty of these individuals also met inclusion criteria for an intervention phase
of the study. (They had regular contact with a drug user who was not in treatment.) These subjects were randomly
assigned to either a unilateral behavioral or 12-step intervention. They additionally completed a Profile of Mood
States (POMS) at intake, and repeated all measures at 10 weeks after treatment intake. We found that most FSOs
report problems with money, the relationship with the drug user, sociaI/emotional issues, and health. Physical
abuse was reported in 33% of the cases. FSOs report social adjustment that is significantly different from a
community sample in some areas, with partners of drug abusers appearing more affected than parents, and drug
abusers themselves with the poorest adjustment The behavioral intervention resulted in significantly better
treatment attendance and completion by the FSOs and in more drug abusers entering treatment. Significant
improvements in mood and social functioning were seen for both groups at follow-up. Reductions in the number
of problems reported on the SONS at follow-up was also noted by both intervention groups. Data from this small
sample suggest that FSOs have significant problems due to involvement with a drug user and that they can benefit
from unilateral interventions.
ACKNOWLEDGMENT: Supported by NIDA grant DA-08907.
241
THE IMPACT OF A SUBSTANCE ABUSE PREVENTION PROGRAM ON PARENTAL
SELF-ESTEEM, COPING, CHILDREARING SKILLS AND SATISFACTION
U. J. O. Bailey
Center for Drug Abuse Research and Dept. Of Human Development and Psychoeducational
Studies, Howard University, Washington, DC
Research has consistently shown certain parental attitudes and behaviors increase risk of child drug abuse while
other behaviors tend to inhibit the involvement in drugs. However, there have been limited prevention programs
aimed at parents of preschool school children. The data presented are from an evaluation of a patent-focused
substance abuse prevention program for Head Start (preschool parents). Pre and post test data were collected on 480
comparison and experimental group parents. Locus of control, self-esteem and parenting skills were significantly
associated with drug use of parents (p<.05). Results revealed significant treatment effects for coping skills (p<.05).
There were no significant treatment effects for, locus of control, opinions about drug. parenting satisfaction, and
parenting skiffs. These findings have implications for targeting prevention efforts toward empowerment and selfefficacy rather than on specific behaviors such as childrearing and attitudes towards drugs.
USE OF INHALANT DRUGS BY 12-17 YEAR OLDS: DATA FROM THE NATIONAL
HOUSEHOLD SURVEY ON DRUG ABUSE
J. Delva, Y. D. Neumark, and J. C. Anthony
Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins
University, Baltimore, MD
Estimated risk of starting to use inhalant drugs has jumped sharply in recent years for 12-17 year old American
youths, with a more modest upswing for 18-25 year olds. Shedding new light on these recent trends, our paper
offers evidence from analyses of epidemiological data collected for the 1990-1995 National Household Surveys on
Drug Abuse (NHSDA). Methods: Each year of operation, NHSDA draws a large probability sample of youths and
adults (e.g., n > 2000 12-17 year olds). Participants are assessed via confidential self-report interviews and
questionnaires. Variance estimation and significance testing accounted for sampling weights and complex sampling
designs. Results: Our estimation of age-specific risk for inhalant drug use shows that the recent acceleration is
not randomly distributed in the population; it differs for sub-types of inhalant drugs. Risk of inhalants use is just as
large for 13 yr olds as for 17 yr olds. There is a recent decrease in inhalants use among “Blacks,” but there is no
consistent male-female difference. Nearly half of recent inhalant users had used inhalants for at least two years;
among inhalants users, multiple occasions of use and use of multiple inhalants are common. Discussion:
Inhalant drug use, often is dismissed as a transitory behavior with trivial public health significance. Recent
epidemiological data challenge this perspective, and invite more detailed investigations.
ACKNOWLEDGMENTS:
Supported by NIDA grants T32DA07292 and DA09592
248
ACCULTURATION, SUBSTANCE USE AND MEXICAN-AMERICAN YOUTH
P. Issari and R. H. Coombs
Drug Abuse Research Center, University of California, Los Angeles, CA and School of
Medicine, University of California, Los Angeles, CA
Mexican-Americans comprise one of the largest, youngest and fastest growing groups in the U.S., with large
numbers of relatively recent immigrants. Because of these circumstances, it is important to examine the
relationship between acculturation and substance use patterns. Acculturation and substance use among MexicanAmerican children and adolescents was assessed for 231 Mexican-American youths of ages 9 to 17 years.
Acculturation to the predominantly European-American majority in the U.S. was conceptualized as a function of
the primary language spoken at home. 1) parent(s) who speak Spanish only; 2) at least one patent who is
bilingual; and 3) parent(s) who speak English only. Because this study investigated illegal behaviors, it was felt
that the best information could be obtained by seeking youth at high risk for substance use at places less identified
with the “official” world, e.g. schools. Ethnographic methods were thus used to recruit subjects off the streets
primarily at youth centers, in contiguous communities of Los Angeles. Consenting youths were interviewed using
standardized, structured interview protocols. Patterns of use were examined for cigarettes, alcohol, marijuana/hashish
and other drugs. Findings indicated no significant differences between groups by level of acculturation (p: chisquare tests). Relatively few of the youths reported smoking cigarettes, and 38.1% reported drinking the past
month. Use of illicit substances was not common among this youth, and marijuana/hashish was the drug of choice
(91.2%) among “users”. Degree of acculturation seemed to bear influence on how often, when and where youth
used substances. The present findings do not support U.S. public stereotypes that less acculturated youth are at
higher risk for substance use.
STAGES OF DRUG USE AMONG AMERICAN INDIAN ADOLESCENTS
D. K. Novins, M. Plunkett, and J. Reals
National Center for American Indian and Alaska Native Mental Health Research, University
of Colorado School of Medicine, Denver, CO
Objective: To determine if the predominant pattern of the progression of substance use among a large sample of
American Indian (AI) adolescents matches the pattern identified by Kandel and colleagues among non-Indian
adolescents [i.e., 1) alcohol; 2) marijuana; 3) other drugs, and 4) cocaine]. Method: Data came from surveys
completed by 1.194 Al high school students. Pairwise comparisons of age of first use for alcohol, marijuana,
inhalants, cocaine, and other illicit drugs were examined. Loglinear modeling was used to describe the sequence of
substance use beyond the pairwise comparisons. Results: Only 35% of these AI youth who used both alcohol and
marijuana reported using alcohol first; 58% tit the previously described progression of substance use. An alternative
model, which fit 92.7% of these Al youth, allowed for the initiation with alcohol, marijuana, or inhalants and
movement from the use of one of these substances directly to the use of other drugs. Conclusions: The early
stages of substance use for these AI youth differ from those described by Kandel and colleagues. The previously
described stages of substance use are not a universal phenomenon, and may show further variation across other
cultural groups.
ACKNOWLEDGMENTS:
Supported by NIDA RO1-DA10039, NIAAA RO1-AA08474, NIMH RO1MH42473 and K20-MH01253.
249
SUBSTANCE ABUSE AND VIOLENCE AMONG ADOLESCENTS LIVING IN A RURAL
ENVIRONMENT
J. M. Beal, D. J. Geyen, S. Heishman, and E. Singleton
Prairie View A&M University,
Center, and Morgan State
Sam Houston State University, NIDA Addiction Research
Substance abuse and violence among America’s youth has emerged as a significant problem, for which no effect
prevention has been developed. This study examined the relationship between substance abuse, violent behavior,
locus of control, and depression. The sample size consisted of 150 adolescents attending a rural high school in
Southeast Texas. Four instruments were administered, the Reynolds Adolescent Depression Scale, NowickiStrickland Locus of Control Instrument, Coopersmith Self-Esteem Instrument, and a questionnaire developed by the
researchers. Analyzes was performed separately for each racial subgroup. Preliminary findings of the subjects self
report usage of alcohol. marijuana, and other illegal drugs indicate a significant correlation to their engagement in
violent or delinquent behavior. Results also indicated a high correlation between depression and violent behavior. A
total of 90% of the respondents scared high on external locus of control. Multiple regression analysis indicated a
difference among the ethnic groups.
LONGITUDINAL TRAJECTORIES OF DRUG USE AND DEVIANT BEHAVIOR AMONG
ADOLESCENTS AND YOUNG ADULTS
V. Johnson and R. J. Pandina
Rutgers University Center of Alcohol Studies, Piscataway, NJ
This study tested the hypothesis that longitudinal trajectories of deviant behavior are differentially associated with
longitudinal trajectories of alcohol or other drug use problems throughout adolescence and young adulthood. Data
were obtained from a random, non-clinical, sample of 1200 subjects who were originally tested in 1979-81 at the
ages of 12, 15 or 18. Subjects returned 3, 6 and 13 years later to provide longitudinal information up to the age of
31. Trajectories of both deviant behavior and drug use problems were constructed. Results of analyses conducted by
age and gender found that subjects who either reported no previous history or limited deviant behavior exhibited few
substance use related problems. In addition, 22% of the habitual alcohol abusers and 46% of the habitual marijuana
abusers were chronic delinquents. Late onset of problem marijuana use was found to be highly associated with both
late onset and chronic deviant behavior, while late onset alcohol abusers tended to exhibit lower levels of delinquent
behavior. At T4, DSM-IV categories of antisocial behavior were examined. Chronic marijuana and alcohol abusing
males of all ages out paced chronic alcohol-only abusing males (and all females) in aggressive and reckless behavior
but 31 year old alcohol abusing males were highest in failed obligations, lying, deceit and lack of remorse. Other
DSM-IV categories varied by age cohort and gender. Results suggest that in this sample of middle and working class
subjects, chronic alcohol abuse is much less associated with chronic levels of deviant behavior than is the persistent
problem use of marijuana and alcohol combined, especially among males, aged 25-28.
ACKNOWLEDGMENTS:
Supported by NIDA grant 03395 and NIAAA grant 05823
250
ONE-YEAR OUTCOME OF ADOLESCENT GIRLS REFERRED FOR CONDUCT DISORDER
AND SUBSTANCE ABUSE/DEPENDENCE
E. A. Whitmore, S. K. Mikulich, K. M. Ehlers, and T. J. Crowley
Addiction Research and Treatment Services, University of Colorado Health Sciences Center,
Denver, CO
Do psychiatric disorders. delinquency, and substance use improve in adolescent females who were previously referred
to day treatment for their comorbid conduct and substance use disorders? What variables are associated with
outcome? Methods: We re-evaluated 46 conduct-disordered (CD), substance-using adolescent females an average
of one year after discharge (range 6-21 months) using the same structured assessment used at intake. Treatment
length averaged 16 weeks (0-57 weeks). Hypothesis: At follow-up, these females will improve their: (1) CD,
(2) psychiatric comorbidity. (3) substance use. Results: Follow-up assessments revealed significant
improvement in (1) criminality and CD, and (2) attention-deficit hyperactivity disorder (ADHD). However,
substance involvement or depression did not improve, regardless of success in or length of treatment. ADHD and
depression were significantly related to drug and other comorbidity outcome at follow-up, but CD, self-concept,
age, or employment were not related to drug or comorbidity outcomes. Conclusions: Although substance use
tends to worsen over time and depression does not change, females’ delinquency and ADHD symptoms appear to
improve at follow-up. ADHD, depression, IQ, and poor peer relationships may be important variables related to
outcome in females.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-06941 and DA-09842.
ADHD AND DEPRESSION IN SUBSTANCE USING DELINQUENTS: RELATIONSHIP TO
NICOTINE DEPENDENCE
S. K. Mikulich, P. D. Riggs, E. A. Whitmore, L. L. Thompson, and T. J. Crowley
University of Colorado Health Sciences Center, Addiction Research and Treatment Service
Denver, Colorado
Major Depression (MDD) and attention deficit hyperactivity disorder (ADHD) are prevalent in adolescents with
conduct disorder (CD) and substance use disorders (SUD). ADHD and CD may be associated with cigarette
smoking, which is generally thought to be an early stage in the developmental sequence leading to further SUD.
MDD is also associated with more smoking in adolescents and adults. Hypotheses: Onset of smoking and
severity of tobacco dependence will correlate with (1) MDD and ADHD severity and (2) the combination of CD,
MDD, ADHD, with onset of smoking or tobacco dependence will jointly explain other SUD, but each variable’s
differential importance may vary by gender. Methods: Structured interviews provided diagnostic and severity
information on 285 male and 82 female adolescents (ages 13-19) referred to treatment for comorbid CD and SUD.
Results: (1) CD, ADHD, and MDD severity correlated with more tobacco dependence as well as more severe
non-tobacco SUD in males and females; ADHD and CD correlated with younger smoking in males only. In
multiple regressions adjusting for age, severity of ADHD, CD, MDD, and tobacco dependence jointly significantly
associated with more non-tobacco SUD (R=.33) in males, whereas only severity of tobacco dependence and
depression significantly associated with other SUD in females (R2= .20). For males ADHD, CD, and MDD in
combination with younger smoking also significantly associated with other SUD (R2=.27). Conclusions: In
these CD/SUD adolescents, tobacco dependence appears to correlate with ADHD, MDD, CD, and other SUD; for
males only, younger onset of smoking demonstrates the same association with other comorbidity and non-tobacco
SUD. Clinical implications are discussed.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA06941, DA09842, and DA00271.
251
AN OPEN TRIAL OF BUPROPION FOR ADHD IN ADOLESCENTS WITH CONDUCT
DISORDER AND SUBSTANCE USE DISORDER
S. L. Leon, P. D. Riggs, L. M. Coffman, and S. K. Mikulich
Department of Psychiatry; Addiction, Research and Treatment Services and University of
Colorado School of Medicine, Denver, CO
Adolescents with conduct disorder (CD) and substance use disorder (SUD) have higher rates of comorbid attention
deficit hyperactivity disorder (ADHD) than those without CD and SDD. Comorbid ADHD may contribute to more
severe SUD. Treatment of ADHD may enhance effective treatment of substance abuse and behavior problems, yet
there are few data regarding pharmacologic treatment of ADHD in this population. Pilot data are presented from an
ongoing study on 7 adolescent boys in a residential treatment program focusing on substance and behavioral
treatments. All bad diagnoses of CD, SUD, and ADHD. Patients were titrated to a maximum dose of bupropion,
100 mgs TID. Conners’ Hyperactivity Index (HI) and Daydream-Attention (DA) scores, along with Clinical Global
Ipression (CGI) severity of illness scores were obtained at baseline and at the 5 week post assessment. Mean
Conners’ HI scores declined from 76.3 to 60.7 (p<.03, Wilcoxon Signed-Ranks Test) (20% decline). Mean DA
scores declined from 59.7 to 52.1 (p<.02, Wilcoxon Signed-Ranks Test) (13% decline). The CGI severity of
illness declined from 4.9 to 2.9 (p<.02, Wilcoxon Signed-Ranks Test) (41% decline). These preliminary data
suggest that bupropion may be a useful treatment for ADHD in adolescents with CD and SUD, calling for a
controlled trial of bupropion in such youths.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 00271
MEASURING TREATMENT PROCESS: GROUP PSYCHOTHERAPIES FOR ADOLESCENT
SUBSTANCE ABUSERS
Y. Kaminer, C. Blitz, J. A. Burleson, R. M. Kadden, and B. J. Rounsaville*
Alcohol Research Center, University of Connecticut Health Center, Farmington, CT and
*Division of Substance Abuse, Yale University School of Medicine, New Haven, CT
The group Session Rating Scale (GSRS) a group therapy process measure was studied to determine 1) its
appropriateness for adolescents, 2) its inter-rater reliability, 3) its internal consistency, and 4) its ability to
discriminate the active ingredients of cognitive-behavioral therapy (CBT) from interactional therapy (IT). Trained
raters independently assessed ten videotaped sessions of group psychotherapy employing the two modalities
involving 32 adolescents diagnosed with substance use disorders in an outpatient setting. Interrater reliabilities
were moderate to high, with those for CBT being higher than those for IT. Internal consistency of CBT items was
moderate, while those of IT were moderately high. Discriminability between the two treatment modalities was
high. The frequency of active ingredients was therapy-specific: high for the relevant and low for the non-relevant
therapeutic modality items. The GSRS was found to be effective in the measurement of treatment process for
adolescents with substance use disorders. It may serve as a useful tool for the training of therapists in providing
manual guided CBT and IT group therapies in clinical and research settings.
ACKNOWLEDGMENTS:
Supported by NIDA grants P50 DA-09241-02 and DA00262-01.
252
A COMPREHENSIVE TREATMENT MODEL FOR COURT ASSIGNED, ADJUDICATED
ADOLESCENT DRUG ABUSERS
J. J. Platt, D. Marlowe, J. Reiss, M. Widman, and V. Lidz
Institute for Addictive Disorders, Allegheny University of the Health Sciences, Philadelphla, PA
We have developed the Comprehensive Treatment model as one condition in a random assignment experimental
evaluation of interventions for drug abusing adolescents adjudicated by the Family Court of Philadelphia and placed
on probation. The model is designed to bring together a series of interventions that have been demonstrated by
previous research to contribute effectively to improved outcomes in substance abuse treatment. Comprehensive
Treatment includes 3 months of intensive day treatment followed by 6 months of after-school outpatient treatment.
Day treatment includes individual cognitive-behavioral therapy, pragmatically focused family therapy, intensive case
management, group training in interpersonal problem-solving skills, daily community meetings, and 3 hours daily
of school in a classroom of 9 or fewer students. In outpatient treatment, clients continue to receive the individual
therapy, family therapy, and case management. The interpersonal skills training is focused on relapse prevention.
Self-Help groups are instituted, and a community service project is scheduled as a culminating experience. The
Comprehensive Treatment design is grounded in the theoretical expectation that each intervention component will
prove effective to a limited degree, but that a number of intervention components should be addictive in efficacy. In
practice. however, the components must be delivered in a carefully coordinated manner to prevent their interfering
with one another. For example, family therapy and individual therapy or case management and individual therapy
may complement and strengthen one another or may conflict with one another and weaken intervention. The
Comprehensive Treatment model includes frequent team meetings to enable staff to coordinate the components of
treatment and manage transitions from day treatment to outpatient treatment smoothly.
ACKNOWLEDGMENT:
94593-V).
Supported by a contract with the Office of National Drug Control Policy (TV-
RELAPSE PREVENTION GROUP THERAPY FOR PATIENTS WITH COEXISTING
SUBSTANCE USE DISORDER AND BIPOLAR DISORDER
R. D. Weiss*, L. M. Najavits*, S. F. Greenfield*, J. Soto, and D. Wyner
Alcohol and Drug Abuse Program, McLean Hospital, Belmont, MA and *Department of
Psychiatry, Harvard Medical School, Boston, MA
Although bipolar disorder is the Axis I psychiatric illness that places individuals at greatest risk for coexisting
substance use disorder, there has been litlle research on the treatment of this population of dually diagnosed
patients. As part of a NIDA Stage 1 Behavioral Therapies Development project, we have therefore been developing
an integrated relapse prevention group therapy for this patient population. Patients with current bipolar disorder and
substance use disorder were eligible for the project, consisting of a 12-week long therapy group. Each hour-long
group consisted of a check-in period, followed by discussion of a topic that was relevant to both disorders (e.g.,
denial vs. acceptance of one’s illness, dealing with family members, getting a good nights sleep). Outcome
measures included substance use, medication adherence, and psychiatric symptoms. Patients were compared with a
cohort of patients with the same diagnostic profile who received “treatment as usual.” i.e., the therapeutic regimen
prescribed by their treatment team, but without the group therapy. The group therapy was an “add-on” treatment,
not a “stand-alone” treatment. Preliminary results indicate promise for the group therapy, particularly in the area of
drug use and medication adherence.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA09400, KO2 DA00326, and DA08631.
253
COMPARING TREATMENTS FOR DUAL DIAGNOSIS
P. Penn, R. Duran, L. Winningham, and S. McDovit
La Frontera Center, Inc., Tucson, AZ
This research evaluated the effectiveness of two treatment models adapted for adults with a dual diagnosis: 12-Step
and Rational Emotive Behavioral Therapy. The aims of the proposed research are to determine (1) to what extent
these two treatment approaches are effective with this challenging population, and (2) whether subject
characteristics will contribute to differential effectiveness of the two approaches. Subjects are randomly assigned to
one of the two treatment modalities. These intensive day treatment programs created for the study meet five days a
week, five hours a day, for six months. Number and types of groups are equivalent for the two programs. Thus far,
data collection is in process for 105 clients. Preliminary results reveal the following subject characteristics: a) over
1/3 have a chronic medical problem, b) half are socially isolated, c) 113 are on probation, d) 96% have used
substances an average of 10 years, e) 3/4 were rated as having moderate to extreme need for alcohol or drug
treatment, and f) need for psychological counseling was rated moderate to extreme for all clients. The most frequent
psychiatric disorder at intake is schizoaffective disorder followed by major depression and paranoid scizophrenia.
However, proportionately more clients with paranoid schizophrenia graduate; clients with primary mood or thought
disorder are most likely to graduate. No one with a primary personality disorder has yet graduated.
ACKNOWLEDGMENT:
Supported by NIDA grant RO1 DA08537 - 004.
COMPARISON OF OPIOID ABUSERS WITH INDEPENDENT VERSUS SUBSTANCEINDUCED MAJOR DEPRESSION
K. B. Staller, R. K. Brooner, V. L. King, M. Kidorf and J. S. Wertz
Johns Hopkins University School of Medicine, Baltimore, MD
Depressive disorder is one of the more common psychiatric syndromes found among opioid abusers. A substantial
proportion of the cases appear to be substance-induced conditions. This study compares the demographic and
clinical characteristics and treatment outcome of 82 opioid abusers with a lifetime diagnosis of major depression.
Patients were newly enrolled in opioid substitution therapy. Cases of major depression were first rated as either
substance-induced (SI) or independent (LD) forms. Diagnoses were made using the Structured Clinical Interview for
DSM-HI-R administered 3 to 4 weeks after admission. Major depression subgroups were compared on demographic
and clinical characteristics and on several measures of treatment outcome. Six month treatment outcome measures
include the ASI (baseline, months 3 and 6), random mine toxicology, and treatment retention. More patients were
classified as having SI versus ID major depression (77% vs. 23%, p<.001), and the ID group contained a greater
percentage of females (89% vs. 62%, p=0.02). The ID group also had a higher lifetime rate of anxiety disorder than
the SI group (37% vs. 13%, respectively, odds ratio 0.345 (0.144-0.827)). Treatment retention over six months
was greater in the ID versus SI group (95% vs. 76%, p=0.017). There were no significant differences between the
two groups’ overall rates of continued drug use during treatment, as determined by self-report and urine toxicology.
These data suggest potentially important differences in characteristics and treatment retention, as well as some
notable similarities in the characteristics and early treatment response among opioid abusers with lifetime
substance-induced versus independent forms of major depression.
ACKNOWLEDGMENT:
Supported by NIDA grant P50 DA 05273.
254
VENLAFAXINE IN THE TREATMENT OF A POPULATION WITH MAJOR DEPRESSION
AND COCAINE DEPENDENCE
D. M. McDowell, F. R. Levin, A. Seracini, and E. V. Nunes
New York State Psychiatric Institute, Columbia College of Physicians and Surgeons,
Department of Psychiatry, Division on Substance Abuse
The link between depression and cocaine abuse is complex and has not yet been fully elucidated. We studied 13
patients who have both cocaine dependence and major depression. All patients were part of another larger doubleblind trial using desipramine and had either not responded, or could not tolerate the side effects to desipramine.
Thirteen patients were enrolled, 10 men and 3 women. The mean age was 37.5 ±7.3, all patients had a Hamilton
Depression rating greater than 14 at baseline, and all patients had used at least $20 worth of cocaine per week in the
four weeks before beginning the study. All patients received weekly relapse prevention therapy. Two patients
dropped out one because of a side effect after a single dose, and one who despite significant improvement in his
depression, elected to enter in patient treatment because of continued cocaine use. The remaining 11 patients had a
significant reduction in mood symptoms with treatment. Hamilton score at baseline was 18 ± 3, Hamilton Score at
week 6 was reduced to 1.6 ±1.4. Nine of 11 bad this response in the first week of treatment. Five patients
achieved total abstinence, and the. rest had a greater than 75% reduction in cocaine use by self report as compared to
baseline. The Clinical Global Improvement (CGI) scores were significantly improved at week 3, and this response
was maintained through the remainder of the study. The median effective dose of venlafaxine for depression
response was 150mg per day, and no serious side effects were reported. These results indicate that venlafaxine may
be a safe, well tolerated, rapidly acting, and effective treatment for patients with depression and cocaine dependence
EFFECT OF IBOGAINE ON ETHANOL (ETOH)
RESPONDING IN MALE WISTAR RATS
INTAKE A1ND MOTIVATED
D. M. Tomkins, M. Tampakeras, and M. Lefebvre
Biobehavioural Research Department, Addiction Research Foundation, Toronto, Ontario,
Canada
Ibogaine has been shown to reduce morphine, heroin and cocaine self-administration in rats. To determine the effect
of ibogaine on ETCH intake, male Wistar rats (n=8) trained on an FR4 schedule of ETOH reinforcement received
injections of ibogaine (10, 20 and 40 mg/kg ip) 30 mins prior to the test session. Ibogaine produced a decrease in
the number of ETOH reinforcers obtained (F(7.21)=4.48, p=0.014) and response rate (F(7,19)=0.69, p=0.003),
while increasing the latency to obtain the first reinforcer (F(7,21)=4.35, p=0.016). An increase in ETOH motivated
responding on the day following ibogaine treatment (F(7,21)=3.56, p=0.032) was noted. In 8 rats trained on an FR4
schedule of reinforcement for a 0.9% saline solution, a comparable profile of responding to that seen in the ETOH
reinforced rats was obtained, and this was similarly affected by ibogaine i.e. decreased number of reinforcers obtained
(F(7,21)=15.1, p=0.001) and response rate (F(7.19)=26.9, p=0.001), and increased latency to obtain the first
reinforcer (F(7,21)=8.0, p=0.001). However, there was no effect on saline responding on the day following ibogaine
treatment (F(7,21)=0.5, NS). These results demonstrate a pronounced ability of ibogaine to suppress ETOH selfadministration. However, as similar effects were observed in saline reinforced tats, the effects of ibogaine on ETOH
consumption may not be wholly related to modification of reinforcement processes, but may reflect a secondary
effect due to motoric impairments.
255
SKILLS TRAINING FOR SUBSTANCE ABUSING SCHIZOPHRENIC PATIENTS
A. Shancr, L. J. Roberts, T. A. Eckman, and J. Wilkins
West Los Angeles VA Medical Center and the Department of Psychiatry, UCLA School of
Medicine
Mast schizophrenic substance abusers either do not tolerate or are not helped by standard treatments for substance
abuse. We adapted cognitive-behavioral drug relapse prevention strategies originally developed for non-mentally ill
substance abusers by using a skills training method originally developed to teach social and independent living
shills to schizophrenics. The intervention consists of three components: 1) Basic Training (eight psychoeducational sessions); 2) Skills Training (24 sessions to teach nine relapse prevention skills) and 3) practice
Sessions (32 sessions paired with the other two kinds of groups during which patients apply newly learned
knowledge and skills to real-life situations). Thirty-four patients with DSM-IV schizophrenia or schizoaffective
disorder and co-occurring substance dependence completed a feasibility study. On a test of drug relapse prevention
knowledge and shills (assessed through role-play), patients scored poorly before the intervention (X=40.9,
sd=11.78), but made large and significant improvements by treatment completion (X=102.0, sd=12.63;
F(33)=601.14, p<.0001). This improvement was maintained at three-month follow-up (X=99.6, sd=11.11). Days
using cocaine, alcohol and marijuana in the prior month fell significantly and remained low at 3 month follow-up.
ACKNOWLEDGMENT:
Supported by NIDA grant R01 DA09436 NH49.
SUBSTANCE USE, PTSD, AND ANGER MANAGEMENT TREATMENT
H. W. Clark, P. M. Reilly, M. S. Shopshire, and K. L. Sees
Department of Veterans Affairs Medical Center, San Francisco, University of California, San
Francisco
High levels of anger are associated with posttraumatic stress disorder (PTSD). Reilly et al. (1995) reported that
PTSD was associated with higher levels of anger in a sample of alcohol and drug users. Despite these higher levels
of anger in patients with PTSD, reductions in anger across a 12-week cognitive-behavioral anger management
treatment (AMT) were comparable to the reduction achieved in a group of drug and alcohol patients without PTSD.
We are now examine the extent reductions in anger are correlated with abstinence from drugs and alcohol. A sample
of 23 patients with PTSD were administered an AMT; patients bad a diagnosis of alcohol dependence and/or cocaine
dependence. Levels of trait-anger and anger-expression were measured at baseline and at weeks 6 and 12 (n=11).
Trait-anger and anger expression decreased significantly between baseline and the end-of-treatment (p <.5). Patients
who completed AMT were more likely to remain abstinent during the 30 days post-AMT compared to patients who
did not complete AMT (43% versus 63%). although this finding requires replication (p =.13). These findings
suggest that reductions in anger may contribute to abstinence, and that further studies should be conducted to
examine the causal role of anger in substance abuse patients.
ACKNOWLEDGMENTS:
VAMC.
Supported by NIDA Grant P50DA09253, San Francisco TRC, and San Francisco
256
THE ROLE OF WEIGHT CONTROL AS A MOTIVATION FOR COCAINE ABUSE
C. Cochrane, R. Malcolm, and T. Brewerton
Medical University of South Carolina, Charleston, SC
Heavy use of cocaine and alcohol in female cocaine abusers with eating disorders has been reported, but the
prevalence and motivation for concurrent substance abuse has not been well investigated. To study this question,
40 males and 37 females between 18 and 48 years old who endorsed cocaine as their primary substance of abuse
were administered the SCID for DSM-111-R the Eating Disorder Inventory (EDI), and the Diagnostic Survey for
Eating Disorders-Revised (DSED-R). Items addressing weight control drugs were added to the DSED as were
questions inquiring about reasons for beginning or maintaining cocaine use. The results showed that 49% of the
37 women used cocaine as a weight control measure while 13% of the males did the same. Thirteen of the 18
women endorsing weight related use of cocaine had a current diagnosis of an eating disorder. Only 2 males (5)%
bad a past history of an eating disorder. Eleven (85%) of those women with a current eating disorder endorsed using
alcohol as an appetite suppressant. Females were significantly more likely than males to endorse beginning use of
cocaine for decreasing appetite ( 2=5.39, p 0.02) and losing weight ( 2=11.94, p 0.0005); females were also
significantly more likely than males to continue using cocaine use for decreasing appetite ( 2=5.65, p 0.01) and for
losing weight ( 2=10.53, p 0.001.) Significant difference also existed between males and females on the Drive for
Thinness subscale of the EDI (F=5.8±6.14, M=1.6±2.1: p 0.0008.) These findings support the need to evaluate
weight control in cocaine users and provide specific treatment aimed at addressing the interaction between the eating
disorder and the substance abuse problem.
PSYCHOLOGICAL CORRELATES OF JOB-SEEKING BEHAVIOR
R. C. Sterling, S. D. Glassman, S. P. Weinstein, A. Lundy, R. Serota, and E. Gottheil
Department of Psychiatry,
Jefferson Medical College, Philadelphia, PA
Current welfare reform initiatives, which have eliminated economic benefits for many able-bodied individuals, have
increased the competition for a limited number of jobs. At the same time, there remains an interest in examining
factors that positively influence and promote job-seeking attitudes and behavior in both those who lose a job, as
well as those who are chronically unemployed. Learned helplessness has been identified as one factor that might
contribute to chronic unemployment. For example, Goldsmith et al. (1995) have suggested that low expectancy
for a successful work search can contribute to a cycle of negative ideation leading eventually to a withdrawal from
the work force altogether. The present study was conducted to see if we could identify factors associated with jobseeking behaviors in a substance dependent population. Subjects were a cohort of 120 unemployed males seeking
admission to a 12-week, outpatient cocaine treatment program. Complete nine-month follow-up data was
successfully obtained on 84 (70%) of these individuals. Twenty-nine (34.5%) were employed either part or fulltime at the time of follow-up. Interestingly, time in treatment was not related to changes in job status.
Discriminant function analysis, employing personality and demographic variables collected nine months earlier at
admission, correctly differentiated those obtaining employment from those not in 75% of the cases, 2 = 28.52,
p<.0001. Variables associated with failing to obtain a job included lower scores on the Generalized Expectancy
for Success Scale, poorer abstract thinking as measured by the Shipley-Hartford Institute for Living Scale, a poor
employment history, difficulties with alcohol, and being older.
ACKNOWLEDGMENTS:
Supported by NIDA grants R18 DA06166 and R29 DA09415.
257
LONG TERM RESULTS OF PSYCHOSURGERY IN COCAINE-SMOKING DEPENDENCE
T. Llosa
COCADI, Miami, FL
Psychosurgery (PS) involves surgical modification of the brain with the goal of reducing the symptoms of the most
severely ill psychiatric patients who have not responded adequately to less radical treatment. Currently, PS is
indicated in some chronic obsessive-compulsive and/or depressive disorders. PS had been used to control addictive
diseases and alcohol but never for cocaine dependence treatment. Medical records of 28 volunteers. 27 males, 1
women, cocaine(coca paste)-smoking-abuse patients (DSM-III criteria), mean age 23.6 years, 17 singles, with avg
4.7 times they have been hospitalized, avg 6.754 years of smoke cocaine(coca paste mixed with tobacco), avg 23.2
coca paste cigarettes per binge(contained avg of 95 mg of cocaine plus 4 mg of nicotine per cigarette), avg 4.6
relapses per week, avg 5 days of longest abstinence in the last year, with delinquential history (89.2%), submmited
to PS(anterior cingulotomy, involving bilateral removal of about 3-4 cm of tissue in Brodmann’s Area 24), during
1981-83, were reviewed. In 1983, subjects with avg 14.5±12.5 (27-2) months after PS showed 67.8% of recovery,
relapse avg dropped to 1.6 per week (p<.001), avg of longest abstinence increase to 289±169 days (p<.001), and
delinquential behavior fell to 37%. In the last review (1995-96). 42.8% (11 m, 1 w), maintains their abstinence, 10
showed no successful (4 were killed in delinquential acts, 2 are in prison), and 6 we did not have any information,
Medical evaluation (included neurological) reveal no deficit or side-effects nor deaths imputed to PS. About the
control group (11 coca paste addicted patients who did not accept to be submitted to PS), 2 subjects killed their
father, 1 was killed by his father, 2 improved with standard treatments and 6 were unsuccessful. This is the first
report about PS results after more than 15 years of follow-up. When we initiated PS treatment, there was not an
agreement that the use of cocaine produced dependence, and because crack was not even consumed, it raised several
medical controversies.
PSYCHIATRIC COMORBIDITY OF CRACK COCAINE USERS IN NON TREATMENTRELATED STUDIES
J. D. Wines, L. H. Lundahl, S. L. Daniels, and S. E. Lukas
ADARC, McLean Hospital/Harvard Medical School, Belmont, MA
Few studies have systematically examined the psychiatric profiles of crack cocaine users who respond to
advertisements for participation in non treatment-related research studies. This study analyzed data collected over 4
consecutive months from 121 respondents (55% mates) to the following advertisement: Paid Volunteers. Healthy
men and women. ages 21-35, for cocaine/hormone related studies. Blood sampling involved. Only 37 of the 123
respondents to a telephone questionnaire admitted to using crack cocaine. Eighteen of these were not included in this
study for a variety of reasons including head trauma, failure to report to lab and suicide ideation. Of the remaining
21 crack users, 67% were male and 53% were minorities. These subjects were given the SCID (DSM-IV version)
by two doctorate level clinicians and detailed questionnaires regarding drug use, antisocial personality disorder, health
status and demographic data. Of those who received a SCID, 61.9% had a lifetime diagnosis of polysubstance
dependence, 42.8% mood disorder, 9.5% anxiety disorder, and 61.9% antisocial personality disorder. There data
suggest substantial psychiatric comorbidity may occur in crack users participating in non treatment-related research
studies and highlights the need for thorough screening by appropriately trained individuals.
ACKNOWLEDGMENTS:
NIDA grants DA03994 and DA00115.
258
COGNITIVE THERAPY
SCHEMA-FOCUSED
SUBSTANCE ABUSERS
FOR
PERSONALITY
DISORDERED
S. A. Ball1 and J. E. Young 2
Yale University1 and Columbia University2
The presence of an untreated personality disorder may lead to worse compliance and outcome in substance abuse
treatment. Therapeutic attention to the symptoms of personality disorder may reduce the severity of substance abuse
and other Axis I symptoms which potentially contribute to relapse. Specific behavioral treatment for antisocial and
borderline personality disordered drug abusers are being tested, but there have been no systematic evaluations of
integrated treatments of a more diverse range of personality disorders commonly seen in substance abusers. This 3year NIDA-funded Stage I behavioral therapies development program study provides 24 weeks of individual
cognitive therapy which integrates relapse prevention with work on early maladaptive cognitive schemas (enduring
negative beliefs about oneself, others, and events). Ten pilot subjects in methadone maintenance have been enrolled,
doctoral-level psychotherapists have been trained. treatment manuals and adherence/competence rating scales have
been developed and the randomized clinical trial (comparing Schema-Focused Therapy versus 12 Step Drug
Counseling in 30 participants) has begun. Four case studies (from different DSM-IV Axis II Clusters) illustrate
diagnostic differences in psychopathology, personality, and interpersonal functioning, the experience of early
maladaptive schemas, coping styles, and substance abuse and psychiatric outcome.
ACKNOWLEDGMENT: Supported by NIDA grant R01 DA10012-01.
PERSONALITY DISORDERS AND CRIMINAL ACTIVITY AMONG COCAINE ABUSERS
M. M. Keeney, D. S. Festinger, D. B. Marlowe, K. C. Kirby, and J. J. Platt
Institute for Addictive Disorders, Allegheny Univ. of the Health Sciences, Philadelphia, PA
The association between personality pathology and criminal activity is well documented. It is often assumed,
however, that substance abuse modifies this relationship. That is, personality-disordered individuals commonly
abuse drugs and alcohol which, in turn. might increase the probability of their engaging in violence and other
crimes. This study investigated the independent contribution of personality disorder diagnoses and symptoms to
criminal activity among crack cocaine abusers when controlling for the severity of drug and alcohol abuse.
Categorical diagnoses of personality disorders were generated from the SCID-II which was administered within two
weeks of intake. Subjects with no Axis II diagnosis served as controls and were compared to subjects diagnosed
with any personality disorder, any Cluster B disorder, and Antisocial, Borderline, Paranoid, or Narcissistic
personality disorder. Axis II data were also analyzed dimensionally using numbers of symptoms within various
diagnostic categories. Results revealed that, holding severity of substance abuse constant, subjects diagnosed with
Cluster B, Antisocial, Narcissistic, and Paranoid Personality disorders reported committing significantly more
violent crimes, and those with Narcissistic personality disorder had greater ASI Legal Composite scores.
Regression analyses revealed that Axis II symptoms accounted for substantial incremental variance in legal history
above that accounted for by substance abuse. These data suggest that substance abuse does not explain most of the
variance in aggressive and criminal behavior among cocaine abusers, and that ASPD is not the only Axis Il
syndrome related to violence.
ACKNOWLEDGMENT: Supported by NIDA grant DA 06986.
259
PATHOLOGICAL GAMBLING IN COCAINE-DEPENDENT OUTPATIENTS
G. W. Hall*, N. J. Carriero, R. Y. Takushi**, L. Kohler, I. D. Montoya, K. L. Preston, and
D. A. Gorelick
NIH-NIDA Division of Intramural Research, Baltimore, MD; *Center for Drug Abuse
Research, Howard University, Washington, DC; and **Psychology Department., University
of Washington, Seattle, WA
Substance abusers have higher rates of pathologic gambling than the general population. Relatively little is known
of the characteristics of co-morbid pathological gambling among cocaine abusers, with most prior studies done
among alcoholics and polydrug abusers. We assessed the prevalence and characteristics of pathologic gambling
among 313 cocaine-dependent (DSM-IIIR) outpatients (200 also opiate-dependent; no other current substance
dependence except nicotine) who entered clinical trials of medication treatment for their cocaine dependence.
Twenty-five (8%) subjects met DSM-IIIR criteria for current pathologic gambling (based on Diagnostic Interview
Schedule), a higher prevalence than in the general population. Subject characteristics included mean age 35.6 years,
80% African-American, 24% female, 82% unemployed. 16% currently married, mean 11.5 years of education,
mean age of onset of pathologic gambling 22.0 years and of cocaine dependence 25.1 years. Compared to the 288
other subjects, the 25 pathologic gamblers were significantly more likely to be unemployed (82% vs 49 %, but did
not differ in other sociodemographic characteristics, age of onset of cocaine dependence (25.7 vs 25.1 years), length
of stay in treatment, or proportion of cocaine-positive urine samples given during treatment, The 18 pathologic
gamblers with concurrent opiate dependence had significantly longer duration of cocaine dependence than the 7
without opiate dependance (12.4 vs 6.6 years) and a higher proportion of cocaine-positive urine samples, but
otherwise did not differ significantly. These findings suggest that pathologic gambling usually precedes
development of cocaine dependence in outpatients with both disorders, but does not significantly influence treatment
response, while concurrent opiate dependence may be associated with a poorer treatment response.
ACKNOWLEDGMENT:
Supported by NIDA intramural funds.
INFLUENCE OF LIFETIME PROBLEM GAMBLING ON METHADONE TREATMENT
OUTCOME
G. Carlson, S. Specker,* and M. Bullock
Hennepin County Medical Center Department of Medicine and *University
Department of Psychiatry
of Minnesota
Pathological gambling (PG) affects 1-346 of the general population but affects 8-15% of those with substance use
disorders. Both substance use disorders and pathological gambling share similar behavioral characteristics and
DSM-IV criteria. The relationship of PG on recovery from substance abuse is unknown. It was hypothesized that
persons with lifetime PG (SOGS>3) would not do as well in treatment as those without PG. Patients (n=370)
admitted to a outpatient methadone treatment program were evaluated using a comprehensive assesment battery at
admission which included the SCID-P, SCID-II, ASI, South Oaks Gambling Screen (SOGS). All patients were
then assigned one of four outcome ratings based on psychosocial functioning and weekly random urine drug screen
analysis at discharge or nine months post admission. Patients rated “Highly Succesful” had significantly lower
SOGS score (F 3,329=3.02, p<.03) than patients rated in the other three categories. Analysis of other contributing
factors such as co-morbid psychiatric conditions are presented as well as the implications of this preliminary study
such as the importance of screening methadone patients for PG and the possibility of a common underlying
etiology such as an impulse control disorder.
260
DRUGS AND CRIME: COMMON AND DISTINCT ETIOLOGIES
M. EnsmingeR*, H.-S. Juon*, and J. McCord**
The Johns Hopkins School of Public Health* and Temple University**
The overall aim of this research project is to examine the pathways from childhood through adolescence and young
adulthood to drug use, crime, other problem behaviors and pathways to successful transitions. The Woodlawn
prospective, developmental study of children provides an opportunity to examine how first grade social adaptational
status, adolescent drug use and assault, social bonds, poverty, and other family circumstances influence the life
course into adulthood. In 1963, Woodlawn was one of the poorest communities in Chicago; most residents were
African American. All first grade children attending Woodlawn’s nine public and three parochial schools were
assessed (N=1242). They were followed as adolescents and most recently as young adults (N=953). Our analytic
strategy used information gathered in the adult follow-up at ages 31-33 to construct homogeneous subgroups of
individuals who had similar socioeconomic, behavioral, and psychological profiles. Using a standard agglomerative
clustering procedure, the males and females were grouped separately in to seven clusters. We examine the childhood
and adolescent family, social, and behavioral antecedents to these clusters. The clusters varied by problem
behaviors and poverty. One cluster showed the overlap of substance use and interpersonal aggression, but other
clusters showed high levels of one but not the other. Clusters with problem behaviors tended to be higher on
poverty. However, not all poor clusters had high drug use/intetpersonal aggression. Continuity existed between
drug use in adolescence and young adulthood. Early family origins were predictive of later poverty, however, there
were important exceptions. First grade teacher ratings of aggression and shy-aggression distinguished mate clusters
high on drug use and/or interpersonal aggression. Social bonds during adolescence were protective.
ACKNOWLEDGMENT: Supported by NIDA grant DA-06630.
ADULT DRUG ARRESTS AS AN INDICATOR OF JUVENILE DRUG ARRESTS: THE
IMPLICATIONS FOR TREATMENT
S. B. Greberman
NIH/NIDA/Division of intramural Research, Baltimore, MD
The purpose of this study is to evaluate patterns of drug arrests by the Federal Bureau of Investigation for the years
1979 through 1993 to determine if an increase in adult arrests results in a change in juvenile arrests. The
1,422,910 juvenile arrests and 11,807,894 adult arrests are categorized by either sale and manufacture (346,771
juvenile, 3,256,191 adult) or by possession (1,076,139 juvenile, 8,551,703 adult) of drug. Drugs are then
categorized by 4 different classifications: 1.opiates, cocaine and derivatives; 2. marijuana; 3. synthetic narcotics; and
4. dangerous non-narcotics. Tie series regression analysis was used to include the influence of time. Increases in
adult arrests are followed by a statistically significant increase (p .0001) in juvenile arrests for sate and manufacture
in Croups 1 and 4. The same pattern of adult and juvenile arrests is seen for sate and manufacture in Croup 3;
however, the statistically significant relationship is not as strong. Only Group 1 shows a statistically significant
relationship (p .0001) of increasing adult arrests to increasing juvenile arrests for drug possession. Sale and
manufacture of drugs is considered a more serious crime than possession. This results in greater efforts by the legal
and law enforcement systems to punish these crimes. This is reflected in the time series regression model
developed here. The model predicts arrests of adults and juveniles more often than for possession offenses. The
model predicts juvenile arrests from adult arrests for possession of opiates, cocaine, and derivatives, the drug
classification containing drugs often considered the most serious. In the U.S., society often feels that adults draw
juveniles to crime. In all cases, this time series model indicates that juvenile arrests increase after adult arrests
increase. An explanation is that the criminal justice systems focus first on adults for either sate and manufacture or
possession arrests in any drug classification group. Since many individuals arrested on drug charges are also users
who are required by the legal system to enter treatment, the arrest patterns may serve as reasonable indicators of age
groups of persons and the change in classes of drugs for which arrested individuals will need treatment over time.
261
DRUG USE AND HIV RlSK BEHAVIORS AMONG ADOLESCENTS DETAINED IN THE
JUVENILE JUSTICE SYSTEM
O. Monohan, B. Danila, J. J. Annon, and M. D. Anglin
Drug Abuse Research Center, Neuropsychiatric Institute and Hospital, University of
California, Los Angeles, Los Angeles, CA
Data from 668 adolescents in juvenile facilities in 13 counties in California were analyzed as part of the California
Juvenile Drug Use Forecasting Program. Analysis of the data show: (1) females made up 11.8% (n=79) and males
made up 88.2% (n=589) of the sample, (2) the mean age was 16.1 years, and (3) the ethnic make-up was 24.4%
African American (n=163), 25.4% White (n=170), 35.8% Hispanic (n=239). and 14.4% Other (n=96). Forty-one
percent (n=262) tested positive for a single drug, and 9.9% (n=66) were positive for two or more drugs including
marijuana (34.6%, n=231), amphetamines or methamphetamines (5.5%, n=37), cocaine (5.2%, n=35), PCP (1.6%,
n= 11), and opiates (1.2%, n=g). Eighty-two percent (n=536) reported being sexually active with 64.5% (n=431)
reporting having more than one sexual partner in the past year, 45.8% (n=306) were not using condoms regularly,
and 47% (n=314) were usually high while having sex, three percent (n=20) had a history of injection of drug use,
and 0.4% (n=3) reported a history of needle sharing. Urine testing indicated that nine males and no females were
HIV-1 Antibody positive. Adolescents detained in the juvenile justice system are an important sub-group of at-risk
youth in need of prevention and early intervention services for drug use and HIV infection among other problems.
Stronger links between the correctional health and public health systems and comprehensive case management
services in the community could improve access to substance abuse treatment programs, HIV education, and health
and mental health services for these young people.
ACKNOWLEDGMENTS:
Supported by the National Institute of Justice, the National Instilute on Drug
Abuse (Training Grant T32DA07272), and the State of California, Department of Alcohol and Drug Programs.
FACTORS ASSOCIATED WITH CRIMINAL RECIDIVISM AMONG SUBSTANCE
DEPENDENT INMATES
F. D. Mulvaney, D. A. Zanis, and M. J. Rutherford
University of Pennsylvania / Philadelphia Veterans Affairs Medical Center, Philadelphia, PA
Convictions related to drug and alcohol abuse have contributed greatly to the problem of prison overcrowding
throughout the United States. Many of these inmates represent substance dependent individuals who are young,
non-violent, and who pose a minimal threat to society. For these individuals, treatment may represent a better
alternative than incarceration, for both them and for society. Moreover, substance abuse treatment may reduce one
of the major frustrations in dealing with an addicted, criminal population -- recidivism. To this end, criminal
recidivism data are presented for a group of approximately 500 substance dependent inmates who served the
remainder of their prison term in community based treatment rather than in prison. Logistic regression analyses
will be used to identify those factors most likely to be associated with rearrested for non-technical violations.
262
INCREASING EMPLOYMENT OF OPIOID DEPENDENT OUTPATIENTS:
BEHAVIORAL INTERVENTION
A NOVEL
J. R. Hollander, M. Kidorf, R. K. Brooner, and V. L. King
Johns Hopkins University School of Medicine, Baltimore, MD
The present study assessed the impact of a new, mandatory employment requirement in a community-based
methadone treatment program. Patients who had been treated on our methadone program for at least one year but
who were not currently employed (n = 36) were required to enhance their treatment with 20 hr of employment (paid
or volunteer). Patients with significant psychiatric or medical disabilities were excluded from the requirement
Patients were informed by counseling staff that they had two months to secure employment. Those who did not
comply within this time period were transferred to higher intensity treatment (i.e., more required treatment groups)
for 10 weeks focusing on resistance to this intervention and were eventually started on a 21-day methadone
detoxification until employment was verified. Seventy-five percent of the patients secured employment ad
maintained the position for at least one month. Positions were found in an average of 60 days. Most patients
(78%) continued working throughout the 6 month follow-up. Those who failed to find work or maintain
employment engaged in more illicit drug use. These results demonstrate that behavioral contingencies can motivate
many methadone maintenance patients to obtain verified employment in the community.
ACKNOWLEDGMENT:
Supported by NIDA grant DA05273-06.
HEALTH STATUS OF EMPLOYED PATIENTS AND PRE-EMPLOYMENT TRAINING
PARTICIPANTS/NON-PARTICIPANTS IN METHADONE CLINICS
M. Widman, V. Lidz, J. DiGregorio, A. K. Platt, and J. J. Platt
Institute for Addictive Disorders, Allegheny University of the Health Sciences, Philadelphia,
PA
Clinical observation of pre-employment training groups at methadone clinics indicated that a large proportion of the
participants appeared to suffer from major illness, thus possible interfering with the ability to find and maintain
work after completing this training. The literature suggested that clinical populations recruited from “street addicts”
often have many serious health problems, but we were not aware of any studies that examined rates of physical
health-related impairments that may limit the success of rehabilitation efforts. To begin to address this shortcoming,
we examined the medical charts of 153 patients enrolled in two methadone maintenance facilities: 58 employed 50
unemployed who attended preemployment training, and 45 unemployed who declined to attend. The results of
annual physicals were evaluated for systems impairment and overall ability to hold a job (pan-time, full-time,
physical, non-physical) by a physician not employed by the clinics who was blind to the individuals' work status.
There was little difference among the groups in individual system impairment. Surprisingly, when overall ability to
hold a job was evaluated, those who were employed were almost universally found to be less able to do so than those
who were unemployed. Those who were employed were found to be equally able to hold full-time work, but less
able to hold part-time work ( 2= 3.55, p = .06) and less likely to be able to hold non-physical work ( 2 = 6.02,
p<.05) while being no more likely to be able to do physical labor. Those who were employed when compared
against those who were unemployed, were also found to be less able to hold any type of work at all ( 2 = 4.67,
p<.05). These results suggest that motivation to work is more important than physical health.
ACKNOWLEDGMENT:
This study was funded by NIDA grant DA08783.
263
COCAINE LEGALIZATION? DESIGNING EXPERIMENTS
T. J. Crowley and J. T. Brewster
Addiction Research and Treatment Services, University of Colorado Health Sciences Center,
Denver, CO
Cocaine legalization (CL) aims to make inexpensive cocaine available legally to drive out illegal dealers. With no
experimental data popular-press articles promote CL (Buckley 1996). Drug-abuse scientists, wanting experimental
data, largely avoid this debate. We explore methodoligic and ethical issues in CL studies. Non-Medical CL might
change laws to increase cocaine availability to the level of OTC drugs, alcohol, or tobacco, aiming at crime
reduction for society generally; increase harm to users themselves would be expected. However, our review suggest
that this experiment would unacceptably increase the general prevalence of cocaine use, morbidity, and mortality.
Another approach proposes non-treatment cocaine use-stations with free, unlimited cocaine for onsite use by
certified addicts. Our review does not predict that this experiment would generally increase unacceptable morbidity
and mortality in the stations. Medical CL would aim to benefit individual addicts by providing controlled doses as
treatment in methadone-like clinics. This would not increase the prevalence of cocaine use. However, we review
evidence that methadone doses induce opioid satiety, while cocaine may induce the cocaine craving; thus, clinic
doses of cocaine might stimulate (rather than reduce) the demand for street cocaine. Moreover, to compete with
street dealers cocaine clinics would need to provide higher doses at lower cost, raising the probability of significant
medical and behavioral toxicity in these outpatients. Thus, the risk/benefit ratio precludes this experiment. We
conclude that the probability of adverse effects properly blocks experiments on cocaine legalization.
PREVALENCE OF DRUG ABUSE AMONG DEAF PERSONS: SURVEY METHODS AND
PRELIMINARY RESULTS
M. F. Goldstein, D. S. Lipton, E. Eckhardt, and F. W. Fahnbulleh, III
National Development and Research Institutes, Inc. New York, NY
Hypothesis: It has been hypothesized that deaf individuals use illicit drugs at higher rates than the general hearing
population. To date, this subject has not been investigated. Method: A computerized video survey in which
questions are available in two sign language modalities, speechreading, and English captions was developed in order
to facilitate understanding and clarity for deaf persons. Respondents answered questions directly, input by computer
touchscreen. Thus, the system has the desirable features of having standardized questions delivered by a person (the
signer or speechreader on screen) as well as the anonymity of a self-administered questionnaire. Interim results:
three hundred sixty-Iwo deaf subjects were recruited via targeted sampling techniques, primarily in New York State.
Self report of lifetime use of marijuana was 39%, cocaine, 13%, heroin, 2%, hallucinogens 6%, for all ages and
gender groups combined. Further analyses by subgroup and comparisons between deaf and hearing populations on
recent and lifetime use of each drug will be presented.
ACKNOWLEDGMENT: Supported by NIDA grant R44 DA08002.
264
A META-ANALYSIS OF DRUG ABUSE TREATMENT EFFECTIVENESS: PRELIMINARY
RESULTS
M. L. Prendergast and D. Podus
UCLA Drug Abuse Research Center Los Angeles, CA
The effectiveness of drug abuse treatment is a question that continues to be raised in policy discussions of public
funding for treatment and within the context of health care reform and managed care. The current study uses metaanalytic techniques 10 code and analyze treatment effectiveness studies conducted in the United States and Canada
since 1965 that meet specified eligibility criteria. The overall objectives of the project are to describe the history
and current state of research on drug treatment effectiveness, to cumulate effect sizes across studies (“What is the
magnitude of the effect of treatment on specific outcomes?”), and to identify factors associated with treatment
effectiveness (“What seems to work, with whom, under what conditions?“). In this preliminary analysis of 102
studies (out of an estimated 380 to be coded), estimated weighted average effect sixes are reported for selected
outcome measures by treatment type. The results are further divided into single-group designs and treatment-control
group designs. For me stronger treatment-control group designs, average effect sizes ranged from .22 to .49 for
substance abuse outcome measures, from -0.13 to .41 for crime measures, and from .16 to .40 for employment and
education measures. The fact that the homogeneity test (Q) was rejected for most of the effect sizes indicates that
additional categorical or multivariate analyses are needed to identify variables that account for the variation in effect
size. Analysis of the full dataset will result in more precise and reliable effect size estimates and in the identification
of moderator variables that might be useful in program design or policy decisions.
ACKNOWLEDGMENTS:
Supported by NIDA grant RO1 DA09151.
A META-ANALYSIS OF DRUG ABUSE TREATMENT EFFECTIVENESS:
CHARACTERISTICS AND METHODOLOGY--PRELIMINARY RESULTS
STUDY
D. Podus and M. L Prendergast
UCLA Drug Abuse Research Center, Los Angeles, California
The effectiveness of drug abuse treatment is an issue that continues to be raised in debate over public funding for
treatment services, health care reform, and managed care. This study reports partial and preliminary findings of a
meta-analysis of studies of treatment effectiveness that were conducted in the United States and Canada since 1965
and which satisfy certain eligibility criteria. The results are based on the first 102 studies to be coded out of an
estimated 380. The overall objectives of the project are to describe the history and current state of research on drug
abuse. treatment effectiveness, to calculate the magnitude of treatment effects on specific outcomes (i.e., the effect
size), and to identify factors associated with effective treatment.
Based on an analysis of the first 102 cases, this study found that studies varied in the amount of information they
reported. All studies provided sufficient information to determine their basic methodology, but they did not always
report data on the demographics of the sample (e.g., age, ethnicity, gender) or describe the treatment being evaluated
in detail. It also found that the studies were heterogeneous. The evaluations were evenly split between those with
a pre-experimentai design and those with a true experimental or quasi-experimental design. Studies also covered a
wide range of treatment modalities and techniques. Other preliminary findings include: most samples were
primarily male; Hispanics were represented less than Whites or Blacks; studies were concentrated in just 19 states;
and heroin was the primary drug problem in most studies.
ACKNOWLEDGMENT:
Supported by NIDA grant RO1 DA09151.
265
ON METHODS FOR THE ANALYSIS OF LONGITUDINAL DATA FROM CLINICAL
TRIALS
K. L. Delucchi and A. Bostrom
Department of Psychiatry, UCSF
A variety of statistical approaches for the analysis of 2-group longitudinal designs are available to the investigator.
We used derived calculations and computer simulations to compare the statistical power of six analytic methods;
Student’s t-test and Mann-Whitney-Wilcoxon rank test on mean least-squares regression slopes estimated for each
subject, and on pre-post differences, multivariate repeated measures analysis of variance (MANOVA) and mixedmodel analysis of variance. Comparisons were made under conditions of sample size, number of assessments, and
dropout rates common to substance abuse research. Factors included effect size, attrition pattern, sample size, and
visit-to-visit correlation levels. Results indicated that simple method often show the best power for detection of
simple (i.e., linear) effects. The use of slope estimates as summary statistics were surprisingly poor under intentto-treat. The MANOVA performed poorly (relatively) due to ‘wasting’ of degrees-of-freedom. Levels of
assessment-to-assessment correlations mattered little but effects MANOVA and the use of slope estimates under
MT.
ACKNOWLEDGMENT:
Supported by NIDA grants P-50-DA-09233.
EFFECTS OF SYMMETRY VIOLATIONS AND MISSING DATA: TYPE I ERROR
FOR MAXIMUM LIKELIHOOD AND LEAST SQUARES ANALYSES
H. M. Rhoades, S. R. Doyle, and J. Grabowski
Substance Abuse-Medication Development Research Center, Department of Psychiatry and
Behavioral Sciences, University of Texas Medical School at Houston, Houston, TX
Missing data occur in nearly every longitudinal study carried out to evaluate the effectiveness of proposed treatments
for substance abuse. Two major problems associated with analyzing longitudinal data using a traditional Repeated
Measures ANOVA approach are missing data and violations of the sphericity (or compound symmetry)
assumptions. Maximum likelihood procedures for analyzing longitudinal designs with missing data are becoming
more prevalent. These programs (e.g., BMDP 5V) allow the user to specify the covariance structure to be modeled
However, in some packages, compound symmetry is the default. Unless the researcher has prior knowledge, an
incorrect covariance model may be used or the data must be analyzed using several covariance models and the best
fitting model chosen. As part of an ongoing series of Monte Carlo analyses, two patterns of non-symmetry are
used to assess Type I (alpha) error associated with Repeated Measures ANOVA/ANCOVA and Maximum
Likelihood analysis strategies. The pattern and degree of missing observations, the pattern of the covariance
structure, and the sample size have been assessed for their effects on Type I error rate, in a two-group, five repeated
measures design. Type I error data will be presented for two linear dropout rates (20% and 60%), two missing data
rates (10% and 33%), and two sample sizes (n=15, 45 per group), under symmetry and two patterns of nonsymmetric covariance matrices. Type I Error for Maximum Likelihood results are inflated over nominal alpha
levels under conditions where compound symmetry is not met.
ACKNOWLEDGMENTS:
Supported in part by U.S.P.H.S. grant DA09262 from N.I.D.A.
266
CAN MATCHING THEORY DISTINGUISH THE MOTIVATIONAL AND THE MOTORIC
EFFECTS OF DRUGS?
J. Dallery and J. S. Lancaster
Morris Brown College
Matching theory states that response rate increases hyperbolically with increases in reinforcement rate. An
interpretation of the equation that describes this function requires that one estimated parameter, k, reflects the total
amount of behavior possible in a given environmental context. and another parameter, r1, reflects the motivational
level of the organism. The use of matching theory to distinguish the motoric and the motivational effects of drugs
is premised on this interpretation. This interpretation, referred to as the response strength interpretation, requires
that any variation in the value of the reinforcer should leave the value of k unchanged. Therefore, the key to
falsifying the response strength interpretation of matching theory is to show that k varies with reinforcer value.
The present experiment varied reinforcer value by manipulating deprivation level (Experiment 1) and the
concentration of sucrose in water (Experiment 2). Rats responded on a series of VI schedules at each level of
reinforcer value. The hyperbola was fitted to the response and reinforcement rates produced at each level of
reinforcer value, and the parameter k was determined. Results show that k varied across reinforcer value. The study
suggests that the current response strength understanding of matching theory is not accurate, and it calls into
question the ability of matching theory to distinguish the motivational from the motoric effects of drugs.
ACKNOWLEDGMENT: Supported by a NIDA, Minority Institutions Research Development Program grant
5R24DA07256-6.
NEUROPSYCHOLOGICAL ASSESSMENT OF DRUG ABUSE: RESEARCH ISSUES
A. Horton-MacNeill, Jr
National lnstitule on Drug Abuse, Rockville, MD
Research findings suggest illicit drug abuse may alter the neurobiology and neuropsychological processes of addicted
human beings. This paper will review research on the residual effects of drug abuse and discuss the research studies
that are needed to elucidate the neuropsychological correlates of the effects of abused drugs. Suggestions will be made
regarding scientific issues involved in designing studies to assess the specific drugs of abuse. In addition, conceptual
issues regarding neuropsychological assessment will be discussed. Also. issues regarding identification of concurrent
comorbid psychiatric conditions in drug addicts will be clarified. Recommendations for specific batteries of
neuropsychological tests to be used in clinical research studies will be provided.
Key Words: neuropsychology, drug abuse, residual effects, cognition
261
KNOCKOUT TRANSGENIC MICE: MU OPIOID RECEPTOR, DOPAMINE AND SYNAPTIC
VESICULAR TRANSPORTERS
I. Sora*, N. Takahashi*, M. Funada*, R. S. Revay*, D. M. Donovan*, L. Sharpe*, H. F.
Liu*, L. L. Miner*, and G. R. Uhl*
Molec. Neurobiol., NIDA-IRP, NIH* and Depts. Neurol. and Neurosci., JHUSM”, Baltimore,
MD
The dopamine and synaptic vesicular monoamine transporters (DAT and VMAT2) accumulate dopamine and serve as
targets for cocaine and amphetamine actions. The mu opioid receptor (MOR) is linked with morphine analgesia and
reward. To further investigate the roles of these proteins in drug actions, we isolated murine 129 genomic clones for
each and produced transgenic mice deleted in 1 (all viable) or 2 gene copies (DAT and MOR viable) that each revealed
modest adaptive changes in other neurochemical systems. Drug responses in these animals reveal dramatic
dependence of morphine analgesia and conditioned place preference reward on MOR expression, dependence of cocaine
reward on DAT expression, and requirement for full DAT and VMAT2 expression for full amphetamine reward.
Heterozygous mice revealed interesting consequences of reducing expression levels to half of wildtype values. These
mice add significantly to our understanding of molecular sites for behaviorally-significant drug actions in the brain,
and suggest substantial consequences of genetic differences in expression of these drug target sites.
COMT, DRD3 AND DRD4 GENE MARKER FREQUENCIES IN POLYSUBSTANCE
ABUSERS AND CONTROLS
D. J. Vandenbergh, L. A. Rodriguez, E. Bendahhou, H. Lachman*, and G. R. Uhl
Molec Neurobiol, IRP-NIDA and Depts Neural and Nsci,
Psych, AECOM, Bronx, NY
JHUSM, Baltimore, MD, *Dep
Allelic variants at the dopaminergic gene loci are candidates to contribute to genetic components of interindividual
differences in vulnerability to substance abuse. COMT (catechol-O-methyltransferase) degrades dopamine while D3
and D4 G-linked receptors recognize it. COMT alleles encode enzymes whose activities vary 3-4-fold. DRD4 alleles
encode receptors that may differ in G-protein coupling efficacies. Comparisons of allele frequencies in nonusing
control research volunteers to those in volunteers reporting substantial polysubstance use revealed that users displayed
significantly more homozygotes for the high activity COMT allele, a trend toward more long-repeat DRW variants,
and no difference in DRD3 markers. Dopaminergic gene variants are candidates for contributions to interindividual
differences in vulnerability to substance abuse.
268
CART PEPTIDE IMMUNOHISTOCHEMISTRY IN THE RAT
E. O. Koylu, P. R. Couceyro, P. D. Lambert, and M. J. Kuhar
Yerkes Regional Primate Center, Emory University, Atlanta GA
CART mRNA is a novel transcript that is increased after psychostimulant administration in brain, The predicted
CART peptide contains a leader sequence and several pairs of basic amino acids suggesting that it is processed and
released. We have made polyclonal antisera against several peptide fragments that span the parent polypeptide (we
acknowledge Drs E. DeSouza and N. Ling for some peptide synthesis). Using immunostaining, we found CART
peptide immunoreactivity in the same cell groups that contain CART mRNA which indicates that the mRNA is
translated. These immunoreactive cells were found throughout the brain and in the pituitary and adrenal medulla.
Antisera raised against several peptide fragments showed somewhat different staining patterns, suggesting that the full
length CART peptide is processed into smaller peptides. These data suggest that CART peptides ate putative
neurotransmitter/cotransmitters involved in several physiologic processes including feeding, drug reward, autonomic
control, sensory function and stress responses.
ACKNOWLEDGMENT: Supported by RR00165.
RAT STRAIN DIFFERENCES IN SENSITIVITY TO THE ANTINOCICEPTIVE EFFECTS OF
MU OPIOIDS
D. Morgan, C. D. Cook, and M. J. Picker
Department of Psychology, University of North Carolina, Chapel Hill, NC
The antinociceptive effects of the mu opioids levorphanol, morphine, buprenorphine, butorphanol and nalbuphine
were assessed in rat strains using a hot water tail-withdrawal procedure. These drugs were chosen to cover the range of
intrinsic efficacy at the mu receptor, from relatively high (e.g. levorphanol and morphine) to relatively low intrinsic
efficacy (e.g. butorphanol and nalbuphine). Sensitivity to the antinociceptive effects of higher efficacy opioids did not
differ across rat strains. In contrast. sensitivity to the effects of lower efficacy opioids varied greatly across the four
strains of rats. For example, in 50 degree water, butorphanol and nalbuphine produced maximal or near maximal
effects in Fischer 344 and Sprague-Dawley rats. In Long-Evans rats, butorphanol and nalbuphine produced halfmaximal effects. Whereas in Lewis rats, no antinociception was observed when tested with butorphanol or
nalbuphine. The pattern of results was similar when tested in 52 degree water; however, the absolute level of
antinociception was consistently lower. These results indicate that the level of antinociception produced by mu
opioids depend not only on the intrinsic efficacy of the drug and the water temperature, but also on the strain of tat
employed.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA05669 and DA10277.
269
NOVEL CART PEPTIDES - A PSYCHOSTIMULANT-LIKE BEHAVIORAL PROFILE
P. D. Lambert 1 , P. R. Couceyro 1 , E. O. Koylu 1 , N. C. Ling 2 , E. B. De Souza 2 , and M. J.
Kuhar1
Neuroscience Division, Yerkes Research Center, Emory University, Atlanta, GA 1 and
Neurocrine Biosciences Inc., San Diego, CA2
CART is a novel, interesting mRNA that is increased by acute psychostimulant drug administration.
Immunolocalization has identified CART peptides in specific brain regions associated with the control of locomotion
and feeding such as the nucleus accumbens, paraventricular nucleus of the hypothalamus and the amygdala. An
endogenous role(s) for CART peptides has yet to be identified and the aim of this study was to examine the effect of
CART peptide fragments (ICV) and central immunoneutralisation of endogenous CART peptides on food intake (FI)
and locomotor activity (LA). Mate Sprague-Dawley rats were cannulated ICV and divided into groups (n=4-12). Each
of four groups received one of three peptide fragments (Frag 1, 1a or 1b) or saline ICV just prior to lights out and FI
(g) in the first 2 hours of the dark phase was measured. The dosing was repeated but following ICV injection food
was withdrawn and LA (m) in the first 2 hours of the dark phase was recorded. CART Frag 1 decreased FI
(3.2±0.2g*) and increased LA (387±118m*) compared to injection of saline (4.1±0.3g; 160±30m). However, Frag 1
specifically increased LA (464m*) with no effect on FI (4.5±0.4), whereas Frag 1b specifically decreased FI
(2.6±.0.3g*) with no effect on LA (153±36). * indicates significant difference from saline p<0.05. Interestingly, ICV
injection of polyclonai antibodies raised against CART peptide fragments significantly increased FI and attenuated
cocaine-induced locomotor activity compared to injection of pre-immune serum. By dividing the larger peptide (Frag
1) into two smaller fragments (Frag 1a and 1b), at a possible in vivo cleavage site, peptides were isolated with
selective effects on either activity or food intake. lmmunoneutralisation studies suggest a role for CART peptides in
the mechanism of action of cocaine-induced locomotor activity and in the central control of food intake. This is the
first evidence for centrally-mediated effects of CART peptides.
INCREASED BREAK-POINTS ON PR SCHEDULE REINFORCED BY IV COCAINE IN 5HT1B RECEPTOR KNOCKOUT MICE
B. A. Rocha, R. Ator, and *R. Hen
Fort Worth, T X a n d
Department of Pharmacology UNTHSC/FW,
Neurobiology and Behavior, Columbia University, New York, NY
*Department of
The present experiment tested the hypothesis that serotonin 5-HT1B receptors are implicated in the reinforcing
efficacy of cocaine. For this purpose, 129/Sv-ter mate mice lacking 5-HT1B receptors (knockout mice; n=12) and the
wild-type (n=7) were tested in cocaine IV self-administration in a progressive ratio (PR) schedule. Subjects were
initially trained to press a lever for fond as a reinforcer, and subsequently implanted with a permanent indwelling
jugular catheter. Two days after surgery, mice started cocaine (2.0 mg/kg/inj) self-administration acquisition under a
fixed ratio 1 (FR1) schedule. Once acquisition criteria (75% of active lever pressings and at least 16/20 injections
within 3-b for three consecutive days) was obtained, mice were switched to the PR schedule, and allowed to selfadminister cocaine for 3-h, upon completion of each ratio, in an exponential sequence from 2 to 603. Once stability
under the PR schedule (number of reinforcers per session not differing by more than 2, for three consecutive days)
was obtained, mice were tested with different doses of cocaine (0.5-4.0 mg/kg/inj); one dose per day, over three
consecutive days. Knockout mice obtained a significant higher number of reinforcers than the wild-type at all doses
tested. An univariate analysis (ANOVA) confirmed a significant effect between genotypes (F(1,8)=7.21; p<0.05).
These results suggest that 5-HT, through activation of 5-HT1B receptors, plays an inhibitory role in the reinforcing
efficacy of cocaine.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-10457.
210
EFFECT OF CHRONIC ‘BINGE’ PATTERN COCAINE ON THE 5-HT2A AND 5-HT1A
RECEPTORS IN THE RAT BRAIN
G. Perret*, J. Schluger*, E. M. Unterwald* ,**, J. Kreuter*, A. Ho*, and M. J. Kreek*
*The Rockefeller University, New York, NY and **New York University Medical Center,
Dept. of Psychiatry, New York, NY
The effect of chronic cocaine exposure on the central serotonergic system in the rat was investigated using
ketanscrin, a selective 5-HT2A receptor antagonist, and 8-OH-DPAT, a selective 5-HT1A receptor agonist, as
tritiated ligands in a quantitative autoradiography study. The regions analyzed include frontal, parietal, agranular
insular and piriform cortex, caudate-putamen, olfactory tubercle, nucleus accumbens, thalamus, hypothalamus,
hippocampus, dentate gyrus, dorsal raphe, septohippocampal nucleus and claustrurn No signficant difference in the
binding of ketanserin was found in any brain region but a significant decrease of the binding of 8-OH-DPAT was
found in the ventromedial hypothalamus (t-test: p<0.001) and the dorsal dentate gyrus (t-test: p<0.05) in the rats
administered with cocaine in a “binge” pattern (14 days, 15mg/kg/injection) as compared with rats administered
with saline. It is known that 5-HT1A receptors modulate HPA axis activity and are probably involved in depression
and anxiety. These data suggest that the 5-HT1A receptors may be involved in the change of the HPA activity and
may participate in the psychiatric manifestation following chronic cocaine administration.
ACKNOWLEDGMENT:
Supported in part by NIH-P50-DA05130.
DOSES OF GBR12909 WHICH SUPPRESS COCAINE SELF-ADMINISTRATION IN
NONHUMAN PRIMATES SUBSTANTIALLY OCCUPY DA TRANSPORTERS
V. Villemagne 1 , D. F. Wong 1 , F. Yokoi1 , K. C. Rice2 , D. Matecka 2 , and R. B. Rothman3
1
Department of Radiology, Johns Hopkins Medical Inst., Baltimore, MD.; 2 LMC, NIDDK,
NIH, Bethesda, MD; and 3CPS, DIR, NIDA, NIH, Baltimore, MD
GBR12909 (GBR) is a high affinity, selective and long-acting inhibitor of DA uptake which has been proposed as a
potential treatment agent. GBR produces a persistent and noncompetitive blockade of DA transporters and
substantially reduces cocaine-induced increases in extracellular DA. Slow i.v. infusion of GBR to Rhesus monkeys
selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis
that doses of GBR which reduce cocaine self-administration in nonhuman primates produce significant occupation
of DA transporters. DA transporters were quantitated in two baboons using [11C]WIN35,428 and PET. The
baboons underwent four PET scans (performed on two separate study days, 3-4 weeks apart). Blood pressure,
temperature, heart rate and oxygen saturation were monitored throughout each study. On the first scan of the first
study day the baboon received saline (3 ml/kg) 90 min before the injection of the radiotracer. GBR (1 mg/kg i.v.)
was infused 90 min before the second [11C]WIN 35,428 study. The second study (34 weeks from the first study
day) was conducted identically to the first study, except that the dose of GBR was 3 mg/kg. Doses of 1 (n=1) and 3
mg/kg (n=2) produced % reductions of binding potential of 18 and 53%, respectively. GBR was welI tolerated in
all baboons. One baboon showed transient bradycardia (that lasted less than 5 min) immediately after the injection
of 1 mg of GBR. No changes in blood pressure or oxygen saturation were observed in any of the baboons. These
results demonstrate that doses of GBR which suppress cocaine self-administration in nonhuman primates also
produce high occupancy of the DA transporter. Viewed collectively with other work, these data strongly suggest
that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in
extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that clinical trials
(planned) of orally administered GBR should use doses which produce at least 50% occupancy of the DA
transporter.
ACKNOWLEDGMENTS:
Supported by DA 09482, DIR NIDA and NIDDK.
271
REDUCTIONS IN DOPAMINE TRANSPORTER AND D 1 RECEPTOR BINDING AFTER
CHRONIC GBR 12909
P. M. Kunko1 , B. Ladenheim 2 , J. L Cadet2 , F. I. Carroll3 , and S. Izenwasser 1
1
3
Psychobiology and 2 Molecular Neuropsychiatry Sections, NIDA, IRP, Baltimore, MD, and
Research Triangle Institute, Research Triangle Park, NC
Chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the
inhibition of dopamine uptake. by cocaine, without changing dopamine transporter binding. The selective
dopamine uptake inhibitors GBR 12909 and RTI-117 also produce partial behavioral tolerance, but their chronic
effects on the dopamine system are unknown. GBR 12909 (25.8 mg/kg/day), RTI-117 (3.62 mg/kg/day), cocaine
(50 mg/kg/day), or vehicle were continuously infused into male Sprague-Dawley tats via osmotic minipump. The
pumps were removed after seven days of infusion, and 24 hours later, [125I]RTI-121 and [3H]SCH 23390 binding
were assessed using autoradiography for dopamine transporters and dopamine D1 receptors, respectively. [125I]RTI121 binding was decreased in both caudate putamen and nucleus accumbens of GBR 12909-treated rats, while
cocaine and RTI-117 slightly inreased [125I]RTI-121 binding. Similarly, only GBR 12909 significantly reduced
[3H]SCH 23390 binding in both brain regions, despite continuous dopamine uptake blockade by all the drugs.
Thus, the combination of a decrease in the number of transporters, along with blockade of uptake leads to a large
excess of synaptic dopamine, which in turn appears to down-regulate dopamine receptors. These findings suggest
that GBR 12909 interacts with the dopamine transporter in a qualitatively different manner from that of cocaine and
its analogs.
ACKNOWLEDGMENT:
Supported by NIDA.
IRREVERSIBLE LIGANDS BASED ON RIMCAZOLE AS PROBES FOR THE DOPAMINE
TRANSPORTER
S. M. Husbands, S. Izenwasser, W. D. Bowen*, B. J. Vilner*, J. L. Katz, and A. H. Newman
Psychobiology Section, NIDA-DIR, Baltimore, MD and *Laboratory of Medicinal Chemistry,
NIDDK, Bethesda, MD
Dopamine transporter (DAT) heterogeneity is demonstrated by high and low affinity components of binding and
dopamine uptake, by cocaine and cocaine analogs. Previous studies have suggested that these different components
play distinct functional roles in the behavioral effects of cocaine. Studies indicate that the high affinity component
is related to the psychomotor stimulant actions of cocaine. Rimcazole is a sigma ligand that is not a psychomotor
stimulant, and indeed attenuates the locomotor stimulant actions of cocaine. Rimcazole binds to the DAT
monophasically and it has been hypothesized that it may be interacting exclusively at a low affinity component of
the DAT. We have prepared irreversible ligands based on the rimcazole structure in which the alkylating moiety
(iothiccyanate, NCS) is attached to the distal nitrogen of the piperazine ring via alkyl chains of varying lengths, or
directly attached to one of the aromatic groups. Importantly, the analog with the highest affinity for the DAT binds
in a monophasic and irreversible manner, as evidenced by the greatly diminished binding of [3H]WIN 35,428 in
tissue that had been pre-incubated with the ligand and then thoroughly washed using centrifugation. We dose
dependent reduction in Bmax occurred without change in the Kd, which is indicative of irreversible binding. In
conclusion, these ligands may prove to be important tools with which to study the significance of the low affinity
site on the DAT. Because rimcazole does not share the behavioral profile of cocaine, and in fact appears to play a
modulatory role, these compounds may provide leads for a novel cocaine-abuse treatment.
272
SYNTHESIS AND MOLECULAR MODELING OF NOVEL AROMATIC SUBSTITUTED 3
DIPHENYLMETHOXYTROPANE ANALOGS
R. H. Kline, S. Izenwasser, J. L. Katz, and A. H. Newman
Psychobiology Section, National Institutes of Health, National Institute on Drug AbuseDivision of Intramural Research, Baltimore, MD
A previously prepared series of para and meta substituted- -diphenylmethoxy-1 H,5 -H-tropane analogs has been
shown to contain compounds that are selective, high affinity probes for the dopamine transporter. Inspection of the
structure-activity relationships (SAR) within this series of compounds via molecular modeling has indicated that
these aromatic substituents play an important role in the potency and selectivity of these compounds. A crossvalidated CoMFA model of the binding domain on the dopamine transporter was constructed using this series of
compounds (predictive r2=0.722). To further explore the optimal structural requirements for potent and selective
dopamine transporter binding, and thus further enhance the model of this binding site, additional compounds
containing particular aromatic substitution patterns were synthesized The compounds were evaluated for inhibition
of [3H]WIN 35.428 binding at the dopamine transporter and [3H]dopamine uptake in rat caudate putamen. ln
general, most of the newly prepared compounds were more potent in inhibiting WIN 35,428 binding (range=23-187
nM) and dopamine uptake (range=139-795 nM) than either cocaine or benztropine. Based on this model, it appears
that relatively large, electron withdrawing groups are not favored at this binding site. The experimentally
determined binding and uptake results of these compounds agreed well with predicted values from the CoMFA
model. Overall, it can be seen that substitution of a small halogen on one or both phenyl rings results in
compounds with highest potency at the dopamine transporter. These findings provide additional SAR at the
dopamine transporter and may provide leads toward the development of novel cocaine therapeutics.
SYNTHESIS AND TRANSPORTER BINDLNG PROPERTIES
PHENYL)TROPANE-2 -CARBOXYLIC ACID ESTERS
O F 3 -(SUBSTITUTED
C. Holmquist, K. K. Keverline-Frantz, P. Abraham, J. W. Boja, M. J. Kuhar, and F. I.
Carroll
Research Triangle Institute, Research Triangle
Center, Baltimore, MD
Park, NC and NIDA Addiction Research
Several 3 -(4-substituted phenyl)tropane-2 -carboxylic acid esters (1 ) were synthesized, and their transporter
binding properties compared with analogous 3 -(4-substitued phenyl)tropane-2 -carboxylic acid esters (2 ), most
analalogs of 1 show a marked increase in selectivity for the dopamine transporter (DAT) relative to the 5-HT
transporter with only a modest drop in potency at the DAT. These results were unexpected as allococaine (3 ) is 60fold less potent than cocaine (4 ) at the DAT. NMR studies suggest that the These results were unexpected as
NMR studies suggest that the 2 ,3 -compound 1 exists predominantly in the boat conformation. Molecular
modeling studies will be presented to assist in the interpretation of the binding data.
213
FUNCTIONAL SELECTIVITY AT THE D 2 DOPAMINE RECEPTOR: DEPENDENCE ON
MINOR AGONIST STRUCTURAL CHANGES
J. D. Kilts1 , A. Audhya 1 , D. E. Nichols 2 , K. L. O’Mallcy3 , R. D. Todd 3 , C. P. Lawler1 , and
R. B. Mailman1
University of North Carolina 1 , Chapel Hill, NC; Purdue University2 , W. Lafayette, IN; and
Washington University3 , St. Louis, MO
It is widely accepted that a major factor in the reinforcing effects of cocaine and some amphetamine-like drugs is
their facilitation of dopamine neurotransmission (e.g., increasing synaptic concentrations of dopamine). Thus, the
ability to activate pre- and postsynaptic dopamine receptors selectively could be a useful tool in the treatment of
individuals abusing these drugs. The present study is an extension of previous work utilizing the D2 agonist
dihydrexidine (DHX) and several of its analogs, compounds that have unusual D2-like functional profiles. In rat
brain preparations, DHX (K0.5 = 100 nM in rat striatum) has agonist properties at functions mediated by
“postsynaptic” D2 receptors (e.g., inhibition of striatal adenylyl cyclase), but no agonist effects in D2-mediated
“presynaptic” functions (e.g., inhibition of nigral cell firing, or inhibition of dopamine synthesis or release),
despite the fact that DHX binds with similar affinity to both pre- and postsynaptic receptors. Previous studies using
D2-transfected MN9D cells, a clonal mesencephalon-derived line that can synthesize and release dopamine (making it
a model of dopamine neurons), showed similar “functional selectivity” of DHX and its analogs in this cell line
transfected with a single dopamine receptor isoform. In MN9D cells, DHX and its analogs inhibited adenylyl
cyclase to the same extent as other full D2 agonists, but not only failed to inhibit depolarization-induced
[3H]dopamine release, but actually antagonized the activity of other agonists. Conversely, dinapsoline, a compound
structurally similar to DHX, does not exhibit this functional selectivity. acting as an agonist at both of these
measures. Dinapsoline is strikingly similar to DHX in terms of the key 3-D pharmacophoric elements believed to
be. responsible for binding to dopamine receptors, differing only in subtle changes to the drug backbone. These data
suggest that minor structural changes that do not affect binding to the receptor can have significant effects on the
functional consequences of drug-receptor interaction, and may determine whether a compound interacting with a
single receptor isoform causes agonist or antagonist functional effects.
[3H]COCAINE BINDING TO HUMAN HIPPOCAMPUS AND AMYCDALA: DISSOCIATION
FROM TRANSPORTERS
B. K. Madras
Harvard Medical School, New England Regional Primate Research Center, Southborough,
MA
Brain regions rich in dopamine are principal targets of cocaine after i.v. administration. Nevertheless, high levels
of cocaine also accumulate in the amygdala and hippocampus (Madras and Kaufman, 1994). We profiled these sites
in human brain, using a high specific activity form of [3H]cocaine. Although technically difficult, radioreceptor
assays revealed saturable and moderately high affinity [3H]cocaine binding sites in the amygdala and hippocampus.
As in striatum, [3H]cocaine binding was inhibited in the nanomolar range by cocaine congeners that block
dopamine transport (WIN 35,428, dichloropane, RTI-55, norcocaine). However, other dopamine, serotonin or
norepinephrine transport inhibitors, including mazindol, GBR12909, difluoropine, citalopram, talsupram were
weak inhibitors of [3H]cocaine binding, as were dopamine, serotonin, and norepinephrine. The data indicate that the
majority of cocaine binding sites in the hippocampus and amygdala are not associated with monoamine
transporters. Although the nature of these tropane recognition sites is not known, the rank order of potency of the
compounds wig facilitate evaluation of their pharmacological relevance.
ACKNOWLEDGMENTS:
Supported by NIDA: DA09462, DA06303, NERPRC: RR00168.
214
COCAINE INTERACTIONS WITH LUTEINIZING HORMONE
J. H. Mendelson, N. K. Mello, and S. S. Negus
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School,
Belmont, MA
Although cocaine is known to affect basal levels of anterior pituitary hormones, there has been relatively little
attention to the possible effects of the hormonal milieu on the acute effects of cocaine. It is generally acknowledged
that cocaine’s reinforcing effects reflect its activities on the dopaminergic system. Cocaine acts as an indirect
dopamine agonist and binds to the dopamine transporter to block dopamine reuptake. There has been considerable
interest in using dopamine receptor selective agonists and antagonists to antagonize or to substitute for cocaine’s
effects, characterization of the dopamine transporter by Kuhar and co-workers indicates that it is a glycoprotein of
which approximately 20 percent is carbohydrate. The anterior pituitary hormone, luteinizing hormone (LH) is also
a glycoprotein, and it’s carbohydrate side chains that are very similar to those found on the dopamine transporter.
This structural similarity suggested that LH might bind to cocaine in blood. We now report that stimulation of LH
release by administration of synthetic luteinizing-hormone-releasng-hormone (LHRH) to four male rhesus monkeys
resulted in a LHRH dose-dependent decrease in peak plasma cocaine levels. After intravenous administration of
placebo-LHRH and 0.8 mg/kg of cocaine, peak cocaine plasma levels averaged 479 (±135) ng/ml. Whereas after
administration of 15 and 30 mcg/kg/iv of active LHRH, peak cocaine plasma levels averaged 278 (±90) and 183
(±56) ng/ml. There was a significant (P<(0.01) negative correlation between plasma cocaine and LH levels. These
studies are in progress.
ACKNOWLEDGMENTS:
Supported by NIDA grants K05-DA00064, K05-DA00101, and DA04059.
REPEATED ADMINISTRATION OF A SELECTIVE KAPPA-OPIOID RECEPTOR AGONIST
DECREASES DOPAMLNE TRANSPORTER NUMBER IN THE NUCLEUS ACCUMBENS OF
THE RAT
S. Izcnwasser*, A. Thompson# , and T. Shippenberg #
*Psychobiology and
Baltimore, MD
#
Neuroimaging Sections,
NIDA Division
of Intramural Research,
It has previously been shown that the selective -opioid receptor agonist U69593 prevents long-term alterations in
behavior which occur following repeated administration of cocaine, Recent data have shown that it also attenuates
alterations in dopamine uptake and release which occur during abstinence from cocaine. The site and mechanism by
which -agonists modulate the actions of cocaine; however, remains unclear. Accordingly, the present study
evaluated the influence of U69593 upon dopamine transporters. Male Sprague-Dawley rats received once daily
injections of U69593 (0.04-0.32 mg/kg) for five days, after which binding of [3H]WIN 35,428 to the dopamine
transporter was measured in the caudate putamen and nucleus accumbens. Saturation curves using increasing
concentrations of labeled ligand were constructed and analyzed via Scatchard transformation so that KD and Bmax
values could be determined. The number of dopamine transporters was dose-dependently reduced in the nucleus
accumbens 3 days following the cessation of U69593, with no change in affinity for [3H]WIN 35,428. In contrast,
U69593 treatment failed to modify transporter binding in the caudate putamen. These data demonstrate that the
repeated administration of a selective -opioid receptor agonist produces alterations in dopamine transporters within
the nucleus accumbens and that this effect is regionally specific. They further suggest that the interaction of
opioid receptor agonists with cocaine is mediated presynaptically, at the level of the dopamine transporter.
ACKNOWLEDGMENT: Supported by NIDA.
215
EFFECTS OF U69593, A K-OPIOID AGONIST, ON D2 AGONIST-INDUCED INHIBITION
OF DOPAMINE DYNAMICS IN THE DORSAL STRIATUM
J. B. Acri**, A. C. Thompson*, A. K. Pani*, and T. S. Shippenberg*
**Medications Development Division, NIDA, Rockville, MD and *Neuroimaging and Drug
Action Section, Addiction Research Center, NIDA, Baltimore, MD
the acute and sensitized locomotor stimulant effects of cocaine in rats can be blocked by repeated prior
administration of the selective -opioid receptor agonist, U69593. Although the mechanism by which U69593
interacts with effects of cocaine is unknown. there is accumulating evidence that K-agonist treatment reduces
mesolimbic dopamine concentrations and that chronic treatment downregulates dopamine receptors in mesolimbic
regions. The present studies were undertaken to further explore the effects of a 3-day, once daily U69593 treatment
on acute responses to the D2/D3 dopamine receptor agonist, quinpirole, using in vivo microdialysis and locomotor
activity measures. Following implantation of microdialysis cannula in the dorsal striatum, each rat was allowed 57 days of recovery and was then treated with 0, 0.10 or 0.32 mg/kg/day U69593 on experimental days 1-3. On
day 5, basal dialysate samples were taken for 1.5 hours, followed by an acute challenge with 0.05 mg/kg quinpirole
SC. Dialysate samples were then taken every 20 minutes for 2 hours. frozen on dry ice, and later analyzed using
HPLC with electrochemical detection. For an additional group of rats, quantitative microdialysis techniques were
used to determine the influence of U69593 treatment on dopamine uptake and extracellular concentration. In a third
group, an acute locomotor challenge with cumulative doses of 0.3-3.0 quinpirole on day 5 followed the same 3-day
U69593 treatment. Results suggested that repeated prior U69593 treatment dose-dependently reduced the acute
effects of quinpirole on diatysate dopamine concentration in the dorsal striatum, and reduced the locomotor
stimulant effects of quinpirole. There was no effect of U69593 treatment on basal extracellular dopamine
concentration or on dopamine uptake, as estimated by quantitative microdialysis techniques. Taken together, these
data suggest that repeated administration of a K-agonist can attenuate D2/D3 -mediated effects in the striatum, and
these results ate consistent with findings that chronic K-agonist treatment downregulates striatal D2 receptors.
These effects may contribute to the ability of K-agonists to block acute and sensitized behavioral effects of cocaine.
DYNORPHIN2-17 ALTERS STRIATAL DOPAMINE DIALYSATE LEVELS AND COCAINEINDUCED BEHAVIORAL SENSITIZATION
A. C. Thompson, W. P. Rea, and T. S. Shippenberg
Integrative Neuroscience Unit, NIDA Division of Intramural Research, Baltimore, MD
Kappa-opioid receptor agonists prevent sensitization to the locomotor stimulant effects of cocaine (Heidbreder, et
al., 19%), reduce cocaine-induced alterations in dopamine dynamics (Thompson et al., 1996), and decrease
dopamine in then, accumbens and striatum (Spanagel et al., 1990, Maisonneuve, et al., 1994). Similar findings
have been shown for prodynorphin-derived peptides that bind to the kappa-opioid receptor (Claye, et al., 1996;. Reid
et al., 1990). The present studies were conducted to determine if the non-opioid dynorphin fragment, dynorphin2-17
(DYN2-17), produces similar behavioral and neurochemical effects. First, the effect of DYN2-17 (0.5 mg/kg, iv) or
vehicle on the acute locomotor stimulant effect of cocaine (20mg/kg, ip) was assessed. No differences in locomotor
activity were observed. Second, the effect of DYN2-17 on behavioral sensitization to the stimulant effect of cocaine
was assessed Rats were treated with cocaine (10mg/kg, ip) or vehicle once daily for 7 days. On the first 5 days,
rats also received DYN2-17 (0.5mg/kg iv) or vehicle 15 min prior to the cocaine injection. Locomotor activity in
response to a cocaine challenge (0, 5, 10 or 20 mg/kg, ip) was assessed 48 hr after the last cocaine pretreatment. The
locomotor stimulant effect of cocaine (10 and 20 mg/kg) was significantly enhanced by prior exposure to cocaine
and DYN2-17 blocked the enhanced response. This effect of DYN2-17 was dose-related and unchanged in rats treated
with nor-BNI, a selective kappa-opioid receptor antagonist. Third, the effect of DYN2-17 on dopamine in the dorsal
striatum was assessed by microdiatysis. DYN2-17, perfused through the microdialysis probe, dose dependently
increased dialysate dopamine concentration. These data suggest that DYN2-17 like kappa-opioid receptor agonists,
prevents the development of behavioral sensitization to cocaine. However, unlike kappa agonists and other opioid
active dynorphin fragments, DYN2-17 does not increase dopamine in dialysate from the striatum. References
available upon request from ACT.
276
EFFECTS OF KAPPA OPIOID AGONISTS ON COCAINE SELF-ADMINISTRATION BY
RHESUS MONKEYS
N. K. Mello and S. S. Negus
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School,
Belmont. MA
Cocaine and kappa selective opioid agonists have opposing effects on brain dopamine levels and kappa agonists
attenuate cocaine’s behavioral effects under some conditions. For example, kappa agonists attenuate cocaine-related
behavioral and reinforcing effects in rats and antagonize cocaine’s discriminative stimulus effects in squirrel
monkeys. In this study, we examined the effects of kappa opioid agonists on cocaine and food self-administration
in cocaine-experienced rhesus monkeys. Cocaine (0.01 and 0.032 mg/kg/inj/i.v.) and food (1 gm banana pellets)
were available in 4 daily sessions on a second-order FR4 (VR16:S) schedule of reinforcement. A series of
benzomorphan and arytacetamide kappa agonists were administered by continuous i.v. infusion. At least two doses
of each kappa agonist were administered chronically for 10 days to groups of 4 monkeys. After each treatment
condition, monkeys were given saline treatment for at least 4 days or until cocaine and food-maintained responding
returned to baseline levels, Our studies with ethylketocyclazocine and U50,488 suggested that kappa opioid
agonists modulate the reinforcing effects of cocaine. Tolerance to adverse side-effects [emesis, sedation] developed
within 1 or 2 days after treatment began. Further studies to analyze the interactions between cocaine and enadoline.
(-) spiradoline, PD117302, bremazocine and Mr2033 are now ongoing. Data obtained will indicate the conditions
under which kappa agonists may influence cocaine’s reinforcing effects and suggest their potential usefulness as
treatment medications.
ACKNOWLEDGMENTS:
Supported by NIDA grants KO5-DA00101, DA02519 and DA04059.
IN VIVO MICRODIALYSIS OF THE VENTRAL PALLIDUM DURING COCAINE SELF.
ADMINISTRATION
G. M. Sizemore, C. Co, S. I. Dworkin, and J. E. Smith
Bowman Gray School of Medicine, Winston-Salem, NC
Work with drug reinforcers has focused on the importance of the nucleus accumbens. Recent research (e.g., turnover
studies, in preparation) suggests a major role for other structures. The present study utilized in vivo microdialysis
of the ventral pallidum during cocaine self-administration (SA) to assess levels of extracellular dopamine (DA) and
serotonin (5-HT). Seven catheterized rats were allowed access to 3 doses (0.17, 0.33 and 0.67 mg/inf) of cocaine
during each session. Doses occurred in ascending order during 1 hr components separated by 10 min blackouts. Two
responses were required to initiate infusions. Infusions/component was a decreasing function of dose. Four rats
served as “yoked controls.” Sessions for these subjects were conducted in operant chambers wired to chambers in
which rats self-administered cocaine. Saline was infused whenever the SA rats produced an infusion. Microdialysis
probes (1.5 mm) were inserted through previously implanted guide cannulae and artificial CSF was perfused at a
rate of 0.5 µl/min. Samples were collected every 10 min. One microliter of the dialysate was injected into a
microbore HFLC system and electrochemical detection used to assess DA and 5-HT. A 0.5 µl atiquot was used to
determine the amount of cocaine. Baseline concentrations of DA and 5-HT averaged, respectively, 2.0 nM and 0.6
nM. At the beginning of cocaine SA, DA increased by 200-300% while 5-HT was increased about 200%.
Increasing doses of cocaine resulted in increases in the concentration of DA, but not 5-HT. The concentration of
cocaine averaged 2.0 VM during the SA of all cocaine doses. Levels of cocaine, DA, and 5-HT were not increased in
the yoked rats. These data suggest that ventral pallidum dopaminergic innervation may have a significant role in
cocaine SA.
ACKNOWLEDGMENTS:
Supported by USPHS grants DA 03628 and DA 06634.
277
PHARMACOTHERAPY OF COCAINE ABUSE WITH RTI-113
M. J. Kuhar, F. I. Carroll*, S. Dworkin
L. Howell, R. Hunter, and K. McGirr
Yerkes Research Center, Atlanta, GA, *Research Triangle Institute, Research Triangle Park,
NC and Bowman Gray School of Medicine, Winston-Salem, NC
Phenylttopancs are reasonable candidates as medications for cocaine abuse. Ideally, such compounds would be potent,
selective for the dopamine transporter, long-acting to facilitate dosing and enter the brain slowly. Many of the RTI
compounds have such properties. We selected RTI-113 a potential prototypic substitute agonist because of its high
potency and selectivity for the dopamine transporter. In rat locomotor activity studies, RTI-113 increased activity and
was potent and long-lasting. ln studies with nonhuman primates, it increased dopamine efflux in the nucleus
accumbens and it had significant stimulant effects on schedule-controlled behavior that were slow in onset and long in
duration; compared to cocaine, RTI-113 was approximately 10 times more potent. In drug self-administration
studies, RTI-113, when administered to rats just prior to the self-administration session, caused a dose-related
reduction in cocaine self-administration. Thus, RTI-113 is a potential medication for treating cocaine abuse in
humans.
ACKNOWLEDGMENTS:
Supported by RR-00165, DA-01161, and DABT63-96-C-0063.
OLANZAPINE ATTENUATES THE DISCRIMINATIVE STIMULUS AND REINFORCING
EFFECTS OF COCAINE
W. M. Meil, J. W. Boja, and M. D. Schechter
Department of Pharmacology,
Rootstown, OH
Northeastern Ohio Universities College of Medicine,
This study investigated the ability of olanzapine, a newly marketed “atypical” antipsychotic with affinity for 5-HT2,
D1, D2, and muscarinic receptors, to block the discriminative stimulus and reinforcing properties of cocaine in male
Sprague-Dawley rats. Subjects were trained to discriminate intraperitoneally (i.p.) administered cocaine (5 mg/kg)
from vehicle using a 2 lever, food-reinforced (FR 10) discrimination procedure. Pre-treatment with i.p. clozapine
(6 - 18 mg/kg) or olanzapine (1.5 - 6 mg/kg) 45 min prior to cocaine administration produced a significant closedependent decrease in discriminative performance and an increase in the time to FR 10 selection. The ability of i.p.
olanzapine to block the reinforcing effects of cocaine was further investigated by using the conditioned place
preference paradigm and the iv drug self-administration procedure. Pre-treatment with olanzapine (1.5 - 4.5 mg/kg)
significantly attenuated the ability of cocaine to produce conditioned place preference. Olanzapine (1.5 - 6 mg/kg)
also dose-dependently attenuated cocaine self-administration (0.33 mg/infusion) on a FR 2 schedule of
reinforcement. These results indicated that olanzapine can block the discriminative stimulus and reinforcing
properties of cocaine.
ACKNOWLEDGMENT: Supported by The Ohio Board of Regents Academic Challenge #3594.
278
EFFECTS OF 7-NITROINDAZOLE, A SPECIFIC BRAIN NOS INHIBITOR, ON COCAINE
DISCRIMINATION IN RATS
S. L. Collins, M. A. Edwards, and K. M. Kantak
Department of Psychology, Boston University, Boston, MA
Pretreatment with the brain and endothelial nitric oxide synthase (NOS) inhibitor NC-nitro-L-arginine methyl ester
(L-NAME) has previously been shown to produce a 3-fold decrease in the ED50 for cocaine in rats trained to
discriminate 10 mg/kg cocaine. Given alone, L-NAME did not substitute for cocaine. In addition, the D1 receptor
antagonist SCH 23390 and the D2 receptor antagonist haloperidol blocked the enhancing influence of L-NAME on
the discriminative stimulus (DS) effects of cocaine (Edwards and Kantak, 1995). Since L-NAME non-selectively
inhibits NOS, it is not clear if its interactions with cocaine were related to brain and/or endothelial NOS inhibition.
The present study examined the effects of the specific brain NOS inhibitor 7-nitroindazole (7-NI) in eight tats
trained to discriminate 10 mg/kg cocaine. Like L-NAME, 7-NI (3.0-17.8 mg/kg) did not substitute for cocaine, but
produced a dose-dependent leftward shift in the cocaine dose-response curve. Pretreatment with 10 mg/kg 7-NI
produced a 3-fold decrease in the ED50 for cocaine (3.6 my/kg vs.1.1 mg/kg). Enhancement of the DS effects of
cocaine by 7-NI was blocked by a low dose of SCH 23390 (0.003 mg/kg) that did not alter the DS effects of
cocaine atone. The ED50 values were similar for SCH 23390 + 7-NI + cocaine (2.7 mg/kg) and cocaine alone (3.6
mg/kg) treatments. The present results support the importance of dopamine receptors for mediating the influence of
7-NI on the DS effects of cocaine, and also suggest that the enhancing effects of NOS inhibitors on cocaine are
specific to brain NOS.
E F F E C T S O F D 2 , D 3 O R D 4 D O P A M l N E RECEPTOR BLOCKADE ON SELFADMINISTRATION OF COCAINE AND QUINELORANE IN RATS
S. B. Caine, S. S. Negus, N. K. Mello, L. Bristow*, J. Kulagowski*, and S. Patel*
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School,
Belmont, MA and *Merck Sharp and Dohme Research Laboratories, Harlow, UK
Novel dopamine receptor antagonists were used to investigate the relative roles of D2, D3 and D4 receptors in the
reinforcing effects of cocaine. Eight male rats self-administering 0.25 mg cocaine i.v. under a FR 5 TO 20s
schedule were pretreated (0.1-10 mg/kg i.p.) with the D2 preferential antagonist L-741,626 or the D3 preferential
antagonist L-745,829. The D2 antagonist was significantly more potent (3%-fold) than the D3 antagonist in
increasing self-administration, and produced a greater than 60% increase above baseline at a dose of 3.0 mg/kg. In
contrast. the D3/D2 agonist quinelorane (0.25 µg i.v., n=5) given in combination with cocaine dacreasol selfadministration rates by greater than 50%. The D2 antagonist (1.0-3.0 mg/kg), but not the D3 antagonist, reversed
the effects of quinelorane on self-administration. In vitro studies revealed 20-fold and 40-fold selectivities, and
nanomolar affinities, for these D2 and D3 antagonists at their preferred receptors, respectively. Moreover ex vivo
studies showed rat brain concentrations approached 10 µM after administration of 10 mg/kg i.p. of either
compound. Finally, pretreatments with the highly selective D4 antagonist L-745,870 (0.3-32.0 mg/kg i.p., n=5)
failed to produce effects consistent with antagonism of the reinforcing effects of cocaine Despite much indirect
evidence that dopamine agonists modulate the behavioral effects of cocaine through D3 receptors, studies with these
particular antagonists fail to support the hypothesis that the reinforcing effects of cocaine are dependent upon, or
modulated through, D3 or D4 receptors in the rat.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA07252, DA00101 and DA04059.
279
BEHAVIORAL EFFECTS OF DOPAMINE D2/D3 AGONISTS IN RHESUS MONKEYS:
INTERACTION WITH COCAINE
R. V. Subrahmanyam, R. H. Mach, and M. A. Nader
Dept. of Physiology/Pharmacology, Bowman Gray School of Medicine, Winston-Salem, NC
The behavioral effects of cocaine have been shown to be mediated in part by dopamine D2 and D3 receptors. In order
to further investigate the receptor mechanisms involved in cocaine’s effects, the D2/D3 agonists quinpirole (D2
binding affinity: 6.4 nM; D3: 1.7 nM), (±)-7-OH-DPAT (D2: 2.6; D3: 0.4) and R-(+)-7-OH-DPAT (D2: 56; D3:
0.57) were examined in two animal models of cocaine abuse. In i.v. self-administration studies (n=3), responding
was maintained under a fixed-interval 5-min schedule of cocaine presentation. When substituted for the baseline
dose of cocaine (0.03 mg/kg/inj), quinpirole (0.001-0.01 mg/kg/inj) maintained rates of responding above saline
rams. indicating mat it was functioning as a reinforcer. Two cocaine-naive animaIs did not acquire quinpirole selfadministration. suggesting that cocaine modified the D2/D3 receptor system. In animals (n=4) trained to
discriminate cocaine (0.1-0.3 mg/kg, i.m., 10-min pretrearment) from saline, quinpirole (0.001-0.56 mg/kg) fully
substituted for cocaine (>80%) in three of four monkeys. Neither (±)-7-OH-DPAT nor R-(+)-7-OH-DPAT fully
substituted for cocaine up to doses that had significant rate-decreasing effects (n=2); consistent with a D3-mediated
effect, R-(+)-7-OH-DPAT was more potent. When me rate-decreasing effects were attenuated by increasing me
pretreatment time, (±)-7-OH-DPAT fully substituted for cocaine. These results indicate that quinpirole and (±)-7OH-DPAT have cocaine-like discriminative stimulus effects. These data provide further support that the behavioral
effects of cocaine may be mediated through dopamine D3 receptors.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA 09142 and DA 08632.
THE GABA TRANSAMINASE INHIBITOR -VINYL
SELF-ADMINISTRATION IN RATS
GABA
ATTENUATES
COCAINE
S. A. Kushner, S. L. Dewey1 , and C. Kornetsky
Department of Pharmacology, Boston University School of Medicine, Boston, MA and
1
Brookbaven National Laboratory, Upton, NY
Previous work in our laboratory has demonstrated that the irreversible GABA transaminase inhibitor -vinyl GABA
(GVG) raises brain stimulation reward (BSR) thresholds and attenuates the threshold-lowering effects of cocaine.
To further test the hypothesis that increased levels of GABA have an inhibitory effect on dopamine-mediated reward
systems, the effects of GVG on i.v. self-administration of cocaine in four male Wistar rats were examined. Rats
were trained to self-administer cocaine (0.3 mg/kg/infusion) on an FR5 schedule. Once stable responding had been
established, rats were injected (ip) with GVG (100, 200, or 300 mg/kg) or saline three hours prior to the start of the
self-administration session. Preliminary results indicate that GVG dose-dependently decreased cocaine intake:
pretreatment with saline reduced responding to 96% of baseline (n=3), 100 mg/kg GVG to 90% of baseline (n=2),
200 mg/kg GVG to 60% of baseline (n=4), and 300 mg/kg GVG to 6% of baseline. These results support those
found previously in our BSR studies and provide further evidence to suggest that increases in GABAergic activity
have an inhibitory influence on dopamine-mediated reward.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA02326 and K05-DA00099 to C.K. and U.S.
Department of Energy, Office of Health and Environmental Research, NIMH grant MH49165 to S.L.D.
280
EFFECTS OF A SLOW-ONSET, LONG-ACTING DOPAMINE REUPTAKE BLOCKER ON
BRAIN REWARD MECHANISMS
E. L. Gardner, X. Liu, W. Paredes, A. Giordano, J. Spector, M. Lepore, K.-M. Wu*, and M.
Froimowitz*
Albert Einstein College of Medicine, New York, NY and *Pharm-Eco Laboratories.
Lexington, MA
Cocaine’s abuse potential has been linked to its rapid blockade of presynaptic dopamine (DA) reuptake in brain
reward loci. Also, persons with vulnerability to cocaine abuse may have hypofunction in these brain reward
systems. Thus, development of slow-onset long-acting DA reuptake blockers for cocaine substitution therapy
seems logical. Using rational drug design and a pharmacophore model, a series of such compounds were
synthesized. The lead compound, CDTP-30,640, was tested in vivo in lab rats in brain reward-related paradigms. It
dose-dependently augmented electrical brain-stimulation reward (BSR) as potently as cocaine, but with a slow-onset
long-acting profile. Its effect on BSR was additive with cocaine, but only when cocaine was given many hours after
it, to coincide with CDTP-30,640's slow-onset peak effect. When co-administered to rats self-administering cocaine
i.v., it dose-dependently reduced cocaine self-administration, When substituted for cocaine in experienced selfadministering rats, it maintained self- administration behavior at slightly above saline levels. Thus, CDTP-30,640’s
action on brain reward mechanisms is cocaine-like, but with a slow-onset long-acting profile, suggesting possible
therapeutic utility.
ACKNOWLEDGMENTS:
Supported by NIDA contract N01 DA48313, the Aaron Diamond Foundation.
and the New York State Office of Alcohol and Substance Abuse Services.
THE EFFECTS OF CHRONIC DOPAMINE
ADMINISTRATION IN RATS
ANTAGONISTS
ON COCAINE SELF-
R. L. Peltier, C. J. Wallis*, and M. W. Oglesby*
Louisiana State University Medical Center, Shreveport, LA and *University of North Texas
Health Science Center, Fort Worth, TX
These experiments tested the hypothesis that chronic administration of the dopamine (DA) antagonists flupenthixol
(FLU), SCH23390 (SCH) and eticlopride (ETI) would produce sensitization to the reinforcing effects of cocaine.
Rats (N=18) were trained to self-administer cocaine (i.v.) under a fixed-ratio 2 (FR2) schedule of reinforcement.
After baseline dose-response curves were obtained, rats were treated chronically with either FLU (3.2 mg/kg/12 hr/5
days; SC), SCH (0.25 mg/kg/12 hr/7 days; SC), or ETI (0.25 mg/kg/12 hr/7 days; SC). Either 24 (SCH and ETI)
or 72 (FLU) hours following the last chronic injection, dose-response curves for cocaine self-administration were
obtained. Chronic administration with the D1 (SCH) or the mixed dopamine antagonist (FLU) shifted the doseresponse curve for cocaine self-administration to the left, indicating sensitization to the reinforcing effects of
cocaine. In contrast chronic treatment with the D2 antagonist ETI shifted the dose-response curve for cocaine selfadministration to the right, indicating tolerance to the reinforcing effects of cocaine. This suggests that both the
D1 and the D2 receptor subtypes are involved in mediating the reinforcing effects of cocaine; but they differ
functionally.
281
BEHAVIORAL EFFECTS OF DOPAMINE D1 LOW-EFFICACY AGONISTS IN MONKEYS
J. Bergman and G. Carey
Harvard Medical School-McLean Hospital, Belmont MA
The effects of dopamine D1 agonists with low to moderate agonist efficacy in studies of adenylate cyclase
stimulation or in radioligand binding experiments to evaluate the effects of GTP on binding affinity (e.g., SKF
77434, SKP 38393, and SKP 75670) have effects that overlap those of dopamine receptor blockers. For example,
they may produce catalepsy-associated behavior in observational studies, decrease leverpress response rates, and
antagonize discriminative-stimulus or reinforcing effects of psychomotor stimulants such as cocaine or
methamphetamine. The present experiments were designed to further evaluate the relationship between D1 agonist
efficacy and behavioral effects by studying the observable and stimulant-antagonist effects of SKF 83959, a D1
agonist that has been reported to produce ameliorative effects in MPTP-treated monkeys, yet to have no agonist
effects in biochemical studies of D1 efficacy. In ongoing observational studies and in experiments in squirrel
monkeys trained to discriminate injections of methamphetamine from vehicle, SKF 83959 (0.3-10.0 mg/kg, i.m.)
does not appear to produce catalepsy-associated behavior, does not consistently reduce leverpress-response rates, and
is not distinguished as methamphetamine. Yet, pretreatment with 3.0 mg/kg SKF 83959 displaces the dose-effect
function for the methamphetamine-like SD effects of the D1 agonist R-6-BrAPB at least 3-fold rightward in all
subjects. These findings suggest, tentatively, that the direct and stimulant-antagonist effects of D1 low-efficacy
agonists may be separable and that in vitro efficacy estimates may not directly correspond to the functional efficacy
of D1 agonists in primates.
ACKNOWLEDGMENTS:
Supported by USPHS DA 03774 and MH 07658.
RAPID ASSESSMENT OF COCAINE SELF-ADMINISTRATION IN RHESUS MONKEYS
G. Carey and J. Bergman
Harvard Medical School-McLean Hospital, Belmont, MA
Recently, self-administration techniques have been developed to allow the assessment of the effects of several doses
of drug in the same session, speeding the evaluation of the compounds reinforcing effects (Winger et al., 1989 Drug
AIcohol Depend. 24: 135-142). In the present study similar techniques were used to train rhesus monkeys (n-4) to
self-administer different doses of cocaine under a fixed-ratio (FR) schedule of reinforcement. After initial training in
single component sessions, experiments were modified to comprise multiple 20-min components, each separated by
a 20-min time-out (TO). During each component monkeys could lever press to obtain up to 10 injections of a
given concentration of cocaine. Each injection condition was signaled by a different visual stimulus; for example,
blue light was associated with no injection, white light with vehicle, green light with 0.01 mg/kg/inj, red light
with 0.1 mg/kg/inj and so on. Doses were presented in ascending order and overlapping dose-ranges were studied on
separated days. Finally, the effects of cocaine were determined at different FR values (FR 10-FR560). Results
show that, with comparable schedule parameters, dose effect functions for cocaine self-administration using
conventional and the rapid assessment procedure (RAP) overlap considerably. Using the RAP. dose-effect functions
wee reproducible over many months, and the effects of individual doses were similar regardless of their order of
presentation within the session. Dose-effect functions were shifted rightward by the D1 dopamine receptor blocker
SCH 39166, and the effectiveness and Potency of the antagonist varied under different FR values. These results
show that rapid assessment procedures can be used to evaluate potential medications for cocaine addiction, and their
effectiveness under different environment conditions.
ACKNOWLEDGMENTS:
Supported by MH 07658, DA 00499, and DA 03774.
282
REINSTATEMENT OF COCAINE-SEEKING BEHAVIOR IN A NONHUMAN PRIMATE
MODEL OF RELAPSE: EFFECTS OF PREFERENTIAL DOPAMINE D1 AND D3 AGONISTS
R. L. Barrett-Larimore and R. D. Spealman
New England Regional Primate Research Center, Harvard Medical School, Southborough, MA
The present study investigated the effects of priming with dopamine D1 and D3 agonists on the reinstatement
extinguished cocaine-seeking behavior. Using a nonhuman primate model of relapse, squirrel monkeys were trained
to self-administer cocaine under a second-order schedule of i.v. injection. Completion of every tenth response (FR
10) during a 10-min fixed interval (FI 10-min) produced a brief (1 sec) visual stimulus, The first FR 10 completed
after the 10-min FI elapsed produced both the brief stimulus and an injection of cocaine. High rates of responding
(0.8-2.0 resp/sec) were maintained under these conditions by 0.1 or 0.3 mg/kg/injection cocaine. Responding was
subsequently reduced or eliminated during a series of extinction sessions in which saline was substituted for cocaine
and the brief stimulus was omitted. Following extinction, responding could be reinstated by administering a
priming (noncontingent) injection of cocaine before the session. Cocaine-induced reinstatement was dose-dependent
and could be mimicked by priming with methamphetamine. Neither the D1 agonists SKF 81297 and SKF 82958
nor the D3 agonist PD 128907 reinstated cocaine-seeking behavior at doses that have been found to mimic the
discriminative stimulus effects of cocaine. In drug combination tests, pretreatment with either SW 81297 or SKF
82958 suppressed cocaine-induced reinstatement of drug-seeking, usually at doses that also suppress schedulecontrolled behavior maintained by non-drug reinforcers. Pretreatment with PD 128907 did not attenuate cocaineinduced reinstatement at any dose tested. The results suggest that pharmacothetapics for cocaine addiction that target
D1 or D3 receptors may be devoid of cocaine-like priming effects. The capacity of D1 agonists to attenuate cocaineinduced reinstatement of drug-seeking warrants further investigation.
ACKNOWLEDGMENTS:
Supported by DA11054, DAC0499, MH14275 and RR00168.
INTRAVENOUS SELF-ADMINISTRATION OF BENZTROPINE ANALOGS BY RHESUS
MONKEYS
J. K. Rowlett, R. H. Kline*, J. L. Katz*, A. H. Newmam*, and W. L. Woolverton
Dept. Psychiatry and Human Behav., Univ. Mississippi
* Psychobiol. Sect., NIH/NIDA, DIR, Baltimore, MD
Med. Ctr., Jackson, MS and
Chloro-substituted analogs (3’-Cl, 4’-Cl) of benztropine (B) bind to the dopamine transporter (DAD and inhibit
dopamine uptake. 3’-Cl has locomotor and discriminative stimulus (DS) effects similar to cocaine (C), whereas 4’Cl weakly stimulates locomotion and only partially reproduces the DS effects of C. Based on this profile, 3’-CI
may have reinforcing effects, whereas 4’-Cl may lack reinforcing effects despite binding to the DAT. To assess this
Possibility, four rhesus monkeys were trained to self-administer i.v. C (0.03 mg/kg/inj, FR 10, 1 hr/day). When
inj/hr were stable (±15% variation for 3 sessions, no upward or downward trend), saline (S) was made available
until responding declined to low levels and was stable. Responding was re-established with C, and doses of C, B,
3’-Cl and 4’-Cl were available for at least the same number of sessions as S, and until responding was stable. C
(0.003-0.1 mg/kg/inj) maintained responding above S levels, whereas B (0.003-1.0 mg/kg/inj) did not. Both 3’-Cl
(0.001-0.3 mg/kg/mj) and 4’-Cl (0.001-1.0 mg/kg/inj) also maintained responding above S levels. Responding at
some 3’- and 4’-Cl doses was more variable and took more sessions to reach stability than C. These data indicate
that although B blocks dopamine uptake, it was not a reinforcer. Although 4’-Cl has diminished C-like locomotor
and DS effects compared to 3’-Cl, both analogs had reinforcing effects. Variable responding maintained by the
analogs may be due to relatively weak effects and/or long durations of action.
ACKNOWLEDGMENT: Supported by NIDA grant DA-10352.
283
FURTHER EVALUATION OF THE BEHAVIORAL EFFECTS OF 2-ß-PROPANOYL-3ß-(4TOLYL)-TROPANE (PTT) IN MONKEYS
A. Birmingham, S. Nader, C. Hubbard, H. Davies*, K. Grant, and M. Nader
Dept. Physiology/Pharmacology, Bowman Gray Sch Med. Wake Forest Univ, WinstonSalem, NC, *Dept. chemistry, Univ. Buffalo
2-ß-propanoyl-3ß-(4-tolyl)-tropane (PTT) is a cocaine analog that binds with high affinity and selectivity to me
dopamine transporter. Previous studies indicated that PTT has a unique behavioral profile in monkeys, having
cocaine-like discriminatlve stimulus effects, but not functioning as a reinforcer when substituted for cocaine. The
purpose of this study was to further evaluate the behavioral effects of PTT in rhesus monkeys. In Exp. 1, monkeys
(N=2) responded under a multiple food-drug-food fixed-ratio (FR) 30 schedule. Food components (1g pellets) Iasted
30 min and the drug component (cocaine 0.03 mg/kg/inj, i.v.) was 60 min. Presession administration of (+)PTT
(0.003-0.056 mg/kg, i.v.) and cocaine (0.01-3.0 mg/kg, i.v.) produced nonspecific rate decreasing effects on foodand cocaine-maintained responding. In Exp. 2, saline was self-administered and the ability of (+)PTT and cocaine to
reinstate responding was evaluated (N=3). Both PTT (0.003-0.056 mg/kg, i.v.) and cocaine (0.03-3.0 mg/kg, i.v.)
resulted in increases in total saline injections. PTT administration resulted in more saline injections compared to
the maximal effects observed following cocaine pretreatments. PTT was at least 1.0-log unit more potent man
cocaine in reinstating responding. These results provide evidence that a drug that does not function as a reinforcer,
but does have discriminative stimulus effects similar to cocaine, can reinstate cocaine-seeking behavior. It is, at
present. not clear whether such an outcome indicates that PTT can induce relapse in cocaine abstinent drug abusers.
ACKNOWLEDGMENT:
Supported by DA 06634.
INDEPENDENT INTERACTION OF ALPRAZOLAM AND CAFFEINE UNDER CHRONIC
DOSE REGIMENS ON DRL 45-S PERFORMANCE
J. L. Falk, Y. Wang, and C. E. Lau
Department of Psychology, Rutgers University, New Brunswick, NJ
In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose
regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low
rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study
investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by me
oral route. Acute alprazoIam and caffeine dose-response curves (DRCs) were characterized and were then used to
determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement
rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined
during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-aIprazolam dose regimens. Complete
tolerance to caffeine induced rate changes was observed on the second day. Incomplete tolerance occurred only at
higher alprazolam doses (7-12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon
discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well
as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam
effects on the two rates under chronic dose regimens. The Pöch DRC method further confirmed the independent
interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic
dose regimens despite the development of tolerance in the latter regimens.
ACKNOWLEDGMENTS:
00142.
Supported by NIDA grant R37 DA-03117 and Research Scientist Award K05 DA-
284
EPHEDRINE AND CAFFEINE ARE CAPABLE OF POTENTIATING EACH OTHERS
AMPHETAMINE-LIKE STIMULUS EFFECTS
R. A. Glennon, R. Young, and M. Gabryszuk
Department of Medicinal chemistry, School of Pharmacy, Medical College of Virginia,
Virginia Commonwealth University, Richmond, VA
Tests of stimulus generalization were conducted using male S-D rats (n=7) trained to discriminate (+)amphetamine
(AMPH; i.p., 15-min psii; ED50=0.3 mg/kg) from 0.9% saline vehicle using a Vl 15-s schedule of reinforcement.
Substitution occurred with (-)ephedrine and caffeine (ED50 doses = 4.5 and 13.0 mg/kg, respectively); (+)ephedrine
produced a maximum of 50% AMPH-appropriate responding at 12 mg/kg and disruption of behavior at higher
doses. This apparently represents the first time an AMPH stimulus has been demonstrated to fully generalize to
caffeine. A fixed dose of caffeine (3 mg/kg; which, by itself, elicited only 1% AMPH-appropriate responding)
puduced a two-fold leftward shift of the (-)-ephedrine dose-response curve (ED50 = 2.8 mg/kg). In a separate
experiment, this caffeine dose plus the ED50 dose of (-)-ephedrine resulted in the animals making >90% of their
responses on the AMPH-appropriate lever. A fixed dose of (-)-ephedrine (2 mg/kg; which, by itself, elicited 0%
AMPH-appropriate responding) produced a two-fold leftward shift of the caffeine dose-response curve (ED50=5.2
mg/kg). These results suggest that (i) ephedrine and caffeine can produce AMPH-like stimulus effects, that (ii) the
AMPH-like stimulus character of ephedrine is associated primarily with the (-)-isomer, and that (iii) (-)-ephedrine
and caffeine are capable of potentiating each others AMPH-like stimulus properties.
ACKNOWLEDGMENT:
Supported in parts by DA 01642.
COMPARISON OF INTRAVENOUS CAFFEINE AND NICOTINE IN COCAINE ABUSERS
B. E. Garrett and R. R. Griffiths
Behavioral Pharmacology Research Unit. Johns Hopkins University School of Medicine,
Baltimore, MD
The present study compared the effects of intravenously administered caffeine and nicotine in cocaine abusers who
were also cigarette smokers. Subjecls (N=9) resided as inpatients on a residential behavioral pharmacology research
unit. Cigarette smoking was permitted. However, cigarette smoking was restricted at least 8 hours before each
session. For consistency with the nicotine intake, subjects were administered caffeine (150 mg/70 kg, b.i.d.) in
capsules, with the last dose given at least 8 hours before each session. In each session, physiological and subjective
data were collected before and repeatedly after an intravenous injection of placebo, caffeine (100, 200, 400 mg/70 kg)
or nicotine (0.75, 1.5, 3.0 mg/70 kg) over a 10-second period. Both caffeine and nicotine produced dose-related
increases in subjective ratings of “drug effect”, “good effects”, “drug liking”, “stimulated” and “high” which peaked
approximately two minutes after injection. Nicotine generally produced greater effects than caffeine on these
measures. On a drug identification questionnaire, the highest dose of nicotine was identified as a stimulant (like
amphetamine, cocaine) by significantly more subjects than the other nicotine or caffeine doses. The majority of
subjects also identified the highest dose of nicotine as cocaine. Overall, both caffeine and nicotine produced positive
subjective effects. However at the doses studied, nicotine produced greater effects and was more likely to be
identified as cocaine than caffeine.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-03890.
285
EFFECTS OF AN ALTERNATIVE REINFORCER AND CAFFEINE ON HUMAN COCAINE
SELF-ADMINISTRATION
J. M. Roll, S. T. Higgins, and J. Tidey
University of Vermont, Human Behavioral Pharmacology Laboratory, Burlington, VT
In this ongoing study we am examining the influence of alternative monetary reinforcement and caffeine
pretrearment on the probability of cocaine use in humans under double-blind laboratory conditions. The
experiment consists of two phases. First, participants choose between cocaine hydrochloride and active placebo,
both of which are administered intranasally in 10 mg unit doses. Those who select cocaine over placebo proceed to
the second phase. During the second phase participants are pretreated with several caffeine doses (0, 150,
300mg/70kg) and then allowed to choose between cocaine and varying amounts of money. To date 12 participants
have completed the first phase of the study, of which, 11 selected cocaine over placebo. Seven participants have
completed the second phase of the study. In 6 of these 7 participants, choice of cocaine decreased as the amount of
money available for me monetary choice increased, demonstrating that the behavioral control exerted by cocaine was
dependent on the magnitude of the alternative reinforcer available. Results suggest that caffeine pretreatment has no
effect on the choice of cocaine versus money. These results demonstrate further the relationship between the
availability of alternative reinforcers and cocaine use, and suggest that caffeine does not alter this relationship.
CHARACTERISTICS OF PATIENTS WITH CHRONIC USE OF OTC ANALGESICS
CONTAINING CAFFEINE
E. C. Strain and R. R. Griffiths
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD
For some patients, chronic use of over-the-counter analgesics (OTCAs) containing caffeine may be related to
caffeine-dependence and/or caffeine withdrawal The purpose of this study was to compare daily users of OTCAs
containing caffeine to daily users of OTCAs not containing caffeine. Chronic OTCA users (N=162) were recruited
through newspaper advertisements and participated in a structured telephone interview that characterized the pattern,
type and amount of their OTCA use, as well as the reasons for their initial and continued use of OTCAs. Thirty of
the 162 participants (18.5%) reported daily use of OTCAs containing caffeine. Their average daily caffeine use
from analgesics was 274 mg (range 48-780 mg). Compared to patients who used chronic OTCAs that did not
contain caffeine, there was no significant difference in their daily non-analgesic related dietary caffeine consumption.
However, users of caffeine-containing OTCAs were significantly more likely to report having headache (a frequent
feature of caffeine withdrawal) as their current, primary, and only pain. In addition, they were significantly more
likely to have gone to special lengths to obtain their OTCA, to have had friends or family members complain
about their OTCA use, and to have tried to quit using OTCAs. These results suggest one component of continued
use of caffeine-containing OTCAs for some patients may be related to the caffeine content of these medications.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA03890, DA00332, and DA00166 from NIDA.
286
CO-MORBID PSYCHIATRIC DIAGNOSIS AND PERSONALITY
DIMENSIONS IN
PATIENTS ENROLLED IN A METHADONE MAINTENANCE TREATMENT PROGRAM
J. Gonz,alez and W. H. Berrettini
Department of Psychiatry and Human Behavior, Biological Psychiatry Section, Thomas
Jefferson University Hospital, Philadelphia, PA
Co-morbid psychiatric disorders among methadone maintenance (MM) patients are clinically challenging and present
difficulties in preventing relapse. Among NM patients, co-morbid diagnoses frequently include unipolar depression
antisocial personality, alcoholism and anxiety disorders. The comorbid psychiatric disorders and personality
dimensions in patients enrolled in an MM program have not been studied extensively. The goal of the present work
is to elucidate co-morbid diagnoses and to describe the personality dimensions in a population of patients in MM
treatment. The results obtained may help establish a relationship between personality dimensions and treatment
response in this population. Each patient was interviewed using the Structured Clinical Interview for DSM-IV for
Axis-I Disorders (SCID-I) and asked to complete the Tridimensional Personality Questionnaire (TPQ). The TPQ
(Cloninger, 1993) yields measures of temperament and character across three dimensions: novelty seeking, harm
avoidance, and reward dependence. Also a structured questionnaire was used to obtain parental psychiatric and
substance abuse history. Adoption studies have indicated that vulnerability to substance abuse may be a partially
inherited condition with strong influences from environmental factors as well. All patients (N =34) currently
included in the study developed opioid dependency (OD) before age 20 with Addiction Severity Index (ASI) score at
least 7 on the drug severity profile and total ASI score of 25 or more. Individuals with epilepsy, schizophrenia,
schizooffective disorder, bipolar illness, or mental retardation were excluded. All patients (19 y/o- 59 y/o) had a
history of relapse after multiple inpatient and outpatient treatment for substance dependence, and at the time of
interview they met criteria for Opioid Dependency (100%). Sedative-Hypnotic Dependency (23.5%). Major
Depressive Disorder (17.6%) and Substance Induced Anxiety Disorder (14.7%). We observed a significant
relationship between alcohol/drug abuse co-morbidity in first degree relatives (mother or father) and substance abuse
in their sibling (62% vs 37%; p=0.013), in comparison with the patients with no co-morbid family history. Only
11 patients (37%) had parents with negative history of Alcohol or Drug Abuse. This is compatible with substantial
heritability of risk for substance abuse/dependence in first degree relatives of these patients. In the personality
dimensions our patients scored high in novelty seeking and harm avoidance but low on reward dependence. Our
results show the high prevalence of psychiatric and substance abuse disorders in this population as observed
previously by Brooner R.K. et al., 1997 and Rounsavibe B.J. et al. 1982, 1986. This population is engaged in
frequent exploratory activities, impwsive decision making with poor social attachment and low sentimentality. This
study has the goal of coil data in =200 probands and controls in order to assess more completely co-morbid
diagnoses and personality characteristics in this population.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-10211.
287
POSTER SESSION IV
REVERSIBLE AND RAPID EFFECTS OF METHAMPHETAMINE ON DOPAMINE
TRANSPORTERS
A. E. Fleckenslein, R. R. Metzger, J. M. Kokoshka, D. G. Wilkins, J. W. Gibb, and G. R.
Hanson
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT
High-dose methamphetamine (METH) administration causes reactive oxygen species formation in vivo. Because of
this finding, and the observation that reactive oxygen species decrease dopamine transporter (DAT) activity in vitro,
effects of METH administration on DAT activity in rat striatum were investigated. A single METH injection
causes a dose-dependent (0-15 mg/kg) decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after
METH administration; an effect attributable to a decreased Vmax of [3H]dopamine uptake. Similarly, multiple highdose administrations of METH (10 mg/kg/dose; 4 injections at 2-h intervals) rapidly decreased DAT function. The
decreases in DAT activity after either a single or multiple METH administrations were reversed 24 h after treatment.
Taken together, these data suggest that METH selectively decreases DAT activity, perhaps through a reactive
oxygen species-mediated mechanism. These findings may have important implications regarding the role of
oxidative events in the physiological regulation of monoaminergic systems.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-05780, DA-04222 and DA-00869.
THE AMPHETAMINE-INDUCED INCREASE IN EXTRACELLULAR DOPAMINE IS
IMPULSE-DEPENDENT AS WELL AS IMPULSE-INDEPENDENT
C. A. Schad; J. B. Justice, Jr.; and S. G. Holtzman
Departments of Pharmacology and Chemistry1, Emory University, Atlanta, GA
The specific opioid receptor antagonist naloxone attenuates the effects of amphetamine in a wide variety of
behavioral paradigms. Naloxone also attenuates the amphetamine-induced increases in extracellular dopamine in
both the striatum (STR) and nucleus accumbens (NACC) of rats. Therefore, it has become of interest to better
elucidate why an opioid receptor antagonist attenuates the effects of amphetamine. One possible explanation for
these observations is that amphetamine, which is known to cause the release of other neurotransmitters, may cause
the release of endogenous opioids which, in turn, cause a disinhibition of central dopamine neurons. In this case,
there would actually be two components to the increase in extracellular dopamine seen after amphetamine
administration: (1) direct release of dopamine by amphetamine acting at the dopamine terminal (i.e. an impulseindependent action), and (2) indirect release of dopamine by amphetamine promoting the release of endogenous
opioids (i.e. an impulse-dependent action). Therefore, this research was designed to determine whether there is both
an impulse-dependenl as well as an impulse-independent component to the increase in extracellular dopamine seen
after amphetamine administration. Microdialysis was performed on adult male rats that had surgically implanted
guide cannula aimed at the dorsal surface of the STR. After the collection of baseline samples, 1µM of the sodium
channel blocker tetrodotoxin (TTX) or vehicle was added to the perfusate of the probe. Thirty minutes following the
initiation of TTX, cumulative doses of SC d-amphetamine (0.0, 0.1, 0.4, 1.6, 6.4 mg/kg) were administered at 30
min intervals. The data indicate that 1µM TTX attenuates the amphetamine-induced increase in extracellular
dopamine by approximately 30%. This observation suggests that the amphetamine-induced increase in extracellular
dopamine does have an impulse-dependent component.
ACKNOWLEDGMENTS:
Supported by NIH Grants DA00541, DA07532, K02 DA00179, K05 DA00008,
DA05649 and NSF Grant IBN-9412703.
288
THE DELTA OPIOID DADLE ATTENUATED METHAHPHETAMINE NEUROTOXICITY
VIA OPIOID AND NONOPIOID MECHANISMS
L-I. Tsao, B. N. Ladenheim, J.-L. Cadet, and T.-P. Su
Molecular Neuropsychiatry Section, Intramural Research Program, National Institute on Drug
Abuse, NIH, Baltimore, MD
The delta opioid peptide DADLE ([D-ala2,D-Ieu5]enkephalin) can prolong organ survival time in an organ
preservation preparation (Chien et al., 1994). As the survival of organ might involve oxidative mechanisms, this
study examined if DADLE might protect against dopaminergic (DA) terminal loss induced by methamphetamine
(METH). Male CD 1 mice received i.p. injections of 5 or 10 rng/kg of METH four times in a day given 2 hrs
apart. DADLE, when given, was injected (i.p.) 30 min before each METH injection. Two weeks later, animals
were sacrificed and brains removed and processed for autoradiographic examination using a DA transporter rnarker
[125I]RTI-121. METH caused 40% (5 mg/kg) and 65% (10 mg/kg) decreases in striatal (ST) DA transporter. The
nucleus accumbens (NA) was less affected by both doses of METH. DADLE at 4 mg/kg completely blocked the
DA terminal loss in all areas induced by 5 mg/kg of METH. In mice receiving 10 mg/kg METH, DADLE (4
mg/kg) completely blocked the DA terminal loss in the medial ST and in the NA. However, a partial blockade was
observed in the lateral ST. Naltrexone was used to lest the involvement of opioid receptors in this action of
DADLE using mice receiving 10 mg/kg of METH. Naltrexone (0.1 mg/kg) reversed the neuroprotective effects of
DADLE in the ST but not in the NA. Thus, DADLE blocks METH-induced DA terminal loss via opioid and
nonopioid mechanisms. DADLE may therefore provide some utility in the treatment of METH neurotoxicity or
abuse and, by extension, of the progressive course of Parkinsonism.
ACKNOWLEDGMENT:
Supported by Intramural Research Program, National Institute on Drug Abuse, NIH.
OPPOSITE EFFECTS OF 7-OH-DPAT ON AMPHETAMINE-INDUCED STEREOTYPIES
AND CONDITIONED PLACE PREFERENCE
T. V. Khroyan, D. A. Baker, R. A. Fuchs, and J. L. Neisewander
Department of Psychology, Arizona Stale University, Tempe, AZ
Low doses of 7-OH-DPAT (0.01-0.1 mg/kg) produce a decrease in locomotion and sniffing, but do not produce
conditioned place preference (CPP). In the first experiment, the effects of these doses of 7-OH-DPAT on motor
behaviors and CPP produced by amphetamine (1 mg/kg) were examined. In the second experiment. the effect of 0.1
mg/kg 7-OH-DPAT on amphetamine (0-10 mg/kg) dose-response curves for the same behaviors were examined,
For both experiments, three two-day conditioning trials were conducted On one day, animals received an injection
of their assigned dose of 7-OH-DPAT co-administered with amphetamine and were placed into a distinct
comment for 40 min. On the other day, animals received an injection of saline and were placed into a different
compartment for 40 min. Locomotion and headbobbing were measured following acute and repealed drug
administration. CPP was assessed the day following the last conditioning trial. In me first experiment.
amphetamine-induced locomotion was dose-dependently decreased by 7-OH-DPAT following repeated administration
which was likely due to the emergence of headbobbing, a behavior not observed with amphetamine alone.
Amphetamine-CPP was not altered by co-administration of 0-0.03 mg/kg 7-OH-DPAT, but was attenuated by coadministration of 0.1 mg/kg 7-OH-DPAT. In the second experiment, 0.1 mg/kg 7-OH-DPAT produced a decrease
in amphetamine-induced locomotion al lower doses of amphetamine (0-0.5 mg/kg). However, 7-OH-DPAT
produced increase in headbobbing and no changes in locomotion at the higher doses of amphetamine (0.5-10
mg/kg). Amphetamine-CPP was attenuated by co-administration of 7-OH-DPAT. These findings suggest that 0.1
mg/kg of 7-OH-DPAT attenuates the reinforcing properties of amphetamine despite enhancing stereotypic
behaviors.
ACKNOWLEDGMENTS:
Supported by USPHS grant DA07730 and HHMI.
289
LM-39, A TETRAHYDROISOQUINOLINE RELATIVE OF THE DESIGNER DRUG MDMA,
AS A TRAINING DRUG IN RATS
R. Young, M. Gabryszuk, and R. A. Glennon
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia,
Virginia Commonwealth University, Richmond, VA
Structurally, LM-39 is related to a putative metabolite of methylenedioxyphenylalkylamines, such as the designer
drug MDMA. We reported the synthesis of LM-39 and that it lacks amphetamine-like locomotor activity in mice
(Med Chem Res 1996, 6, 412); LM-39 also fails to substitute for (+)amphetamine in 1 mg/kg (+)amphetaminetrained rats (7% appropriate responding at 5 mg/kg). But we reported that LM-39 (5 mg/kg) produces 75% MDMAappropriate responding in rats trained to discriminate MDMA from vehicle; this suggests that LM-39 possesses
some MDMA-like characler. To further characterize this agent, we trained 5 male S-D rats to discriminate LM-39
(5 mg/kg; ip) from vehicle using a VI 15-s schedule of reinforcement (ED50=0.9 mg/kg). Administration of
MDMA resulted in a maximum of 76% LM-39-appropriate responding at 1 mg/kg; higher doses resulted in
disruption of behavior. Interestingly. the LM-39 stimulus generalized to a positional isomer (LM-40; ED50=2.7
mg/kg) although LM-40 had been previously shown to lack MDMA-like stimulus properties (i.e., 16% MDMAappropriate responding). LM-39 may represent the first member of a structural class of agents with a novel
behavioral profile.
PHARMACOLOGICAL EFFECTS OF MDMA IN HUMANS:
STUDY
A DOSE-FINDING PILOT
J. Caml, M. Mas, M. Farré, L. San, P. N. Roset, A. Mas, S. Poudevida, and R. de la Torre
Dept. of Pharmacology and Toxicology, Institut Municipal d’lnvestigació Mèdica (IMIM),
Universitat Autònoma de Barcelona, Barcelona, Spain
3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative. Although MDMA is an
increasingly popular recreational drug among american and european young people, there are only few experimental
data of its pharmacological properties in humans. This study was designed to assess the acute pharmacological
effects of MDMA, and to determine the dose to be used in future investigations. Six healthy male recreational users
of MDMA participated in different experimental sessions (4-8). They received single oral doses of MDMA (50, 75,
100, 125 and 150 mg), amphetamine sulphate (AMP 20, 30, 35, 40 mg) or placebo. Drugs were administered
double-blind and randomized (lower doses were allocated before higher doses for safety reasons). Study variables
included: vital signs (blood pressure, heart rate, temperature, pupil diameter), psychomotor performance (reaction
time, DSST, Maddox-wing), and subjective effects (visual analog scales, ARCI-49 item short form and POMS
questionnaires). MDMA and AMP produced a dose-related increase in blood pressure, heart rate (different time profile
for both drugs) and pupil size (only MDMA). No significative changes were found on psychomotor tasks, although
AMP produced an sligth improvement. MDMA produced higher scores on subjective effects and drug-induced
euphoria (“high”, “liking”, ARCI-MBG) than AMP. A dose-response relationship was found for MDMA effects.
Only MDMA poduced slight changes in visual and body perceptions. The results seems to indicate that MDMA
could have a high abuse potential.
ACNOWLEDGEMENTS:
PNSD.
Supported by grants: FIS 97/1198, CIRIT 95-SGR-00432, ISC-III 97/4344 and
290
THE DISCRIMINATIVE STIMULUS EFFECTS OF AMINEPTINE IN RATS
M. Mallaret, M. Dematteis, C. Villier, G. Baragatti*, and G. Bessard*
CEIP * Laboratoire de Pharmacologie, CHU de Grenoble, Cedex France
Amineptine hydrochloride is an antidepressant with general properties supposed to be similar to those of
amitriptyline. Amineptine is used as an antidepressant in France, in Spain and in Italy. Amineptine which is mainly
dopamine reuptake pump blocker, has been subject to and withdrawal has beenprolonged and difficult. Eleven
Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg i.p.) from saline. The discriminative stimulus
effects of amineptine (1 ; 2.5; 5 ; 10; 15; 20 mg/kg i.p.) and (+)-amphetamine (0.3; 0.6; 1.25; 2; 2.5; 5 mg/kg
i.p.) were studied after administration. The complete generalization was obtained at 15 mg/kg for amineptine, and 2
mg/kg for (+) amphetamine. Generalization from cocaine stimulus to amineptine or (+)-amphetamine was an
increasing function of dose. Amineptine, a dopamine reuptake pump blocker used as an antidepressant, is abused in
France by drug addicts. We showed, in rats trained to discriminate cocaine from saline, amineptine substituted for
cocaine as a discriminative stimulus. In rats trained to discriminate (+)-amphetamine from saline, amineptine
substituted for (+)-amphetamine as a discriminative stimulus. Drug discrimination procedure, in which amineptine
showed cocaine-like activity, confirms a posteriori, the abuse potential of amineptine.
COMPARATIVE PHARMACOLOGY OF METHAMPHETAMINE AND COCAINE: DRUG
DlSCRIMINATlON AND PHYSIOLOGIC EFFECTS
J. Mendelson; P. Jacob, III; R. P. Nath; S. Welm; and R. T. Jones
Drug Dependence Research Center, Langley Porter Institute, University of California, San
Francisco
Because both cocaine and methamphetamine are psychostimulant sympathomimetics which block synaptic
monoamine reuptake, we compared pharmacologic effects of methamphetamine and cocaine in 12 subjects. Blood
pressure (SBP and DBP), heart rate (HR), rate pressure product (RPP), and subjective drug effects were compared
after double-blind, placebo-controlled, 1 min intravenous infusions of 0.6 mg/kg cocaine or 15 mg
methamphetamine. Data was analyzed by ANOVA. Both drugs raised SBP and RPP. Cocaine increased HR by
25±15 compared with a small decrease after methamphetamine of 3±9 bpm. A greater increase in DBP occurred
after methamphetamine than cocaine (14 vs 10 mmHg). The increased RPP after methamphetamine was due to
increased SBP but not HR. In contrast, cocaine increased RPP primarily by increasing HR. Peak intoxication was
higher with cocaine than methamphetamine (58±34 vs 18±23), probably due to the relatively low
methampheramine dose. Subjects correctly distinguished cocaine from methamphetamine within 3 minutes or less
by qualitative subjective differences in drug experience. We conclude from this preliminary experiment that cocaine
and methamphetamine have physiologic and subjective differences which may mediate risks of drug toxicity or
dependence.
ACKNOWLEDGMENT:
Supported by NIDA Contract 271-87-8123.
291
REVERSAL OF ETHANOL-INDUCED BODY SWAY BY METHAMPHETAMINE IN
STANDING HUMANS
M. J. Baggott, J. Mendelson, S. Welm, W. Ellis, and R. T. Jones
Drug Dependence Research Center, University of California, San Francisco, CA
Stimulant drugs are known to affect motor system behaviors. However, since young, healthy adults perform so
well in measurements of motor behaviors, it is difficult to show a performance improvement. In this double-blind
study, ethanol was used to impair stance stability, allowing the effects of methamphetamine to be examined in 8
healthy nondependent methatnphetamine-experienced volunteers (7 male, 1 female). Ethanol (1.0 g/kg administered
orally in divided doses over 30 minutes) or placebo was followed, 60 minutes after ethanol administration began, by
(S)-(+)-methamphetamine HCl (30 mg intravenously over 1 minute) or placebo. Stance stability, in both eyes
open and closed conditions, was measured before and at 35, 120, 220, 320, 520, and 620 minutes following ethanol
using a stable platform which quantified components of body sway (path length, average distance from median, and
Romberg ratios). Methamphetamine alone had no effect on body sway. Ethanol produced an increase in eyes open
path length and eyes closed average distance from median. The ethanol-induced increase in body sway was
antagonized by the subsequent administration of methamphetamine. Subjective ethanol intoxication was attenuated,
but not eliminated. by methamphetamine. Methamphetamine’s ability to antagonize ethanol-impaired stance
stability suggests that motor behavior tasks may be insufficient for assessing ethanol intoxication in individuals
who may be stimulant users.
ACKNOWLEDGMENTS:
271-90-7307.
Supported in part by USPHS Grants DA-01696, DA-00053 and NIDA Contract
EFFECTS OF D-AMPHETAMINE IN WOMEN DURING THE FOLLICULAR AND LUTEAL
PHASE OF THE MENSTRUAL CYCLE
A. Justice and H. de Wit
Department of Psychiatry, The University of Chicago, Chicago, IL
Little is known about the interactions between ovarian hormones and responses to psychoactive drugs in humans.
Studies with laboratory animals indicate that hormones may have direct or indirect actions in the central nervous
system, which may influence responses to psychoactive drugs. For example, estrogen may have direct actions on
dopaminergic neurons, and dopamine is also thought to mediate the behavioral effects of stimulant drugs. In the
present study, 12 healthy, regularly-cycling women received d-amphetamine (AMPH; 15 mg, oral) and placebo at
two hormonally distinct phases of the menstrual cycle, the follicular phase, and the luteal phase. The follicular
phase is characterized by low levels of estrogen and progesterone, whereas the luteal phase is characterized by higher
levels of estrogen and progesterone. Subjective, behavioral and physiological effects were assessed for 4 hours after
drug administration. It was hypothesized that the effects of AMPH would be greater during the luteal phase due to
higher levels of estrogen. Results of preliminary analyses indicate that regardless of phase, AMPH produced its
prototypic effects of increasing stimulation, elation, and heart rate. Interestingly, there was some support for a phase
by drug interaction on measures of stimulant-like effects and heart rate. Contrary to our hypothesis, AMPH
appeared to have a greater effect during the follicular phase than the luteal phase. Positive correlations were
observed between plasma estradiol levels and these effects within the follicular phase, but not within the luteal
phase. It is possible that the high levels of progesterone present during the luteal phase are in some way masking
potential estrogen and dopamine interactions.
ACKNOWLEDGMENTS:
Supported by DA-02812 (HdW), T-32-DA-07255 (AI) and MO1RR00055.
292
IS NOVELTY-SEEKING BEHAVIOR RELATED TO DRUG-INDUCED LOCOMOTOR
ACTIVITY IN INBRED RAT STRAINS?
T. A. Kosten, C. N. Haile, and E. Brodkin
Yale University School of Medicine, New Haven, CT
In humans, the propensity to use drugs is related to “novelty-seeking.” Rats prefer novel places and acquisition of
amphetamine (AMP) self-administration and AMP-induced activity correlates with locomotor activity in a “novel”
environment and with corticosterone (CORT) levels. Yet, locomotor activity does not measure novelty-seeking
because rats cannot escape from the apparatus. Rather, it may be a stress response. This study examines the
relationship between novelty-seeking behaviors, CORT responses, and AMP-induced locomotor activity by
assessing these in inbred rat strains (Lewis and Fischer 344) known to differ in behavioral responses to drugs and in
CORT levels. Novelty responses were assessed in a place conditioning apparatus, a playground maze, and during the
first exposure to a locomotor apparatus. Following these first exposures. CORT was assayed and fecal boli
measured. The latter measures were assessed after restraint stress, too. These measures were compared to locomotor
activity induced by AMP (2 mg/kg SC). Fist, novelly responses differed across procedures. Lewis rats preferred a
novel environment (place conditioning) but showed the lowest locomotor counts during the first locomotor
apparatus exposure and the fewest novel object contacts (playground maze). F344 rats avoided the novel
environment but showed greater locomotor counts and novel object contacts. Second, the novelty apparatus
exposures caused less stress than restraint; CORT levels were lower for Lewis and SD rats and fecal boli were lower
for F344 and SD rats under these conditions. Third AMP-induced activation was related to different novelty
measures across strains, Finally, these results provide some support for the notion that AMP responses are related
to inherent locomotor activity in a novel environment and to CORT levels. Compared to F344 rats. Lewis rats have
lower CORT levels and lower locomotor activity in a novel environment and after AMP. Yet, these factors did not
consistently predict AMP-induced activity. Further, Lewis rats more readily acquire cocaine self-administration.
EFFECTS OF PRIOR EXPOSURE TO AND PRIMING WITH AMPHETAMINE ON THE
SELF-ADMINISTRATION OF A LOW DOSE OF THE DRUG
P. J. Pierre and P. Vezina
Department of Psychiatry, The University of Chicago, Chicago, IL
Prior exposure to amphetamine is known to result in both sensitized locomotor responding to and an increased
propensity to self-administer the drug. However, the relationship between sensitized locomotor responding and
enhanced self-administration remains unclear. The present experiment further examined this relationship. Rats were
administered 10 preexposure injections of either amphetamine (AMPH-PRE: 1.5 mg/kg IP) or saline (SAL-PRE:
1.0 ml/kg IP) and, following catheterization, were given the opportunity to self-administer amphetamine. During
the self-administration sessions, an ACTIVE (10 µg/kg amphetamine per infusion, IV) and an INACTIVE lever
were inserted into the test chamber. Prior to the first eight daily self-administration sessions, animals were given a
priming injection of amphetamine (1.0 mg/kg IP), followed by 3 sessions with no priming and concluding with 2
final sessions with priming. On the first session with priming, the AMPH-PRE animals showed sensitized
locomotor activity relative to the SAL-PRE rats. Both groups self-admininstered amphetamine, however, when
priming injections were discontinued, the AMPH-PRE animals continued to lever press and the SAL-PRE animals
ceased responding. When the priming injections were restored the SAL-PRE animals resumed sell-administering
amphetamine at levels equivalent to their AMPH-PRE counterparts. Temporal measures of ACTIVE lever
responding revealed that early in acquisition AMPH-PRE rats increased responding during the time-out period
(TORs). Both increased TORs and locomotor activity levels later characterized the AMPH-PRE rats when drug
priming was discontinued. These data show that prior exposure to amphetamine indeed produces enhanced levels of
locomotion and self-administration, but also reveal a complex relationship between these two responses to and for
amphetamine.
ACKNOWLEDGMENTS:
Supported by USPHS grant # DA-09397 and grant # T32-DA-07255.
293
OPIOIDS MODIFY THE DISCRIMINATIVE STIMULUS EFFECTS OF d-AMPHETAMINE
IN SQUIRREL MONKEYS
K. R. Powell and S. G. Holtzman
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA
Five monkeys were trained to discriminate 0.3 mg/kg of d-amphetamine (i.m.) from saline using a discrete trial
termination/avoidance task. Dose-effect curves were determined for d-amphetamine and cocaine, the kappa opioid
agonists, Cl-977 and U69,593, and the mu opioid agonist, morphine. The dose-effect curve of d-amphetamine was
redetermined in the presence of various doses of all three opioids and the dose-effect curve of cocaine was
redetermined in the presence of morphine. d-Amphetamine and cocaine substituted dose-dependently in all monkeys.
In four of the five monkeys, U69,593 substituted partially or completely for the d-amphetamine discriminative
slimulus (DS). CI 977 substituted completely in two monkeys, but not at all in the other three monkeys,
Morphine engendered no substitution in four monkeys and complete substitution in one monkey. The damphetamine dose-effect curve was shifted by U69,593, CI 977, and morphine, but these effects were highly
variable across monkeys. The dose-effect curve of cocaine was not altered by morphine in the three monkeys tested
thusfar. These data suggest that both kappa and mu opioids can modulate the DS effects of d-amphetamine in
squirrel monkeys; however, they do so with a high degree of variability. The DS effects of cocaine do not appear to
be altered by morphine.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 23765.
d -AMPHETAMINE DISCRIMINATION IN HUMANS: EFFECTS OF TRAINING DOSE AND
RELATION TO SUBJECT-RATED DRUG EFFECTS
S. H. Kollins and C. R. Rush
Department of Psychiatry and Human Behavior and Department of Pharmacology
Toxicology, University of Mississippi Medical Center, Jackson, MS
and
Preclinical laboratory studies suggest training dose is an important determinant of subsequent discrimination
performance. The present experiment assessed the discriminative-stimulus and subject-rated effects of damphetamine in separate groups (N=4/group) of human volunteers trained to discriminate between placebo and either
10 mg (low dose) or 20 mg (high dose) d-amphetamine. d-Amphetamine (1.25, 2.5, 5, 10, and 20 mg) increased
drug-appropriate responding as a function of dose and produced clear dose-related stimulant-like effects (e.g., “Like
Drug,” “Stimulated,” ‘TaIkative”) in the low-dose group. The dose-response functions for discrimination
performance and subject-ratings were virtually identical. further supporting the notion that the discriminativestimulus and subject-rated effects of drugs covary. In the high-dose group, d-amphetamine also generally increased
drug-appropriate responding and subject-rated effects as a function of dose. However, the dose-response functions for
discrimination performance and subject-ratings were somewhat dissimilar. These findings suggest that the
discriminative-stimulus and subject-rated effects of commonly abused drugs are not isomorphic, and that
discrimination performance in humans is not based solely on “subjective” drug effects. These findings are also
concordant with preclinical research and extend the findings regarding the effects of training dose in humans to
another pharmacological class. Future research should focus on the relation among these effects and their relevance
to the assessment of the abuse potential of drugs.
ACKNOWLEDGMENT:
on Drug Abuse.
This research was supported, in part, by grant DA 10325 from the National Institute
294
A COMPARISON OF THE PRECLINICAL PHARMACOLOGY OF MODAFINIL AND
AMPHETAMINE-LIKE DRUGS
P. C. Contreras1, D. M. Edgar2, E. Mignot2, T. M. Engber1, and J. L. Vaught1
1
Cephalon, Inc., West Chester, PA and ‘Stanford Sleep Research Center, Stanford University,
Stanford, CA
Modafinil is a chemically and pharmacologically unique compound that reduces excessive daytime sleepiness (EDS)
in narcoleptics in two phase III clinical trials. Like amphetamine, modafinil increases wakefulness in a variety of
preclinical models. However, the wakefulness produced by modafinil differs from amphetamines in that modafinilinduced wakefulness does not result in a surge in NREM rebound sleep and does not increase locomotor activity
when normalized to wakefulness. Some of the effects of modafinil are attenuated by prazosin, but modafinil does not
affect cataplexy, a behavior that is attenuated by a1-adrenergic agonists, or modify the actions of a-adrenergic
agonists in vitro. Thus, modafinil is not a direst or indirect a-adrenagic agonist, but may require an intact a1adrenergic system in order to demonstrate an increase in wakefulness. Modafinil does not bind potently to the
dopamine uptake site (Ki=2 µM) and its in vivo effects are not modified by dopamine antagonists. Modafinil is
inactive in behavioral, electrophysiological and neurochemical paradigms of dopamine activation. Modafinil, unlike
amphetamine or cocaine, does not induce ipsilaleral rotations in rats with unilateral 6-OHDA lesions. Thus,
activation of dopaminergic pathways does not underlie the in vivo actions of modafinil and suggests minimal abuse
potential. In summary, modafinil selectively increases wakefulness by a mechanism that is different from that of
amphetamine-like agents. Thus, modafinil provides an alternate approach to treating EDS.
SENSITIZATION TO APOMORPHINE IS MANIFEST WITHIN HOURS, CONDITIONING IS
MANIFEST ONLY WEEKS LATER
P. B. Silverman and P. L. Bonate
Psychiatry and Behavioral Sciences, U. of Texas Health Set., Houston. TX
Rats were lesioned in one substantia nigra with 6-hydroxydopamine. Two to three weeks later they were tested for
circling in response to 0.05 mg/kg apomorphine. Animals which made fewer than 60 turns/20 min were tested with
apomorphine again 2. 4 and 16 hours later (group 1) or 4. 8 and 12 hours later (group 2). Some rats not responsive
to the first dose circled actively in response to the second;
a majority circled by the fourth dose (12-16 hr after the
first) with mean rotations increasing - 10-fold (Fig.1).
Sensitized rats remained sensitized for months. Rats that
did not sensitize to apomorphine within 4 injections were
ultimately found to have less extensive striatal
dopamine depletions than those that did. The
pharmacokinetics of apomorphine argue that the sensitized
behavior cannot be atributed to drug accumulation. Most
rats that became sensitized also ultimately became
conditioned to circle contralaterally in response to being
placed, unrugged, into the rotation environment, but this
conditioned behavior was not seen until weeks after initial
Fig. 1. Sensitization to apomorphine
treatment.
develops within hours.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-06269.
295
RESPONSIVENESS TO SEROTONERCIC DRUG CHALLENGE AFTER HIGH-DOSE
FENFLURAMINE TREATMENT
M. H. Baumann, T. A. Bryant, M. A. Ayestas, and R. B. Rothman
CPS, NIDA/NIH, IRP, Baltimore, MD
IT is well established that fenfluramine (FEN) can deplete brain serotonin (5-HT) in animals, but functional
impairments associated with such 5-HT depletion have been difficult to identify. In the present work, we examined
neumendwine responsiveness to 5-HT agonists in rats exposed to repeated high-dose FEN treatment. Mate rats
fitted with indwelling catheters received FEN (20 mg/kg, sc. bid) or saline for 4 days. At 1 and 2 weeks after
treatment, rats were challenged with iv FEN (3 mg/kg), MCPP (a 5-HT receptor agonist, 3 mg/kg), or saline.
Repeated blood samples were withdrawn and plasma was assayed for prolactin and corticosterone by RlA. Both
FEN and MCPP increased circulating prolactin and corticosterone in all rats. However, FEN-induced corticosterone
secretion was blunted in FEN-treated rats. In addition. prior exposure to FEN significantly attenuated the prolactin
response evoked by either FEN or MCPP. The repeated FEN regimen dramatically reduced (> 50%) 5-HT and 5HIAA levels in the ventromedial hypothalamus, basolateral amygdala, and hippocampus. These data suggest that
depletion of 5-HT after high-dose FEN is accompanied by functional alterations in 5-HT systems mediating
neroendocrine transduction. Whether changes in responsiveness to FEN and MCPP are indicative of true 5-HT
neurotoxicity remains to be determined.
ACKNOWLEDGMENT:
Generously supported by NIDA Intramural Research Program.
ANORECTIC AMPHETAMINES DIFFERENTIALLY AFFECT MONOAMINE TRANSMISSION IN RAT BRAIN
M. A. Ayestas, R. B. Rothman, and M. H. Boumann
CPS, NIDA/NIH, IRP, Baltimore, MD
A number of amphetamine derivatives are prescribed as appetite suppressants. but few studies have examined the
neurochemical actions of these drugs in vivo. We evaluated the effects of several amphetamine analogs on
extracellular DA and 5-HT in rat nucleus accumbens using in vivo microdialysis. Microdialysis probes were
inserted into previously implanted guide cannulae and perfused with Ringers’ solution overnight. On the following
morning, phentermine, phendimetrazine, diethylpropion, or fenfluramine was infused locally through the probe (10
and 100 µM), and dialysates were assayed for DA and 5-HT by HPLC-EC. Phentermine was the only analog to
significantly elevate DA after a 10 µM dose (300%, P<0.01). At 100 µM, phentermine increased DA 15-fold while
the other drugs caused only modest increases. Fenfluramine was the only analog to significantly elevate 5-HT at 10
µM (600%, P<0.001). At 100 µM fenfluramine produced a 15-fold rise in 5-HT whereas the other drugs elicited
small variable increases. Our findings show that phenylethylamines with similar anorectic potency display
differential effects on DA and 5-HT neurons. The results with phendimetrazine and diethylpropion are especially
noteworthy; these drugs stimulate locomotor activity and maintain self-administration behavior yet fail to
appreciably affect extracellular DA in the nucleus accumbens. Thus, the psychostimulant properties of some
amphetamine analogs may involve non-DA mechanisms.
ACKNOWLEDGMENT:
Generously supported by NIDA Intramural Research program.
296
ABUSE LIABILITY ASSESSMENT OF SIBUTRAMINE
L. M. Schuh, C. R. Schuster, and J. A. Hopper
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of
Medicine, Detroit, MI
Sibutramine is a serotonin and norepinephrine reuptake inhibitor under investigation as an anorectic agent. This
study examined acute subjective, reinforcing, and physiological effects with the primary goal of assessing the abuse
liability of sibutramine. Cole (unpublished data) demonstrated low abuse potential for 20 and 30 mg sibutramine
(doses within the therapeutic range for weight loss); however no data existed on the abuse potential of
supratherapeutic doses. This study, therefore examined higher doses (25 and 75 mg) of sibutramine and compared its
effects to placebo and d-amphetamine (20 mg) as a standard positive control. Twelve polydrug abusers with no
history of dependence on any drug served as subjects in this six-week, double-blind, placebo-controlled,
inpatient/outpatient study. Subjects participated in four drug sessions, in which they completed subjective effects
scales including the Profile of Mood Stales (POMS). Visual Analog Scales (VAS), and the Addiction Research
Center Inventory (ARCI). The Multiple Choice Procedure (MCP; Griffiths et al., 993) was used to evaluate
reinforcing efficacy. In this procedure, volunteers made choices between receiving increasing monetary amounts or
another drug dose. Sibutramine 25 mg produced subjective effects that were indisringuishable from placebo.
Sibutramine 75 mg produced significant unpleasant effects, and volunteers would give up an average of $4.04 from
their study pay rather than receive the drug again, d-Amphetamine 20 mg served as an adequate positive control. It
therefore appears that sibutramine lacks abuse liability in acute dose testing.
ACKNOWLEDGMENT:
Supported by a grant from Knoll Pharmaceutical Company.
FLUOXETINE TREATMENT OF SMOKABLE AMPHETAMINE DEPENDENCE IN THE
NORTHERN MARIANAS ISLANDS
M. D. Herbst
Department of Public Health, Commonwealth of the Northern Marianas Islands
We performed an open trial of Fluoxetine as pharmacotherapy for amphetamine dependence in a rural pacific island
setting. Twenty-two subjects who met DSM-IV criteria for amphetamine dependence were entered into the study,
which lasted 8 weeks. Mean dose of Fluoxetine was 35mg. The medication was well tolerated and 19 of the 22
(86%) completed the study. The study population was ethnically diverse, consisting primarily of native pacific
islanders. Study participants were evaluated on intake for co-morbid psychiatric disorders with 33% meeting criteria
for Major Depression. 24% Anxiety Disorder, 14% Psycholic disorder, and 4% Eating disorder. Study participants
were screened weekly for self report drug use and drug craving and bi-weekly for drug urine testing. Improvement
was demonstrated for all outcome measures in this open trial with reduction in amphetamine positive drug urine
tests from 63% at intake to 15% at week 8. Mean self reported amphetamine use dropped from 1.9 times per week
at intake to 0.2 times per week at week 8. Conclusions: Fluoxetine was well tolerated and accepted as
pharmacotherapy in this rural pacific island population and may be associated with improved treatment outcome.
Additional study in a double blind trial is needed to further evaluate the use of this medication in the treatment of
amphetamine dependence.
297
A COMPARISON OF CURRENT AND FORMER STIMULANT ABUSER’S SCORES ON
THE WENDER UTAH RATING SCALE
S. L. Simon*, A. Huber*,*, and W. Ling *,**
*West Los Angeles Va Medical Center Medications Development Unit, Los Angeles, CA; and
**Matrix Institute On Addictions, Los Angeles, CA
A recurring problem in the diagnosis of attention deficit hyperactivity disorder (ADHD) in adults is the retrospective
diagnosis of childhood ADHD. The Wender Utah Rating Scale 25 item form has been found to have good
reliability (Rossini & O’Connor, 1995) and to correctly identify 86% of adults with ADHD (Ward et al., 1993).
The prevalence of ADHD in populations of individuals abusing stimulants is higher than expected. This raises the
question of whether the retrospective diagnosis of childhood attention deficit hyperactivity disorder in substance
abusers is affected by their current drug use. To address this question we used scores on 25 questions from the
Wender Utah Rating Scale. We compared a cohort of 28 subjects who are presently abusing methamphetamine with
scores acquired as follow-up data from 47 former stimulant abusers treated for stimulant abuse in a Matrix clinic.
All participants reside in the same area of San Bernardino County, California. There is a significant difference
(1=2.27 df,73 p=.026) between the mean scores of the two groups. The mean score of the current abusers is 12
points higher than that of the former abusers. In addition the range is offset by about the same amount. The
current abusers scores run from 9 to 93. while the scores of the former abusers run from 0 to 89. The variances of
the two groups are equal. However, although 42% of the current abusers scored above the cutoff of 46 for ADHD
and only 25% of the former abusers scored above 46, this difference was non significant. These results are
consistenl with about a 10 point effect of current methamphetamine abuse on the Wender Utah Rating Scale. Thus
stimulant use may affect a subject’s perception of his or her childhood, and the number of abusers identified with
adult ADHD may be over estimated.
ACKNOWLEDGMENTS:
CHARACTERISTICS
TREATMENT
Supported by the NIDA/DVA interagency agreement # 1 Y01 DA 50038-00.
OF STIMULANT
ABUSERS
AND
THEIR
RESPONSE TO
A. L. Hasson1,2 , V. Gulati2 , A. Huber 1,2,3 , R. A. Rawson1,2,3 , W. Ling 1,3 , and P. Brethen2
Los Angeles Addiction Treatment Research Center1; Matrix Institute on Addictions2; and West
Los Angeles VAMC3
Stimulant abuse continues to present a significant public health concern. Characteristics of and the responses to
treatment for 500 methamphetamine (MA) and 224 cocaine (COC) users seen at the Matrix Institute from 1988-95
are presented. The treatment provided was structured, cognitive/behavioral approach that included early recovery
skills, family education, and relapse prevention groups. Results indicate intranasal use is preferred by MA users
(55%) although the popularity of smoking is on the increase. MA users started using at a younger age (21.4 yrs.
vs. 23.7 yrs.) and used heavily for a longer period prior to entering treatment (41.2 mos. vs. 39.7 mos.) compared
to COC users. Intravenous MA use has a more severe impact on the user than other routes of administration,
characterized by heavier use, greater criminal justice involvement, and more psychiatric complications. The two
groups responded equally to the Matrix model of treatment in terms of participation, retention, and percent negative
urine toxicology screens. These data support this treatment approach as one that can be effective for stimulant
users, but the data also highlight the need for additional effective prevention and treatment strategies.
ACKNOWLEDGMENTS: Supported by NIDA grant 5 RO1 DA09419-03 to Friends Medical Science
Research, Inc., and a contract from the Center for Substance Abuse Treatment (CSAT)
298
LONG-TERM OUTCOMES FROM METHAMPHETAMINE ABUSE
A. Huber1,2,3 , V. Gulati1,2, R. A. Rawson1,2,3 ; W. Ling1,2,3 , P. Brethen2, and A. Hasson1,2
Los Angeles Addiction Treatment Research Center 1 , Matrix Institute on Addictions 2 , West
Los Angeles VAMC3
Methamphetamine abuse is spreading rapidly, with little information available regarding the persistent effects of
chronic use. We present the results of a CSAT funded follow-up of 100 cocaine and 100 methamphetamine abusers
one to five years after treatment admission to the Matrix Institute on Addictions. The follow-up included measures
of current medical and psychiatric status (Brief Symptom Inventory), current drug/alcohol use and related effects
(Addiction Severity Inventory), and recent service utilization including health care, legal, and public service access.
A description of the sample of methamphetamine users across all these measures will be presented, as well as a
description of bow these two groups differ at the time of follow-up.
COMPARISON OF BASAL MOTOR ACTIVITY, COCAINE-STIMULATION AND BRAIN
COCAINE LEVELS IN MICE
L. H. Gold, L. H. Parsons, C. J. Heyser, A. J. Roberts, I. Polis, and J. S. McDonald
Department of Neurophamacology, The Scripps Research Institute, La Jolla, CA
Genetically related differences in motor activity are considered to reflect differences in exploratory drive, reactivity to
novelty and general level of arousal. Within and between session habituation and cocaine-induced motor stimulation
were examined in 4 inbred strains (Balb/cByJ, DBA/2J, C57BL/6J and SJL/J), an F1 Hybrid (C57BL/6J x SJL/J)
and an outbred strain (CD1). Strain differences were observed in total amount of locomotion during the first 2h
exposure to the test apparatus with Balb mice exhibiting the highest, C57, Hybrid and CD1 mice intermediate, and
SJL and DBA the lowest levels. All strains exhibited within session habituation, although only the Hybrid, CD1
and SJL mice showed a reduction in activity from the first to the second habituation session. All mice exhibited
cocaine (30 mg/kg) induced increases in zone entries and 5 of the 6 strains exhibited increased rearings compared to
saline. Rearings were not changed or decreased by cocaine only in the Balb mice. Locomotor sensitization
following a second administration of cocaine (30 mg/kg) was observed in DBA and CD1 mice. Measurement of
cocaine and its metabolites in brain tissue by HPLC following a single cocaine 30 mg/kg injection revealed that
C57 had the highest brain cocaine concentrations compared to all other strains. Norcocaine was highest in DBA,
CD1 and SJL compared to Hybrid and C57 mice. Benzoylecgonine was lowest in C57, SJL and Hybrid compared
to Balb and DBA mice. These data illustrate genetic differences in cocaine-induced motor stimulation that cannot be
solely attributed to differences in motor reactivity to novelty or cocaine pharmacokinetics and contribute to a
comparative database for cocaine-sensitive behaviors in various strains of mice.
ACKNOWLEDGMENT:
Supported by NIDA grant R01 DA-10191.
299
LOCOMOTOR RESPONSE OF THE C57BL/6J MOUSE TO CHRONIC “BINGE” PATTERN
COCAINE: DEVELOPMENT OF TOLERANCE
A. Ho. S. D. Schlussman, Y. Zhou, and M. J. Kreek
The Rockefeller University, New York, NY
Behavioral, and concomitant neuroendocrine and molecular changes in the brain of rats in response to cocaine
administered in a “binge” pattern designed to mimic the way cocaine is taken by humans, have been studied in
several laboratories. In order to exploit the genetic information of different strains of inbred mice and to serve as a
background for studies in recently developed transgenic mice, we have extended me study of the effects of chronic
“binge” pattern cocaine administration (BPCA) to the well studied C57BU6J mouse. Method: Six individually
caged adult makes received three daily injections of cocaine (15/mg/kg ip) at hourly intervals starting half an hour
into the light portion of the 12-12 hr light-dark cycle, and six received saline on the same schedule for 14 days,
Spontaneous locomotor activity of each mouse was monitored in its home cage. Results: Cocaine-treated mice
showed significantly higher levels of locomotor activity across the hour following each injection than did saline
controls, F(1, 10)= 13.61, p<0.01, in agreement with our earlier study in Fischer rats (Unterwald et al., 1994). But,
in contrast to our finding of behavioral sensitization in the rat in that study, the locomotor response of C57 mice to
BPCA was less pronounced (Newman Keuls post hoc test, p< 0.05). and shorter in duration, after chronic BPCA;
that is, tolerance to the locomotor stimulating effect of cocaine was found. Also, in contrast to the still elevated
plasma corticosterone levels found after 14 days BPCA in the rat (Zhou et al., 1996), corticosterone levels after 14
days BPCA in the C57 mice were not significantly elevated. Conclusion: This study demonstrates differences
between the rat and the mouse in response to binge cocaine administration. Further studies with inbred strains and
transgenic mice, as well as between species, should help to elucidate the varied effects of cocaine. References
available from authors.
ACKNOWLEDGMENTS:
Supported by NIDA Center Grant P50-DA05130 and DA00049 to MJK.
EFFECTS OF “BINGE” PATTERN COCAINE ON LOCOMOTOR ACTIVITY AND
STEREOTYPY IN MALE C57BL16J and 129/J MICE: A DOSE RESPONSE STUDY
S. D. Schlussman, A. Ho, A. E. Curtis, and M. J. Kreek
The Laboratory of the Biology of Addictive Diseases. The Rockefeller University. New
York, NY
With the expanding use of genetically engineered animals in addiction research it has become increasingly important
to characterize the response to drugs of abuse in mouse strains commonly utilized as host strains for transgenic and
knockout mice such as the C57BL/6J and 129/J strains. Therefore. the psychomotor stimulating effects of 4 doses
of cocaine, administered in a “binge” pattern (3 equal injections at hourly intervals) were examined in adult mate
C57BL/6J and 129/J mice. Mice were injected with either saline or cocaine (2.5 mg/kg/injection - 15
mg/kg/injection) in a “binge” pattern for 3 days. Spontaneous locomotor activity was monitored 24 hours daily in
the home cage. Behavioral stereotypy was measured in the home cage at 15, 30, and 45 min following each
injection. Behavioral stereotypy was observed following injections of 10 or 15 mg/kg of cocaine in C57BL/6J
(Dose main effect: F(4,31) + 34.6; p < 0. 0001) and 129/J mice (Dose main effect: F(4,25) = 28.9; p < 0.0001). Lower
doses of cocaine did not produce a consistent expression of behavioral stereotypy in either strain. Interestingly, the
magnitude of stereotypy was significantly lower in 129/J mice compared to C57BL/6J mice at identical doses of
cocaine. C57BL/6J mice also demonstrated a dose dependent cocaine-induced stimulation of spontaneous locomotor
activity following administration of 10 or 15 mg/kg of cocaine (Dose main effect F(4,31) = 15.1 p < 0.0005;
Newman-Keuls post hoc tests: p < 0.005). 129/J mice did not exhibit increased locomotor activity in response to
any dose of cocaine tested in the present study. These results extend earlier reported dose response findings in the
mouse and provide a direct comparison of the psychomotor stimulating effects of cocaine in two strains of mice
frequently utilized as host strains for transgenic animals. These data help establish a baseline for behavioral analysis
of transgenic mice.
ACKNOWLEDGMENTS:
Supported by NIDA center grant P50-DA 05130 and DA 00049 to MJK.
300
GENDER DIFFERENCES IN COCAINE RESPONSIVITY IN RATS
Q. D. Walker, S. Li, and C. M. Kuhn
Department of Pharmacology, Duke University Medical Center, Durham, NC
The purpose of the present study was to explore gender differences in the behavioral response to cocaine in rats alter
a single dose, and after repeated cocaine treatment Male and female rats were treated for 3 or 14 days with saline or
cocaine (15 mg/kg, ip, bid). Twenty four hours after the last dose, a dose response curve for cocaine-induced
locomotor activation was determined by administering saline, 10.20 or 40 mg/kg of cocaine to animals from both
chronic treatment groups. Locomotion was assessed using an Opto Varimax system and a manual rating scale
derived from that of Ellinwood. Acute cocaine administration caused a significantly greater stimulation of locomotor
activity in females than in males. After 3 days of cocaine treatment, automated locomotion scores for both males
and females were enhanced relative to animals treated repeatedly with saline but there was no gender difference in
sensitization. After 14 days of treatment, both chronic cocaine-treated males and females showed increases in
cocaine-stimulated behavior with both behavioral measures relative to chronic saline-treated animals. Females
showed markedly enhanced stereotypies at higher cocaine doses, although there was no global gender difference in
sensitization. These results suggest that females show substantially greater responses than males to the first cocaine
dose. ‘the enhanced production of stereotyped behaviors after longer chronic treatment might not reflect greater
sensitization, but the higher starting point from the large response to the acute dose.
ACKNOWLEDGMENT:
Supported by NIDA GRANT DA09079.
THE LOCOMOTOR STIMULANT AND DISCRIMINATIVE STIMULUS EFFECTS OF
COCAINE: ASSESSMENT OF THE 5-HT1B/1D ANTAGONIST CR127935
A. C. McCreary, P. M. Callahan, and K. A. Cunningham
Department of Pharmacology and Toxicology, University of Texas Medical Branch,
Galveston, TX
Stimulation of 5-HT1B receptors appears to mediate the locomotor hyperactivity induced by the 5-HT1B/1A agonist
RU 24969 and (+)-3,4-methylenedioxymethamphetamine (MDMA) and RU 24969 enhances the discriminative
stimulus effects of cocaine (COC). In the present study, we assessed the ability of the 5-HT1B/1D antagonist
GR127935 (GR) to alter the hyperactivity induced by COC, RU 24969, and MDMA in locomotor activity
monitors which measured peripheral, central and rearing activity. CR (5 mg/kg sc) significantly attenuated
peripheral (-29%) and rearing activity (-53%) induced by COC (15 mg/kg, N=B/group), but 2.5 and 10 mg/kg of GR
was without significant effect. Likewise, the peripheral activity induced by RU 24969 (2 mg/kg, ip) and MDMA (3
mg/kg, ip) was attenuated by GR (2.5 mg/kg, sc). The ability of GR to alter the stimulus effects of COC was also
assessed in rats trained to discriminate COC (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 paradigm
(N=8). The stimulus effects of COC (10 mg/kg, ip) were not altered by pretreatment with GR (1-8 mg/kg, ip) and a
fixed dose (2 mg/kg, ip) failed to shift the COC dose-response curve (0.625-10 mg/kg, ip). Although the
antagonism of r5-HT1B/1D receptors may attenuate the hyperlocomotor effects of RU 24969 and MDMA, the
discriminative stimulus and hyperlocomotor effects of COC appear to be resistant to GR. This questions the role of
r5-HT1B/1D in the COC cue and suggests a minor role for this receptor subtype in the modulation of the locomotor
effects of COC.
ACKNOWLEDGMENTS:
Supported by DA 00260 and DA 06511.
301
EFFECTS OF INJECTION OF SCH 23390 INTO THE VENTRAL TEGMENTAL AREA ON
COCAINE-INDUCED SENSITIZATION
J. D. Steketee and L. A. Rowe
Department of Pharmacology and Therapeutics, Louisiana State University Medical CenterShreveport, Shreveport, LA
The mesolimbic dopamine system has been reported to play an important role in the development of behavioral
sensitization to psychostimulant drugs. Previous studies have shown that intra-ventral tegmental area (VTA)
injections of the dopamine D1 antagonist SCH 23390 blocked the development of the sensitized motor-stimulant
response to amphetamine (Vezina, J. Neurosci. 16: 2411, 1996) and the acute motor-stimulant response to cocaine
(Steketee and Braswell, Behav. Pharmacol., In Press). This study tested whether intra-VTA SCH 23390 could block
the development of cocaine-induced sensitization. Male Sprague-Dawley rats received bilateral cannulae implants 1
mm above the A10 region for microinjections and 3 mm above the nucleus accumbens for in vivo microdialysis 1
week before the start of an experiment. On day 1, rats received intra-VTA injection of saline (0.5 µl/side) or SCH
23390 (15 nmol/side) 5 min before systemic injections of saline (1.0 ml/kg) or cocaine (15 mg/kg). The rats
received the same injection regimen on days 2-4 in their home cage. On day 11, all rats received cocaine (15 mg/kg)
injections. On days 1 and 11, motor activity and dopamine concentrations in the nucleus accumbens were
monitored following injection. Intra-VTA SCH 23390 attenuated the acute response but did not alter the
development of the sensitized behavioral response to cocaine. However, SCH 23390 did block the acute and
development of the sensitized neurochemical responses to cocaine. These data suggest that dopamine D1 receptors
in the VTA may be partially involved in the development of sensitization to cocaine.
ACKNOWLEDGMENT:
SEROTONIN-4
ACTIVITY
Supported by NIDA Grant DA-08079
RECEPTOR
ANTAGONIST
AND
COCAINE-INDUCED
MOTORIC
D. C. Ohuoha, A. Brockington, G. Elmer, and R. B. Rothman
Clinical Psychopharmacology Section, DIR/NIDA/NIH, Baltimore, MD
Over the years, there have been many srudies that indicate that serotonin (5-HT) is able to modulate the activity of
central dopamine (DA) neurons in the mammalian brain. DA-mediated behaviors such as stereotypy, hyperactivity
and catalepsy are modified by alterations in central 5-HT transmission. Cocaine injections in rodents have been
shown to induce some of these behaviors in rodents. Recently 5-HT4 receptors have been implicated in morphine
condition place preference. The aim of this study was to examine the effect of 5-HT4 receptor antagonist on cocaine
induced locomotor activity and stereotypy. We examined mice pretreated with GR125487D (0.001, 0.01, 0.1 mg/kg
icv) prior to ip administration of 3, 10, 30 mg/kg of cocaine. Results indicate that GR125487D produced a dosedependent suppression of locomotor activity: F(Dose)=7.95 df=4.38; P<0.01. At 0.001 mg/kg, GR125487D
produced no significant degree of locomotor depression and maximal locomotor depression at 0.01 mg/kg. The
maximally depressant dose of GR125487 significantly depressed saline and cocaine-induced locomotor activity.
F(pretreatment)=45.7; df=7.30; p<.01. These data indicate that GR125487D does not selectively decrease cocaineindeced motoric activity.
ACKNOWLEDGMENT:
Supported by NIDA Division of Intramural Research
302
BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF LOCAL AND SYSTEMIC
4-CHLOROBENZTROPINE IN THE RAT
B. K. Tolliver 1 ; L. B. Ho 1 ; L. M. Fox1 ; K. Hsu, Jr. 1 ; A. H. Newman2 ; J. L. Katz 2 ; and S.
P. Berger 1
1
Department of Psychiatry, University of California, San Francisco and Veterans Affairs
Medical Center, San Francisco CA and 2NIDA Addiction Research Center, Baltimore MD
The current studies compared the novel tropane analog 4-chlorotenztropine (4-Cl-BZT) and cocaine for their abilities
to stimulate locomotor activity and to elevate extracellular dopamine in the nucleus accumbens as measured by in
vivo microdialysis. Peripherally administered cocaine was found to be approximately twice as efficacious as a
locomotor stimulant than 4-Cl-BZT. and was behaviorally active at lower doses than 4-Cl-BZT. At 10 mg/kg i.p.,
only cocaine elevated nucleus accumbens dopamine and induced locomotor activity. Unlike the rapid onset and short
duration of action of cocaine, the locomotor stimulant effect of i.p. 4-Cl-BZT remained modest and sustained (to 2
hours) for all behaviorally active doses tested. When perfused locally through the microdialysis probe, both cocaine
and 4-Cl-BZT dose-dependently elevated extracellular dopamine in the nucleus accumbens, with both drugs effective
at 10-1000 µM and maximally effective at doses 100 µM. However, 4-Cl-BZT elevated extracellular dopamine to
a much greater extent than cocaine when infused directly into the nucleus accumbens (approximately 2500% of
baseline maximally versus 500 % of baseline for cocaine). Furthermore. the duration of action of 4-Cl-BZT was
significantly longer than that of cocaine. Whereas the effect of cocaine on exlracellular dopamine levels persisted for
less than one hour, dopamine levels remain elevated above basal levels 4-5 hours after termination of 4-Cl-BZT
infusion. Despite the pronounced effects of locally perfused 4-Cl-BZT on extracellular dopamine, bilateral
microinjection of 4-Cl-BZT (30-300 nmol/side) directly into the nucleus accumbens induced only a modest
sustained locomotor stimulation relative to the marked and rapid locomotor response to intra-accumbens cocaine
(30-300 nmol/side). These results indicate that cocaine and 4-Cl-BZT differ in their behavioral efficacy after either
peripheral or local administration, despite the ability of both drugs to elevate extracellular dopamine in the nucleus
accumbens in vivo.
ACKNOWLEDGMENTS:
Supported by USPHS Grant DA 07376 and F32-DA05715.
NOVEL NMDA/GLYCINE SITE ANTAGONISTS BLOCK COCAINE-INDUCED
LOCOMOTOR SENSITIZATION AND BEHAVIORAL TOXICITY
A. G. Kanthasamy1 and R. R. Matsumoto 2
1
Department of Neurology, University of California Irvine, Irvine, CA 2 Department of
Pharmacology and Toxicology, University Oklahoma Health Science Center, OK
The effectiveness of two novel NMDA/glycine site antagonists, ACEA- and ACEA-1328, were characterized
against cocaine-induced convulsions, lethality, and locomotor sensitization. Pretreatment of Swiss Webster mice
with these antagonists dose-dependently attenuated cocaine-induced convulsions and lethality; these effects were
pharmacologically antagonized with D-cycloserine. Most importantly, following a lethal dose of cocaine, ACEA1021 was effective in preventing death in 57-8646 of animals when they were post-treated either immediate prior to
or after the occurrence of a seizure. In addition, at doses that did not alter spontaneous locomotion, the antagonists
eliminated the development of locomotor sensitization to chronic cocaine, and abolished its acute stimulatory
effects. The NMDA/glycine site partial agonist [R]-HA-966 also attenuated cocaine-induced convulsions, but the
AMPA-selective antagonists, NBQX, failed to provide protection. These novel NMDA/glycine site antagonists are
well tolerated in vivo and are not associated with the unfavorable side effects seen with previously tested noncompetitive antagonists. These compounds are the first of their kind in showing protective effects against cocaineinduced convulsions, lethality, and locomotor sensitization and suggest that NMDA-receptor mediated excitatory
mechanisms play important role in cocaine abuse and toxicity.
303
-OPIOID RECEPTOR AGONISTS POTENTIATE THE MOTOR EFFECTS OF COCAINE IN
THE RAT
A. B. Patterson and S. G. Holtzman
Emory University School of Medicine, Atlanta, GA
Endogenous opioids modulate the brain dopamine systems and the effects of drugs that act via those systems, such
as cocaine. To examine the possible role of -opioid receptors in these modulatory effects, the selective -opioid
receptor agonists [D-Pen2-DPen5]enkephalin (DPDPE) and [D-Ala2-D-Leu5]enkephalin (DADLE) were tested in
combination with cocaine for effects upon motor activity in rats. DPDPE (0, 10, 100 µg/10µl) or DADLE
(0, 1.0, 3.0, 10µg/10µl) was given intracisternally as a 20 min pretreatment followed by cocaine (0, 5.6, 10, 17.5
mg/kg) given intraperitoneally as a 5 min pretreatment. Activity was recorded for 1 hr (n=8 all groups). DPDPE
and DADLE both dose dependently increased the distance traveled and stereotypy counts following cocaine
administration (p<0.05). For example, 10µg DPDPE and 10µg DADLE increased the distance traveled following
5.6 mg/kg cocaine from 2263±1120 cm to 12610±4364 cm and 11227±2174 cm respectively. These results
suggest that activation of central -opioid receptors potentiates the motor stimulatory effects of cocaine.
ACKNOWLEDGMENTS:
Supported, in part. by F31 DA05687, K05 DA00008, and R01 DA00541, all
from the National Institute on Drug Abuse, NIH.
MORPHINE-INDUCED MOTOR ACTIVITY IS ENHANCED IN RATS TRAINED TO
DISCRIMINATE COCAINE, BUT NOT AMPHETAMINE
D. R. Woolfolk and S. G. Holtzman
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA
We evaluated the effects of morphine (0.56, 2.0, 3.0, 5.6, 15 mg/kg, s.c.) on the motor response of male SpragueDawley rats that had been trained to discriminate either 10 mg/kg cocaine or 1.0 mg/kg d-amphetamine from saline,
and had been in an ongoing study over a period of 11.8 (4.4-19.1) or 10.5 (5.8-15.2) months, respectively. These
groups of rats were also tested for sensitization and cross-sensitization to both of the training drugs. As compared to
the drug-naive controls, the cocaine-trained rats showed significantly higher horizontal activity counts, more
ambulation, and more stereotypy in response to morphine, whereas the amphetamine-trained group of rats did not.
Cross-sensitization to morphine occurred independently of whether or not there was sensitization to the motorstimulant effects of me training drug itself. The difference between the groups in responsiveness to the motorstimulating effects of morphine must be due to the difference in the training drugs. Both groups were closely
matched with respect to age and history of experimental testing. Moreover, the doses of the training drugs were
equivalent in terms of discriminability and in motor-activating effects in the naive rats. Thus, long-term intermittent
exposure to cocaine has effects on the neuronal substrates that mediate the motor response to morphine that are
different from those of long-term intermittent exposure to amphetamine.
ACKNOWLEDGMENTS:
Supported by Grants DA00541 and K05 DA00008, NIDA/NIH.
304
EFFECTS OF COCAINE ABSTINENCE ON HUMAN MOTOR ACTIVITY
J. L. Jewell, R. Stauffer, R. Ross, R. Nelson, and D. A. Gorelick
NIH/NIDA Division of Intramural Research, Treatment Branch, Baltimore, MD
Much behavioral work with cocaine in animals has used motor activity as the dependent variable, but there is little
systematic data on human motor activity involving cocaine We studied the motor activity of 12 cocaine-dependent
(DSM-IIIR) research volunteers, [10 African-American (8 males, 2 female), 2 Caucasian males] during 90 days of
monitored cocaine abstinence on the closed DIR research ward. Mean age was 32.8 years; range 26-39 years.
Subjects’ motor activity was recorded over 24-hour periods by wrist-watch sized activity monitors (Mini
Motionlogger Actigraph, Ambulatory Monitoring, Inc., Ardsley, NY) worn on their dominant wrist. These
monitors record intensity of motor activity using a accelerometer generating a signal strength proportional to
motion regardless of its plane or smoothness. Because of missing data, activity was analyzed separately over 3
intervals: Days 7-14 (N=9), Days 14-50 (N=10), Days 50-86 (N=6). Typical circadian activity variation was
evident with lower activity between 11p.m.- 6 a.m. and higher activity between 7 a.m. - 11 p.m. There was a
decrease in activity during mid-day (noon - 4 p.m.) only on day 10. These findings suggest that middle and late
cocaine abstinence was not associated with substantial motor activity changes.
DAYTIME AND NIGHTTIME SLEEP PATTERNS DURING COCAINE ABSTINENCE
D. A. Gorelick, J. Jewell, R. Nelson, B. Ross, and R. Stouffer
NIH/NIDA Division of Intramural Research, Baltimore, MD
Early stimulant withdrawal is associated clinically with increased sleep and dreaming. This has been confirmed by
two prior sleep laboratory (polysomnography) studies of cocaine withdrawal lasting 3 days (n=3) and 3 weeks (n=9).
We evaluated both nighttime and daytime sleep parameters in 12 chronic (mean [SD] 6.7 [3.7] years of regular
cocaine use), heavy (23.1 [4.2] days used in past 30) cocaine users during 90 days of monitored (by random urine
testing) abstinence on the closed DIR research ward, beginning 1.0 [0.5] days (range 0.5-2) after last cocaine use.
Motor activity was recorded continuously by wrist-watch sized activity monitors (Mini Motionlogger Actigraph,
Ambulatory Monitoring, Inc., Ardsley, NY) worn on the dominant wrist. Sleep parameters (duration, sleep
efficiency [% time asleep], sleep latency [time to first sleep episode]) were generated using the scoring algorithm of
Cole et al. (1992) (Action-W computer program, Activity Research Services, San Diego, CA), which is based on
6-min weighted sums of activity counts (shown to correlate 0.9 with polysomnography in normal subjects). Sleep
parameters were analyzed separately for out-of-bed (daytime) and in-bed (nighttime) phases defined by subjects’
written activity logs. Data were analyzed for 24-hr periods about weekly, beginning day 3 of admission, with n=711 because of missing data. There were few robust or significant changes in sleep parameters over time. There
were trends towards decreasing nighttime sleep duration and efficiency and increasing sleep latency as cocaine
abstinence continued. These findings are limited by the small and varying sample size, the absence of data from the
first 2-3 days of abstinence. (when most change may be occurring), and the indirect nature of the sleep data (sleep
scoring method never directly validated in cocaine users).
ACKNOWLEDGMENT:
Supported by NIDA Intramural funds.
305
AN OPEN-LABEL PILOT SAFETY STUDY OF LOFEXIDINE FOR THE TREATMENT OF
OPIATE WITHDRAWAL
E. Yu 1 , B. H. Herman 2 , P. J. Fudala 1 , A. Montgomery 2 , C. N. Chiang 2 , R. Walsh 2 , W.
Macfadden 1 , K. Kampman 1 , V. Dhopesh 1 , J. Cornish 1 , F. J. Vocci2 , P. Bridge 2 , and C. P.
O’Brien1
1
University of Pennsylvania, Department of Psychiatry and the Department of Veterans
Affairs Medical Center, Philadelphia, PA; and 2 NIH, National Institute On Drug Abuse,
Medications Development Division, Rockviiie, MD
Preliminary data have indicated that lofexidine, an alpha-2 adrenergic receptor agonist, may be effective for the
clinical management of the opiate withdrawal syndrome while producing less hypotension than clonidine. The
present 20-day, ongoing, inpatient study is being conducted to assess the relative safety of lofexidine and to obtain
information related to its potential efticacy. Twenty-five to 30 subjects (total) will be studied at three plateau doses
of lofexidine (1.6, 2.4, and 4.0 mg/day). Opiate-dependent individuals are stabilized on morphine subcutaneously
(25 mg four times daily) for 8 days. On day 9, morphine is discontinued and lofexidine is administered daily
through day 18. No medication is administered on days 19 and 20. The 1.6 and 2.4 mg/day groups have been
completed. Nine subjects have taken lofexidine in the 1.6 mg/day dosage group and no serious adverse medical
events have teen observed. Three of these subjects have completed the protocol; live dropped out secondary to
opiate withdrawal symptoms and one for personal reasons. Nine subjects have taken lofexidine in the 2.4 mg/day
group; again, no serious adverse medical events have been observed. Five of these subjects have completed the
protocol and four dropped out secondary to opiate withdrawal symptoms. Five subjects in this group exhibited
orthostatic hypotension. Of these live. four also reported vertigo that quickly resolved upon sitting. None of the
subjects at either dose level experienced syncope, symptomatic bradycardia or persistent hypotension. Recruitment
has just begin for the 4.0 mg/day dose group.
ACKNOWLEDGMENTS: Britannia Pharmaceutical Limited and an interagency agreement (YO1-DA30011)
between the National Institute On Drug Abuse and the Philadelphia Veterans Affairs Medical Centers.
SAFETY AND EFFICACY OF LOFEXIDINE ASSISTED METHADONE WITHDRAWAL
3
1,2
1,3
2
J. Myles 1,2 , K. Fuchs , F. Law , J. Melichar , and D. Nutt
1
Avon Drug Problem Team, Frenchay Healthcare NHS Trust, Blackberry Hill Hospital, Manor
Road, Fishponds, Bristol, UK; 2 Psychopharmacology Unit; and 3 Department of Health
Psychology, University of Bristol, Tyndall Avenue, Bristol, UK
Background: The 2 agonist lofexidine, is now widely used in the UK, to attenuate the signs and symptoms of
opiate withdrawal. The side effect profile of lofexidine is less severe than that of clonidine and therefore it should
offer a safer. more acceptable treatment. We hypothesised that “rapid induction” onto lofexidine on discontinuation
from opioid (where the dose was increased to peak levels over 2 days, typically 1.6mg/day), could be managed safely
and would be acceptable to patients and that such induction would attenuate symptoms of opioid withdrawal
sufficiently to retain the patients in treatment. Procedures: Twenty-five opioid dependent patients underwent a
10-14 day lofexidine-assisted methadone withdrawal on an in-patient psychiatric unit. The Opiate Treatment Index
(OTI) was performed on admission, and BP. pulse, Gossop Opiate Withdrawal Scale, and Profile of Mood States
were performed daily. Results: The OTI showed the sample to be long-term opioid addicts (3-21 years), aged 2050 years, dependent on 20-60mg methadone. No acute adverse reactions to lofexidine were observed but adjustment
of dosing on a day to day basis was necessary in nearly 50% due to reduction in blood pressure. Opiate withdrawal
symptoms typically peaked within 48-72 hours after cessation of methadone. Seventy-five % of the sample
completed detoxification, and noncompletion was associated with a failure to reach the peak dose of lofexidine.
ACKNOWLEDGMENTS:
Supported by National Health Service Research and Development project grant
number: R/15/16-08-94/NUTT/D.
306
OBJECTIVE ACTIGRAPHIC MEASUREMENT OF THE EFFECT OF HYPNOTICS DURING
LOFEXIDINE ASSISTED METHADONE WITHDRAWAL
F. Law1,2 , S. Wilson2 , J. Melichar 1,2 , and D. Nutt2 , J. Myles 1,2
1
2
Avon Drug Problem Team, Frenchay Healthcare Trust, Blackberry Hill Hospital, Bristol, and
Psychopharmacology Unit, Univ. of Bristol, Bristol, UK
Background: Sleep has never been measured objectively during the first 6 weeks of methadone withdrawal. This is
surprising as methadone withdrawal has now been used for about 50 years, sleep is severely disrupted during acute
withdrawal, it takes 3-6 months to return to normal following withdrawal, and is implicated in relapse. There is no
good evidence that hypnotics are effective during acute withdrawal. We hypothesised that both drugs would increase
total sleep time (TST), reduce the number/frequency of arousals and sleep latency during acute withdrawal.
Procedures: Thirty long term opioid dependent (3-21 years) humans underwent a 10-14 day lofexidine assisted
methadone withdrawal (15-60mg) on an inpatient psychiatric unit, while wearing the Actigraph activity monitoring
system (Cambridge Neurotechnology Ltd, UK). Actigraph measures are known to correlate highly with sleep EEG
measures. Subjects were their own controls. We compared the night of the hypnotic with the night before and night
after on days 0-10 off methadone, for either 25-50mg promethazine or 7.5-15mg Zopiclone on alternate nights.
Results: Zopiclone caused a significant decrease in night waking, the length of the wakings, in the number of
sleep/wake shifts, and an increase in the length of the sleep bouts. TST was non-significantly increased by about 15
minutes. The amount of sleep obtained varied widely (SD=2 hours). Surprisingly there were no changes in sleep
latency, and no changes with promethazine (which was also being used to treat anxiety in both groups). These
findings demonstrate the potential of actigraphy and that zopiclone assists sleep during acute opioid withdrawal.
ACKNOWLEDGMENTS:
94/NUTT/D.
Supported by National Health Service R&D grant number: R/15/16-08-
CLINICAL STUDY OF SCOPOLAMINE DETOXIFICATION FOR THE TREATMENT OF
HEROIN ADDICTS
G. Yang, K. Kun, and W. Zhou
Ningbo Drug Withdrawal Research Center, Ningbo, China
Preclinical study has shown that scopolamine could not only reverse morphine antinociceptive tolerance, but also
block the naloxone precipitated withdrawal symptoms in morphine dependent rat and monkey and facilitate the
morphine excretion. A study on evaluating the efficacy of treatment of heroin addicts (n=100) by scopolamine
detoxification was undertaken, methadone (10 days program) group (n=50) and clonidine treated group served as
controls. The results showed that the scores of abstinence syndrome in scopolamine detoxification group was lower
than that those in clonidine treated group in the first three days of protocol, but this difference disappeared in the late
stage of treatment, while the scopolamine detoxification was effective as methadone detoxification in the control of
abstinence syndrome during the first live days of treatment but the difference in the scores of abstinence syndrome
between scopolamine and methadone group was observed during the late five days of protocol. Treatment results
were evaluated after a 6-month follow-up, there was a lower percentage of morphine catabolites in urine in the group
of patients treated with scopolamine than that in methadone or clonidine treated group. The side-effects produced by
scopolamine in general were dry mouth, somnolence, tachycardia blurred Eaton and so on, which relieved gradually
or disappeared with the decreasing of its dose. In conclusion, scopolamine does not result in potential dependence
and has definite curative effect in the treatment of heroin addiction.
307
EFFECTS OF BUTORPHANOL, HYDROMORPHONE, AND NALOXONE IN OPIOIDWITHDRAWN VOLUNTEERS
R. V. Fant, E. C. Strain*, I. A. Liebson*, and G. E. Bigelow*
NIDA/DIR/Clinical Pharmacology Branch and *Johns Hopkins University School of
Medicine, Baltimore, MD
This study sought to determine whether the opioid mixed agonist-antagonist butorphanol alters withdrawal
symptom severity in hydromorphone-maintained volunteers exhibiting signs of spontaneous opioid withdrawal.
Butorphanol was compared to naloxone (an opioid antagonist), hydromorphone (an opioid mu agonist), and saline in
opioid-withdrawn volunteers, participants were 12 opioid-dependent volunteers who resided on a clinical research
ward and were maintained on hydromorphone, orally administered daily in four 10 mg doses (40 mg/day total).
prior to pharmacologic challenges, subjects were not administered maintenance doses of hydromorphone for 23 hrs
such that challenge sessions took place while subjects exhibited signs of opioid withdrawal. Challenges were
administered two times per week and consisted of a double-blind intramuscular injection of: butorphanol (0.375,
0.75, 1.5, 3 and 6 mg), naloxone (0.1 and 0.2 mg), hydromorphone (5 and 10 mg), or saline placebo. Physiologic
measures and subject- and observer-rated behavioral responses were measured before dosing and for 2.5 hr after drug
administration. Five of the 12 subjects who completed the protocol scored a mean of at least 2 on the
Himmelsbach observer-rated withdrawal scale (possible range: 0 - 7); data analyses were based on these 5 subjects.
Butorphanol and hydromorphone decreased withdrawal severity and increased scores on adjective scales and visual
analog scales measuring opioid agonist effects. Naloxone slightly increased scores on opioid antagonist adjective
scales and a subject-rated visual analog scale measuring “bad drug effects”. These data indicate that butorphanol may
be administered to volunteers maintained on short-acting opioids to alleviate withdrawal symptoms without
precipitating withdrawal.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-08045, DA-00166, and DA-00050.
THE EFFECT OF CYCLOSERINE ON NALOXONE-PRECIPITATED OPIATE WITHDRAWAL
M. I. Rosen and T. R. Kosten
VA Connecticut Healthcare System, Department of Psychiatry, West Haven, CT
NMDA antagonists attenuate opiate withdrawal in pre-clinical studies. The antimicrobial Cycloserine (CYC) is a
partial agonist at the strychnine-insensitive glycine binding site in vitro and attenuates opiate withdrawal in vivo.
The effect of CYC pretreatment on precipitated opiate withdrawal was studied in hospitalized heroin-dependent
subjects stabilized on Levorphanol 6mg po tid. After an acclimatization challenge, 3 double-blind challenges were
done with balanced, randomized pretreatment with placebo, CYC 375mg, or 750mg/70kg. pretreatment was in a
single oral dose 6 hours before i.v. Naloxone 0.4mg/70kg. Opiate withdrawal measures were summarized as AUCchange and analyzed in a one-factor repeated measures ANOVA with planned comparisons of each active CYC dose
to placebo. Six subjects completed all challenges. a seventh did not complete the 375mg CYC, and an eighth did
not complete the 750mg CYC, prior to naloxone, CYC trended (p <.06) to lower total recall scores on the Buschke
Selective Reminding Test (means of 109 after placebo, 105 after 375mg, and 99 after 750mg), and had no
significant side effects. Within subject, withdrawal severity was relatively consistent across challenges. There were
no trends towards attenuation of any withdrawal symptoms by CYC. Cycloserine, at the doses tested, showed no
promise as a treatment of opiate withdrawal.
ACKNOWLEDGMENTS:
Supported by NIDA grants P50DA09250 (TRK), K20DA00191 (MIR).
308
ACUTE IBOGAINE AND COCAINE: ACTIONS AND INTERACTIONS IN RHESUS
MONKEYS
M. D. Aceto, E. R. Bowman, and Z. Ji
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical
College of Virginia, Richmond, VA
Ibogaine, an alkaloid from the shrub Tabernanthe iboga, is said to be useful in the pharmacotherapy of stimulant
abuse (H. Lotsof, patent #4,587,243). It was tested in a cocaine hyperarousal model (Rausch) designed to
investigate a stage of dependence most likely associated with compulsive abuse and other psychopathological
changes (Aceto and Bowman, Arzniemittel-Forschung 43, 1993). Three or 4 monkeys (M. mulatta) per treatment
regimen were pretreated s.c. with ibogaine (2 or 8 mg/kg) or vehicle (veh) and 20 min later received sterile saline
(sal) or cocaine (1 mg/kg) i.v. Each animal was individually tested and observed by a trained “blind” evaluator who
scored each monkey for the following signs: checking, escape attempts, restlessness, tremors and oral dyskinesias
(chewing and tongue movements). The high-dose ibogaine-sal-treated monkeys displayed significantly more total
signs than veh-sal treated monkeys and significantly fewer signs than the veh-cocaine group. When ibogaine and
cocaine were given together, an increased incidence of tremors occurred, In addition, 2 monkeys receiving the highdose ibogaine-cocaine dose regimen convulsed. It is concluded that ibogaine did not attenuate cocaine-induced
hyperarousal; instead, it increased the incident of tremors and convulsions and perhaps stereotyped behavior in
combination with cocaine. The results suggest that treatment of compulsive cocaine abusers with ibogaine
(acutely) may have adverse consequences.
ACKNOWLEDGMENT:
Supported by NIDA DA 06876.
AN OPEN-LABEL STUDY OF A FUNCTIONAL OPIOID KAPPA ANTAGONIST IN THE
TREATMENT OF OPIOID DEPENDENCE
R. B. Rothman*, D. A. Gorelick*, P. R. Eichmiller†, B. H. Hill†, J. Norbeck†, and J. G.
Liberto†
*DIR, NIDA, NIH, Baltimore, MD and †VA Medical Center, Baltimore, MD
Several lines of evidence, including the well-established observation that kappa opiate agonists produce dysphoria
and psychotomimetic effects in humans, suggest that dysfunction of the endogenous kappa opioid system may
contribute to opioid and cocaine addiction. The objective of this open-label study was to determine the effectiveness
of a functional kappa antagonist as a treatment for opioid dependence. Fifteen treatment-seeking heroin dependent
(DSM-IV) men (41±7 yrs old; 19±8 years heroin use) who were eligible for methadone maintenance but did not
want it enrolled in the study. After inpatient detoxification at the VA and a naloxone-challenge test to verify that
they were not physically dependent on opioids, subjects received naltrexone (50 mg po per day) to block mu opioid
receptors. On the fourth day, patients received liquid buprenorphine (4 mg sl), a partial mu agonist and a kappa
antagonist, in addition to naltrexone. All patients received medication at the clinic six days per week and a full
program of psychosocial treatment. Outcome variables included pupillary diameter, urine toxicology, self-reported
drug use, the SCL-90, ASI and the Beck Depression Inventory. Five patients (33%) completed the three-month
study. Four were abstinent from opioids and cocaine for the entire study, and one was abstinent from opioids and
cocaine for the last nine weeks. Six subjects dropped out due to either minor side effects or disliking the sensation
of sublingual buprenorphine. Initial analysis of the data shows no changes in pupillary diameter. The positive
response to treatment exceeds that ordinarily expected from naltrexone alone (90% dropout). These promising
results suggest that controlled studies of this medication combination should be conducted.
ACKNOWLEDGMENT:
Generously supported by NIDA Intramural Research Program
309
BUPRENORPHINE AND NALOXONE INTERACTIONS IN OPIATE-DEPENDENT
PATIENTS STABILIZED ON BUPRENORPHINE
R. T. Jones, J. Mendelson, R. Upton, E. Lin, and S. Welm
Drug Dependence Research Center, Langley Porter Institute, University of California, San
Francisco
Buprenorphine and naloxone combinations should have a lower abuse liability than buprenorphine atone for the
treatment of opiate dependence. To assess the tolerability, comparative pharmacology, and absolute bioavailability
of sublingual buprenorphine and naloxone, 9 opiate-dependent (8 men, 1 woman) volunteers were stabilized on 8
mg sublingual buprenorphine for 12 days. On days 9-11, subjects were given, in a doubleblind, 3x3 Latin square,
within-subjects design, sublingual buprenorphine 8 mg alone or combined with naloxone 4 mg or 8 mg. A 30 min
infusion of buprenorphine 4 mg and naloxone 4 mg on day 12 was used to determine absolute bioavailability.
Plasma buprenorphine and naloxone were measured by LC/MS/MS. Results show daily administration of sublingual buprenorphine attenuates opiate withdrawal. No differences in opiate agonist or antagonist effects were seen
between the sublingual buprenorphine and naloxone combinations and buprenorphine alone. Slowly administered
intravenous buprenorphine and naloxone had only minimal withdrawal effects. Buprenorphine bioavailability, atone
or in combination with naloxone,was -42%. Bioavailability of naloxone 4 mg and 8 mg was 9 and 7%, respectively, when combined with buprenorphine. Buprenorphine and naloxone combinations appear to be well tolerated.
ACKNOWLEDGMENT:
Supported by NIDA Contract 271-90-7307.
TESTING THRICE-WEEKLY ADMINISTRATION OF BUPRENORPHINE: PLASMA
CONCENTRATION AND THERAPEUTIC EFFECTIVENESS
M. C. Chawarski, R. S. Schottenfeld, P. G. O’Connor, and J. Pakes
Department of Psychiatry, Substance Abuse Center, Yale University New Haven, CT
Ten opiate dependent volunteers were maintained on three thrice-weekly dose schedules (A, B, and C) presented in a
random order for two three week periods, and on a daily schedule (D) for one week at the end of the trial. Plasma
samples were obtained 24.48, and 72 hours following administration of a three-day dose (A=32, B=40, and C=44
mg/70kg). and 24 and 48 hours following administration of a two-day dose (A=16, B=24, and C=34 mg/70kg).
Three plasma samples were collected 24 hours following daily administration of buprenorphine 16 mg/70kg. Urine
samples were collected three times per week, as well as daily information about withdrawal symptoms and use. of
heroin. cocaine, alcohol, and other drugs. Results: All doses of buprenorphine were tolerated well by all subjects.
The rate of withdrawal symptoms was low and did not differ across dosing schedules. Plasma buprenorphine showed
a wide range of variability between subjects, and individual plasma levels did not stay consistently low or high
across different dosing schedules for the same subject. Higher doses of buprenorphine resulted in higher plasma
concentrations at each time point and plasma concentration decreased with time. The plasma buprenorphine at 72
hours following the administration of the three-day dose and at 48 hours after the two-day dose remained comparable
to plasma concentrations at 24 hours following daily administration of 16 mg/70kg of buprenorphine. The
differences in proportions of opiate positive urine toxicology results across dosing schedules did not reach the level
of statistical significance. The average, self-reported amount of heroin was not statistically different across the
dosing schedules. The highest reported rate of heroin use occurred 48 to 72 hours following administration of the
three-day dose, when buprenorphine plasma levels were lowest. The lowest reported rate of heroin use occurred 0 to
24 hours following administration of either the two- or three-day doses of buprenorphine, when the plasma levels
were highest.
310
SEXTUPLE THE DAILY BUPRENORPHINE DOSE DOES NOT SUPPRESS SUBJECTIVE
WITHDRAWAL BEYOND 96 HOURS
E. A. Jacobs, W. K. Bickel, N. M. Perry*, and E. L. Tzanis
University of Vermont, Burlington, VT and *University of Connecticut, Farmington, CT
In previous research, quintuple (QN) the daily maintenance (M) dose of buprenorphine (BUP) administered every 120
hours did not suppress subjective complaints of withdrawal beyond 96 hours in opioid-dependent outpatients. This
study compares QN dosing and SX dosing (sextuple M dose administered every 120 hours) to assess the effects of
increasing the BUP dose in abating opioid withdrawal. Ten of 21 randomized subjects receiving BUP (sublingual M
doses: 4 mg/ 70 kg, n=4; 8 mg/ 70 kg, n=6) completed the double-blind, placebo-controlled, 2-treatment, cross-over
trial. Participation was contingent upon opioid abstinence and daily attendance. Eleven subjects were discharged due
to noncompliance, 7 were under QN conditions and 4 were under SX conditions. Prior to randomization. subjects
were exposed to six times their M dose under observation, and ratings of agonist effects were minimal in all
subjects. Following baseline M dosing, subjects received each treatment (QN and SX), in a random order, for 4
repetitions. Subjects received placebo on interposed days. Measures of opioid agonist and withdrawal effects were
assessed daily. Although observer-ratings of withdrawal increased across time since the last active dose under both
conditions, the differences between the mean ratings and baseline measures were not statistically significant.
Subjective ratings of withdrawal were significantly greater than baseline (M) ratings beyond 96-hrs post dosing
under both the QN and SX conditions. There was no evidence, however, that subjective ratings of withdrawal
differed between the two conditions. Thus, these preliminary results suggest that sextuple BUP doses do not abate
withdrawal complaints for 5 days in opioid-dependent outpatients.
CRAVING DESPITE HIGH BUPRENORPHINE MAINTENANCE DOSAGES IN OPIATE
DEPENDENCE
J. Bouchez, D. Touzeau, and P. Beauverie
Clinique Liberté, Department of Substance Abuse, Paul Guiraud Hospital, Bagneux, France
Buprenorphine is reported to be agonist at µ-opioid receptor and antagonist at -receptor. It appeared as a potent
analgesic available as sublingual tablet. For the treatment of opioid dependence, its specific pharmacological
properties were studied on clinical trial comparing methadone and buprenorphine maintenance treatment. Initially
frequency of use and low- high-dose were discussed, and recently higher dosages were suggested (8 mg/d).
Nevertheless, such studies remain discussed in term of clinical eflicacy. In our clinical experience, we had to cope
with patients who require more than 8 mg/d (up to 48 mg/d). In our sample (N = 150), we assessed therefore clinical
status in patients who claimed the need of higher daily buprenorphine dose and who complained of craving
symptoms. Addiction Severity Index, MADRS, Hamilton Anxiety, and SCL-90 were quoted. DSM III-R diagnosis
for psychiatric comorbidity and personality disorders were explored. Buprenorphine route of administration and
individual social status were examined. We compared patients receiving less and more than 8 mg/d (Mann-Whitney
and 2 tests). Our study consist in preliminary results which confirm clinical heterogeneity in dose-response pattern
for maintenance treatment and raise questions about adequacy in daily dosage suggested or reached. Our data suggest
that patients with co-dependence, more psychological distress, and worst social conditions may require higher
dosages than 8 mg/d. Buprenorphine efficacy on specific psychopathological dimensions may need future studies.
311
BUPRENORPHINE/NALOXONE: HIGHER DOSES CORRELATE WITH NEGATIVE URINE
TOXICOLOGY RESULTS
D. A. Ling1, A. Huber1,2,3 , W. Ling1,2,3 , and V. C. Charuvastra1
Los Angeles Addiction Treatment Research Center1 and Matrix Institute on Addictions2, West
Los Angeles VAMC3
In the first clinical trial of its kind, twenty-five subjects were admitted to a six-week study using a buprenorphine /
naloxone combination tablet. Twelve elected to continue receiving medication after the conclusion of the pilot
study, at 4,8,16, and 20 mg doses, in order to evaluate the effect of longer treatment with the combination tablet.
Dosing adjustments made during the continuation period were based upon urine toxicology results, objective
ratings, and subjective reports of over- or under-medicating. Of those who received at least one dose increase, 59%
showed increases in percent negative urine toxicology results with concurrent increases in dose. Fifty-two percent
(52%) of the original twenty-five subjects never showed a treatment response based on urine toxicology. The
subjects in this trial bad a relatively short period of daily use prior to entering treatment and, coupled with the high
percentage of those who failed to respond at any dose, we report that these doses of opiate substitution are
insufficient for severely dependent opiate users but may be useful for treatment of moderate opiate dependence.
ACKNOWLEDGMENT:
Supported by NIDA grant P50 DA09260 to Friends Medical Science Research, Inc.
COMPUTERIZED QUALITY OF LIFE ASSESSMENT
BUPRENORPHINE FOR OPIATE DEPENDENCE
IN A CLINICAL TRIAL OF
D. W. Raisch*, D. Garnand*, M. S. Jones*, A. Huber, and W. Ling
*VA Clinical Research Pharmacy Coordinating Center, Albuquerque, NM and the LA
Addiction Treatment Research Center, Los Angeles, CA
Opiate dependent patients enrolled in a study comparing liquid and tablet formulations of buprenorphine completed
the Short Form 36 (SF-36) health status survey. Patients completed the SF-36 independently each month during
the four month study. Patients used a free-standing computer to complete the survey. This allowed data to be
entered directly into the data base and, since patients were prompted for all questions, helped to assure complete data
collection. During the trial patients also completed the survey by pencil and paper. Thus, reliability of the
computerized version could be evaluated. Finally, the patient’s satisfaction with the computerized health status
survey was assessed during the study and upon termination. A preliminary analysis was conducted using data from
72 patients, with 55 having completed the survey twice, 44 three times, 30 four times, and 17 all five times. The
summated, transposed scores of each health dimension upon enrollment were as follows: physical function 77.3,
role physical 73.7, bodily pain 63.2, general health 66.2. vitality 50.8, social function 68.1, role emotional 77.2,
and mental health 59.8. Among the 44 patients having completed the survey twice, the dimensions of general
health, mental health, vitality, and bodily pain improved significantly in the second month of the study (p<.05,
paired t-test). These preliminary results suggest that the SF-36 health status survey is sensitive to improvements
in quality of life associated with opiate treatment.
ACKNOWLEDGMENTS:
Studies Program.
Supported by an Interagency agreement between NIDA and VA Cooperative
312
EVOLUTION OF THE QUALITY OF LIFE OF PATIENTS UNDER SUBSTITUTION
TREATMENTS: PRELIMINARY RESULTS
D. Touzeau, M. Jauffret, and A. Coppel
Clinique Liberté, Department of Substance Abuse, Paul Guiraud Hospital, Bagneux, France
FoIIow-up of 100 patients, 30 under sulfate of morphia 40 under methadone and 30 under subutex. It’s a qualitative
method consisting in semi-directive interviews organized around four points: access to medical care and prevention,
socio-demographic situation, relational and psychological system and consumption of drugs. Our datas show a
general improvement of the quality of life of the patients under sulfate of morphia. The treatment helped those 30
patients to build up a new project in their life. Concerning the follow-up of 100 patients : 1 patienl is dead of HIV.
1 patient is in hospital, 1 patient is incarcerated, we have lost sights of 2 patients. 2 patients have slopped their
treatment in accord with their practitioner, 8 patients have gone through a relay a doctor in town. Among the 100
patients, 85 still get their prescription in the Clinique Liberté.
COMPARISON BUPRENORPHINE AND METHADONE MAINTENANCE IN OPIATE
ADDICTS
E. Harald, F. Gabriele, J. Reinhold, S. Shirt, G. Wolfang, and P. Lukas
Clinical Department of General Psychiatry, University Clinic of Psychiatry, Vienna, Austria
Methadone maintenance therapy is broadly established in Europe. Since 1987, methadone maintenance in opiate
addicts is available in Austria, where presently 2500 subjects have been enrolled (8 million inhabitants). In 1993,
we started to maintain subjects in an oral slow-release morphine maintenance program, where 1000 opiate dependent
subjects with a mean daily dosage of 540mg have been enrolled. In USA, buprenorphine has been studied for many
years in opiate addicts, no controlled studies have been performed in Europe so far. In 1996, buprenorphine was
registered in France for maintenance therapy in opiate addicts. In the drug addiction out-patient clinic in Vienna a
study with an open, controlled study design in comparing methadone and buprenorphine has been performed in
opiate dependent subjects (DSM-IV 304.0). Twenty subjects on methadone were investigated over a study period of
6 months. The mean age in the study population (35 male and 5 female subjects) was 25,5 years, the mean duration
of opiate dependence was 7,5 years. prior to tie study, all subjects were abusing heroin. The subjects were seen
twice a week and received band-outs for the days between, supervised urine samples for toxicology were taken at
each visit. The mean daily dosage of buprenorphine was 8mg, the mean oral dosage of methadone was 75mg.
Preliminary results demonstrate that in regard to consumption of illegal drugs both groups were comparable.
313
LAAM IS NOT LESS POTENT THAN METHADONE: A RELATIVE POTENCY
COMPARISON OF ACUTE AGONIST EFFECTS
T. Eissenberg, M. L. Stitzer, G. E. Bigelow, A. R. Buchhalter, and S. L. Walsh
Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine,
Baltimore, MD
Prior reports suggest that levo-alpha acetyhnethadol (LAAM) is less potent than methadone, with a relative potency
ratio of 0.8:1.0. However, This ratio appears to be based upon clinical trials that did not test multiple LAAM doses
as is typically done in studies of relative potency. This study examined the relative potency of the acute agonist
effects of LAAM and methadone using a within-subject, double-blind, double-dummy design. Nondependent,
opioid-experienced, male volunteers (N = 5) received single doses of LAAM and methadone (15, 30, and 60 mg/70
kg, p.o.) and placebo. Test doses were administered once weekly according ma Latin-square design. Seven subjects
were, scheduled to participate, but when 3 subjects failed to complete the study due to clinically significant
respiratory depression after 60 mg/70 kg LAAM, the study was terminated for safety reasons. Physiological,
subjective-report, and observer-rated measures were collected regularly for 12 hours to assess the magnitude and
duration of drug effects. Data from all three domains indicate that LAAM is not less potent than methadone under
acute dosing conditions. In fact, non-significant trends on many measures suggest that LAAM is more potent than
methadone. An accurate LAAM methadone relative potency estimate may aid determination of adequate doses for
daily methadone maintenance patients who choose to switch to more convenient thrice-weekly LAAM maintenance.
ACKNOWLEDGMENTS: This research was supported by USPHS grants P50 DA05273, R01 DA04011,
T32 DA07209, and K05 DA00050.
OPIOID CROSS-TOLERANCE AND WITHDRAWAL DURING LAAM MAINTENANCE:
A DOSE RESPONSE STUDY
E. J. Houtsmuller, S. L. Walsh, K. J. Schuh, R. E. Johnson, M. L. Stitzer, and G. E.
Bigelow
Dept. Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,
Baltimore, MD
Levo-alpha-acetylmethadohadol (LAAM) is currently approved as an opiate maintenance treatment. This double-blind
study was designed to characterize withdrawal suppression and opioid blockade produced by two different LAAM
maintenance doses. Outpatient opioid-dependent volunteers were stabilized (5-7 weeks) on 25 (n=8) or 75 mg (n=8)
LAAM administered every-other-day with placebo administered on intervening days. Following stabilization. four
inpatient randomly-ordered experimental sessions were conducted at 24, 48, 72, and 96 hr after LAAM dosing; these
intervals are consistent with those that occur during regular thrice-weekly treatment and following a missed dose.
During each session, ascending doses of hydromorphone (0, 6, and 12 mg i.m.) were administered 45 min apart;
physiological, subjective and objective effects were recorded throughout the session. Physiological and subjective
indices of opioid withdrawal measured at baseline increased with time since last LAAM dose, but were not
dependent on the maintenance dose. Withdrawal symptoms were mild in both groups, even at 96 hrs after LAAM
dosing. Hydromorphone produced dose-related opioid agonist effects at all intervals in the 25 mg LAAM group;
these effects were substantially attenuated in the 75 mg LAAM group. The since last LAAM dose had little
influence on bydromorphone effects in either group. Thus, LAAM 75 mg provides opioid blockade and withdrawal
suppression for up to 96 hr, whereas LAAM 25 mg is relalively ineffective at producing significant opioid
blockade.
ACKNOWLEDGMENT:
Supported by NIDA grant DA 05273.
314
LAAM: WHAT ABOUT BLOOD LEVELS?
W. Ling1,3, A. Huber1,2,3 , C. R. Deutsch1,2, Y. Kintaudi1, and R. A. Rawson1,2,3
Los Angeles Addiction Treatment Research Center 1 ; Matrix Institute on Addictions 2 ; and
West Los Angeles VAMC3
As the clinical use of LAAM is increasing, many clinicians who have come to appreciate the clinical utility of
methadone blood levels. have begun to wonder if LAAM blood levels are readily available and if they would also
be useful clinically. This type of information is virtually non-existent in the literature. The metabolism of
LAAM is, however, more complex than that of methadone. LAAM, which has opiate effects of its own, has two
active metabolites, nor-LAAM and dinor-LAAM, with the former being 7- to 10-fold more active than the parent
compound. Because the Los Angeles Addiction Treatment Research consortium has been conducting clinical
studies with LAAM, we decided to take advantage of the availability of a group of patients maintained on steady
LAAM doses. In this ongoing effort, we have obtained blood levels of the two active metabolites of LAAM from
nearly 50 patients.
OPIATE TREATMENT OPTIONS: PATIENTS PREFER LAAM
C. R. Deutsch1,2 , A. Huber 1,2,3 , R. A. Rawson1,2,3 , W. Ling 1,3 , P. Kintaudi1 , S. Muhammad 1 , T.
Ragsdale 1, and D. Molnar-Southon1
Los Angeles Addiction Treatment Research Center 1 ; Matrix Institute on Addictions 2 ; and
West Los Angeles VAMC3
To date there has been little documentation on individual preferences for opiate treatment. We evaluated treatment
preferences for 93 subjects enrolled in one of two ongoing LAAM studies. Opiate treatment preferences were
measured using a survey of attitudes and by noting treatment choices al the completion of the study. Surveys were
administered at study completion/termination and the results to date (n=44) indicate strong preferences for LAAM
over methadone on 13 of 16 treatment characteristics. Patients behavior also indicate clear preference for LAAM;
only 9 to 93 subjects enrolled have elected for early termination of treatment with LAAM. In addition, 80% of
subjects (n=25) chose to continue LAAM treatment at the conclusion of the study protocol. Patient characteristics
including conclusion of the study protocol. Patient characteristics including SCID derived psychiatric diagnoses and
ASI subscale scores will be evaluated as predictors of patient retention and other treatment effects with LAAM.
Subjects’ preferences for LAAM at the conclusion of the trial provides some of the best evidence of its acceptance.
315
A PILOT STUDY ON THE ADJUNCTIVE USE OF CIMETIDINE WITH LAAM FOR
MAINTENANCE PHARMACOTHERAPY IN OPIATE DEPENDENT PATIENTS
S. Rao, A. Oliveto, T. R. Kosten, M. C. Chawarski, and S. Ball
Department of Psychiatry, Yale University School of Medicine
LAAM maintenance on a thrice weekly basis has been shown tO be as effective as daily methadone maintenance.
However, it has been clinically observed that patients on LAAM maintenance report higher levels of opiate
withdrawal symptoms on Mondays as compared to Wednesdays and Fridays. Administering a higher dose of LAAM
will not change the pharmacokinetics of the drug. It would result in a higher peak plasma level of LAAM without
significantly prolonging it’s half-life. We hypothesized that Cimetidine may prolong the duration of action of
LAAM through competitive inhibition of the cytochrome P-450 enzyme system in the liver resulting in more
continuous prevention of opiate withdrawal symptoms, leading to increased treatment compliance and reduced illicit
opioid use. Sixteen opiate dependent subjects were inducted onto LAAM maintenance during week 1 (Dose: 30 mg
on Mon, Wed and 39 mg on Fri), randomized to Cimetidine or placebo for weeks 2-5 and crossed over for weeks 69. Cimetidine/ placebo was discontinued at the end of week 9. During week 10 subjects were either detoxed from
LAAM or transferred to the clinical program. There was no difference between the subjects use of illicit opioids
while they were on LAAM-Cimetidine [52% (SD=50)]versus LAAM-ptacebo[60% (SD=49)]. Subjects did not use
less illicit opioids on the week-end (measured by U.Tox screens) on Mondays as compared to the rest of the week
while they were on LAAM-Cimetidine. While on LAAM-Cimetidine, 33% (SD=47) of the urine toxicology
screens were positive for cocaine compared to 53% (SD=50) when on LAAM-Placebo. We plan to do further
analysis comparing the blood levels of LAAM while subjects were on Cimetidine versus placebo and correlating it
to their scores on the opiate withdrawal rating scale.
ACKNOWLEDGMENT:
Supported by: NIDA-P50-DA04060.
DIFFERENCES AMONG INTRAVENOUS AND INTRANASAL OPIATE ABUSERS
M. Carpenter, M. A. Chutuape, and M. L. Stitzer
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD
This study examines differences between intravenous (IV) opiate abusers and those who exclusively used
intranasally (IN). Matched on age (X=31.7), race (83% African American, 17% Caucasian), and gender (57% Male),
27 IN users and 27 IV users were recruited from a three day inpatient detoxification unit. Subjects were compared
based upon self-reports of drug use from the Addiction Severity Index (ASI), administered during the detoxification
treatment. Subjects were interviewed again at 1 and 3 months following their discharge to assess drug use and
treatment utilization. Although no significant differences were found in subjects’ reported heroin use at intake (28
of the previous 30 days for both IV and IN), it was found that intravenous users had more days in the past 30 of
alcohol use to the point of the effects being fell, and multiple drug use (i.e., more than 1 drug used per day).
Despite age matching, IV users also reported more lifetime months of regular cocaine and multidrug use, as well as
a more extensive history of alcohol use, with both an earlier onset and a longer history of drinking to the point of
the effects being felt. Furthermore, while none of the IN users overdosed on drugs at all in their lifetime, the group
of IV users averaged more than one overdose. One and three month results indicated few differences, although drug
usage for both groups declined. The results show that intravenous users represent a group of opiate abusers who
have both a more severe drug abuse pattern and a more extensive history of other drug use than intranasaI drug
abusers. These observations may have implications for treatment intervention and prognosis.
ACKNOWLEDGMENT:
Supported by research grant DA10192 from the National Institute on Drug Abuse.
316
OUTCOMES FOR HEROIN ABUSERS FOLLOWING 3-DAY INPATIENT
DETOXIFICATION
M. L. Stitzer, M. A. Chutuape, and D. R. Jasinski
Johns Hopkins University School of Medicine
Inpatient detoxification services are popular with drug abusers. and may have therapeutic utility particularly if
followed by longer-term aftercaretreatment. This study examined 6-month outcomes for i.v. opioid abusers (n=118)
following enrollment in a 3-day inpatient Chemical Dependence Unit. Addiction Severity Index interview was
administered at 1, 3 and 6 months post-detox. The followup sample was 67% male, 77% African-American and 38
years old on average and includes 94.4% of all patients who received initial interviews on thedetox unit. Relapse
was common; 20% relapsed to first heroin use on day of discharge, 50% by end of week 1 and 80% by one month
post-discharge. However, average days of heroin use afer detox declined 10 50% of predetox levels (10-15 days
versus 28-30 days in the last 30). Money spent on all drugs declined to 25% of amount spent in 30 days pre-detox.
At each followup point, 15-20% reported (urine verified) heroin abstinence; 20-30% reported regular use (21-30 days
in past 30), while the remainder reported occasional use (1-20 days in past 30). In the fist post-detox month, 60%
sought treatment (formal or self-help); 33% attended some form of treatment for more than one week. The study
showed considerable individual variability in outcome after a brief inpatient detox. Although relapse is common,
average levels of drug use are much lower after than before detox. Motivation for change appears to be high in this
population, as evidenced by the number who seek and enter aftercare treatment. Targeted efforts to transition detox
patients into aftercare could be a cost-effective way to delay relapse and improve longer-term outcomes.
ACKNOWLEDGMENT:
Supported by NIDA grant DA10192.
OPIOID CRAVING AND ATTITUDINAL CHANGES IN OPIOID ADDICTS TREATED IN A
M-DAY AMBULATORY DETOXIFICATION PROGRAM
U. Malkerneker, B. Poddig, and J. Valdivia
Edward Hines, Jr. VA Hospital, Hines, IL
The decreasing availability of inpatient substance abuse units has resulted in the shift of treatment from an inpatient
to outpatient setting. For many opioid addicts, detoxification treatment with alpha-adrenergic drugs has not been
successful. This study was designed 10 determine the efficacy of a 30 day ambulatory detoxification program
utilizing gradual dose reductions of methadone and thrice weekly educational groups. Patients were assessed via a
detailed drug use history, completion of a visual analog craving scale for heroin, presence of withdrawal symptoms,
and urine toxicology samples at baseline and weekly thereafter. In order to assess patients’ perceived ability to cope
effectively without drugs, the Drug-Taking Confidence Questionnaire (DTCQ) was obtained at baseline and at
completion of program. Fifty-six patients were included in the study Mean age was 43 years and mean use of
heroin was 18 years. Fifty-one percent of sample completed the ambulatory detoxification program. there were no
significant differences in completers (C) versus noncompleters (NC) in respect to length of heroin use or history of
previous methadone treatment. Average length of treatment for C group was 27 days compared to 13 days. There
were no significant differences between groups in regards to baseline ratings in DTCQ or cravings for heroin.
Completers did have a significant difference (p<.05) in baseline vs termination craving scores. Eighty-two percent of
completers continued with aftercare treatment compared to 7% of noncompleters. In summary, an ambulatory
detoxification program can be considered a viable treatment option for heroin dependent patients.
317
WEEK-2 PERFORMANCE PREDICTS 6-MONTH TREATMENT RESPONSE AMONG
METHADONE MAINTENANCE PATIENTS
M. A. Belding, M. Y. Iguchi,* A. R. Morral,* A. T. McLellan, and D. A. Zanis
University of Pennsylvania/VAMC Center for Studies of Addiction, Philadelphia, PA; and
*Allegheny University of the Health Sciences, Philadelphia, PA
We examined urinalysis (UA) results and counseling attendance during the first 2 weeks of treatment to determine
whether the early performance of 59 methadone maintenance patients could predict subsequent treatment response.
Patients were dichotomized into outcome groups based on treatment retention and month-6 UA results. Poor
outcome was defined by dropping out of treatment or submitting 50% or more cocaine or opiate-positive month-6
urine specimens. Good outcome was defined by remaining in treatment and submitting less than 50% cocaine or
opiate-positive urines. Logistic regression analyses indicated that week-2 UA results and counseling attendance
made independent and additive contributions to the prediction of 6-month outcome, though patient background
factors (including pre-treatment drug use and psychosocial problem severity) did not. Strikingly, there were no good
6-month outcomes among the 20 patients who submitted one or more opiate-positive week-2 mines and failed to
attend 2 scheduled counseling sessions in weeks 1-2. Among patients attending 2 counseling sessions and
submitting 2 week-2 opiate-negative urines, 60% had good outcomes. These results were supported by secondary
analyses using self-reported cocaine and heroin use in month 6 as outcome measures. Thus, 6-month outcomes
were well predicted by early treatment performance. It remains a question whether these week-2 performance
variables are indicators of patient motivation, or whether interventions that increased the likelihood of their
occurrence would also improve subsequent treatment response. Generalizability is limited by the small sample size
and specific treatment characteristics (e.g., twice weekly UAs and scheduled weekly counseling). Nonetheless, the
results suggest that it may be possible, very early, to identify methadone patients unlikely to respond well to
treatment as usual.
ACKNOWLEDGMENTS:
Supported by NIDA grants R01 DA06096 and P50 DA07705.
NEW SELF-REPORT INSTRUMENTS FOR MEASURING ENVIRONMENTS OF
METHADONE AND LAAM MAINTENANCE PATIENTS: PRELIMINARY FINDINGS
D. A. Wasserman1,2 , M. G. Weinstein2 , and A. L. Stewart 3
Mental Health Service, VAMC San Francisco1 ; Department of Psychiatry2 and Institute for
Health and Aging 3 ; and University of California-San Francisco, San Francisco, CA
The goals of this ongoing project are to develop self-report measures of the environments of methadone and LAAM
maintenance patients and to test hypotheses relating environmental variables to treatment progress. Environmental
domains studied include general level of reinforcement, stress (including daily stressors, chronic strains, and major
life events), social influences on drug use and abstinence, perceived drug availability, and perceived risks of drug use.
The project has three stages. In Stage 1, “Item Development and Pretesting” (now completed), we created initial
versions of each measure and administered them to a pretest sample. Following modifications, we began Stage 2,
“Psychometric Development,” now in progress. Stage 2 (n=240) focuses on the psychometric adequacy of the
measures. Interim data from 100 Stage 2 participants suggest adequate internal consistency and one-week test-retest
reliability. Future psychometric work in this stage will include extensive item analysis using exploratory and
confirmatory factor analysis. In Stage 3, “Validation” (n = 120), we will examine validity using other self-report
instruments and objective data on patients’ environments. The new measures, when completed, should contribute to
scientific understanding of patients environments and clarify environmental correlates of treatment progress. Final
versions of the measures and extensive reliability and validity data will be available upon study completion.
ACKNOWLEDGMENTS:
Supported by NIDA grants #1 RO1-DA09124 and #P50-DA09253.
318
PATIENT SATISFACTION SURVEY CONDUCTED BY CONTINUOUS QUALITY
IMPROVEMENT COMMITTEE AT METHADONE MAINTENANCE TREATMENT
PROGRAM IN NEW YORK CITY
L S. Brown, Jr.; M. Chu; L. Pitt; J. E. Rawls; and R. Sage
Addiction Research and treatment Corporation and Harlem Hospital Center/College of
Physicians and Surgeons, Columbia University
In the era of managed care, substance abuse treatment, like other areas of health care, has been subject to reviews of
how to improve its delivery and effectiveness. Continuous Quality Improvement (CQI) programs have been one
way to assess the delivery of substance abuse services. A major component of any CQI program is patient
satisfaction. During 1995, the first year of a patient satisfaction survey at a large methadone maintenance program
(N = 2,300) in New York City, a 30% random sample of patients was surveyed using a standardized instrument.
The survey was administered by the patient Advisory Committee Members offering assistance to their peers. At the
time of the survey, the mean length of stay of the respondents was 45 months with a median of 36 months. Over
75% patients responded that the care was satisfactory to excellent. Patients enrolled for less than 36 months
responded more favorably than those. in treatment for more than 36 months regarding their satisfaction with the staff
and the availability of medical services. This information suggests that patients with longer lengths of drug abuse
treatment may have different expectations of substance abuse care than those patients who are enrolled more
recently.
PROGRAM QUALITY EFFECTS ON PATIENT DRUG USE DURING METHADONE
MAINTENANCE
P. C. Nwakeze, S. Magura, and S. Demsky
National Development and Research Institutes, New York, NY
This study 1) measured the program quality variables found in Ball and Ross (1991) to be related to patient drug
use, 2) identified how clinic differences in methadone program variables affect heroin and cocaine use, and 3)
attempted to replicate the seminal Ball and Ross (1991) results with a larger sample of 17 methadone clinics.
Principal components analysis reduced 22 treatment domain variables to eight program factors. Program quality
variables were importanl factors in lower heroin use during the first year of treatment; patients’ pre-treatment
variables were generally more related to cocaine use than heroin use. Methadone dose was unrelated to heroin use,
but was associated with higher cocaine use in the second and third years of treatment. Two counselor characteristics:
being in recovery. and being tough-minded about addiction (i.e., more disapproving of drug use) were related to
higher heroin use in the third year of treatment. Compared with Ball and Ross, this study found different numbers
of program factors to be associated with patient drug use, probably due to studying 17 clinics instead of just six.
However, both the Ball and Ross and current studies identified similar program factors, namely counseling contacts,
director involvement and director experience to be associated with lower drug use by patients. The two studies also
found that longer length of stay in treatment was associated with less patient drug use.
ACKNOWLEDGMENT:
Supported by NIDA Grant No. DA08761.
319
PSYCHOSOCIAL TREATMENT FOR METHADONE PATIENTS: IS MORE BETTER?
S. K. Avants, A. Margolin, T. R. Kosten, J. Sindelar, R. Schottenfeld, B. Rounsaville, S.
Stine, N. Cooney, and S. H. Li
Yale University, West Haven VA, and National Institute on Drug Abuse
Two intensities of manual-guided psychosocial treatments for unemployed inner-city, methadone-maintained
patients were compared in a randomized clinical trial. Outcomes included retention in treatment and illicit drug use.
Of the 308 patients who were eligible for the study, 291 began their assigned treatment; 237 (81%) completed the
12-week study -- 82% completed the high intensity, 25-hour per week, Day Treatment Program; 81% completed the
lower intensity, 2-hour per week skills training group. Contrary to hypothesis, there were no significant
differences in illicit drug use between patients assigned to the two treatment intensities, as assessed by twice weekly
mine toxicology screens for opiates and cocaine. Drug use decreased significantly for patients receiving either
treatment intensity. Exploratory data analyses suggested that patients with high psychiatric severity scores on the
ASI and patients in “bad standing” in their methadone program may benefit from more intensive treatment, and that
patients new to methadone without these problems may more appropriately be referred to psychosocial interventions
of lower intensity.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA08754(SKA); DA00277 (SKA); DA00122(TRK).
UNRELIABILITY AND REASONS FOR UNRELIABILITY IN REPORTS OF
CONSEQUENCES OF SUBSTANCE USE
L. B. Cottler and W. M. Compton
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
As part of a NIDA-funded study on the nosology of DSM substance use disorders, the one week test-retest reliability
of the criteria for DSM-IV substance use disorders was tested, as measured by the WHO/NIH Composite
International Diagnostic Interview Substance Abuse Module (CIDI-SAM). In this study of 344 substance users,
we test the hypotheses that a) women are more reliable reporters than men, b) community subjects are less reliable
in their reporting of drug use symptoms than subjects in drug treatment; and c) persons meeting criteria for a DSMIV dependence disorder are more reliable than persons with subthreshold impairment. In addition to assessing the
one-week test-retest reliability, our study assesses the self-reported reasons for discrepancies from one interview to
the next. The CIDI-SAM is highly reliable for assessing DSM-IV dependence on opiates, cocaine, and alcohol.
Cannabis dependence is less reliably reported, suggesting further evaluation is needed in both criteria and
assessment. Men and women and community and treatment subjects were equally reliable. Tolerance, withdrawal,
physicaI/psychoIogical problems, and persistent desire to cut down need improvements. The common reasons for
not reliably reporting symptoms include: misunderstanding the question, not remembering the answer, and not
paying attention.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-05585.
320
DIFFERENCES ACROSS ETHNICITY IN RELIARILITY OF DIAGNOSING DSM-IV
SUBSTANCE USE DISORDERS
J. Horton, L. B. Cottler, and W. M. Compton
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
Cross cultural research on substance use disorders (SUD) demands diagnostic measures and criteria that apply equally
well to persons of different ethnic backgrounds. To evaluate the acceptability and reliability of SUD in different
ethnic groups, comparisons were made of the one week test/retest agreement on DSM-IV substance dependence
disorders for 214 African American (AA) and 130 Caucasian ( C ) respondents using the Composite International
Diagnostic Interview-Substance Abuse Module (CIDI-SAM). Overall we found excellent reliability, using kappa
(k) statistics, in diagnosing both AA and C respondents with alcohol dependence (AA k=.76; C k=.82) and opiate
dependence ( AA k=.79; C k=.76, excellent reliability for diagnosing AA respondents with cocaine dependence
(k=.85), good reliability for diagnosing C respondents with cocaine dependence ( k =.70), fair to good reliability for
both AA and C respondents with cannabis dependence (AA k=.51; C k=.68). Reliability of the dependence/abuse
criteria was consistent with the overall diagnostic reliability but some variation was noted. No significant
differences in the kappas were found between the two ethnic groups for any of the substance dependence diagnoses
and only one dependence or abuse criterion (“continued use of cocaine despite physical/psychological problems”)
differed significantly between AA and C respondents. These initial results indicate that DSM-IV dependence
diagnoses as measured by the CIDI-SAM apply equally well to AA and C respondents.
ACKNOWLEDGMENTS:
Supported by NIDA Grants DA05585, DA00209.
PREDICTIVE VALIDITY OF SUBSTANCE DEPENDENCE DIAGNOSES
M. Kidorf, R. K. Brooner, V. L. King, K. B. Staller, and J. Wertz
Johns Hopkins University School of Medicine, Baltimore, MD
The present study examined the predictive validity of DSM-III R SCID-based substance dependence diagnoses (i.e.,
cocaine, sedative, and alcohol) for 518 opioid dependent outpatients entering methadone maintenance. Patients were
followed for one year of treatment, which involved daily methadone substitution supplemented by individual and
group counseling. Urine specimens were tested randomly one IO four times per month. Cocaine dependence was the
most prevalent current disorder (31%), followed by alcohol (21%) and sedative (16%) dependence. Patients diagnosed
with current cocaine, sedative, or alcohol dependence were more likely to use these drugs than were patients with
past only or no dependence syndrome. Current cocaine dependence, but not sedative or alcohol dependence, predicted
early treatment drop-out. The results demonstrate the predictive validity of severaI substance dependence diagnoses
common among patients in substance abuse or other psychiatric treatment settings.
ACKNOWLEDGMENT:
Supported by NIDA grant I P50 DA 05273.
321
CONCURRENT VALIDITY OF SUBTYPING ACCORDING TO LEVEL OF SOCIOPATHY
AMONG ANTISOCIAL SUBSTANCE ABUSERS
J. J. Cecero, S. A. Ball, and B. J. Rounsaville
Yale University School of Medicine, Department of Psychiatry
Research in the concurrent and predictive validity of the DSM diagnosis of Antisocial Personality Disorder (APD)
has found that this diagnostic category, which focuses exclusively on behavioral criteria may be less clinically
useful in the assessment and treatment of antisocial substance abusers than subtyping according to the character trait
of sociopathy. Among substance abusers with APD. those with lower sociopathy seem to have less severe pretreatment psychiatric and substance abuse severity than their counterparts with higher sociopathy. This study of 370
inpatient and outpatient alcohol, cocaine, and opiate abusers uses MANOVAs and planned comparisons to contrast
non-APDs to APDs with low vs high sociopathy, as determined by a median-split of scores on the California
Personality Inventory - Socialization Scale (CPI-So), on pre-treatment measures of substance abuse and psychiatric
severity. PreIiminary analyzes indicate that those APDs with high sociopathy score significantly higher than APDs
with low sociopathy on drug use severity (ASI) and on several measures of psychiatric severity (depression, anxiety,
hostility, psychoticism, somatization). These findings both support the validity of this subtyping and suggest that
attention be directed to the assessment of sociopathy in the clinical management of APD substance abusers.
Additional analyses will evaluate 12 month follow-up measures.
SUBSTANCE ABUSE TREATMENT OUTCOMES AND PROGRAM DURATION
M. McCann1,2 , J. Zogg 1,2 : R. Rawson1,2,3 , K. Miotto 1,3 , and W. Ling 1,2,3
Matrix Center 1 ; Friends Research Institute 2 ; and University of California, Los Angeles
(UCLA) 3
The new managed cam environment requires behavioral health care providers to furnish better care for more people
at a lower cost. Payors and patients alike want to see treatment outcome data demonstrating clinical efticacy and
cost efficiency. This study examined the efficacy of a substance abuse treatment program delivered in three different
durations at a privately-funded Southern California treatment center. Subjects entered either a two-, four-, or sixmonth program consisting of weekly relapse prevention and psycho-education groups, urine testing, and blood
alcohol testing. Treatment outcomes such as addiction severity and level of functioning were examined with regard
to length of stay. Seventeen (17) subjects from the two-month program and 45 subjects from the four-month
program completed three interviews, one each at baseline, discharge, and six-month follow-up. Twenty-six (26)
subjects from the six-month program completed interviews as baseline and discharge only. Instruments included
the Addiction Severity Index, the Basis 32, and measures of overall satisfaction. Self-repotted relapse data were also
Included. All programs produced Improvement in drug and alcohol use and in levels-of-functioning, and all were
rated highly by patients. Additionally, the different treatment durations produced comparable outcomes on all
measures.
ACKNOWLEDGMENT:
Research, Inc.
Supported by NIDA grant 5 RO1 DA09419-03 to Friends Medical Science
322
SEXUAL AND PHYSICAL ABUSE: DO THEY COMPROMISE DRUG TREATMENT
OUTCOMES?
V. Gil-Rivas, R. Fiorentine, and M. D. Anglin
UCLA Drug Abuse Research Center, Los Angeles, CA
Histories of sexual and physical abuse are frequently reported by individuals participating in substance abuse
treatment. These experiences may be associated with psychopathology and poor drug treatment outcomes. This
paper presents the findings from a longitudinal study of 330 subjects participating in 26 outpatient treatment
programs. Sexual abuse among women was associated with higher levels of depression, anxiety, suicidal ideation,
suicide attempts, and PTSD, while physical abuse was associated with fewer psychological disturbances. For men,
sexual abuse was associated only with anxiety. Physical abuse was associated with depression, anxiety, suicidal
ideation, and PTSD. However, no significant association was found between sexual and physical abuse, and lower
levels of treatment engagemenl or drug use at follow-up. These findings indicate that mere is a complex connection
between abuse, psychopathology, treatment engagement and relapse. Clinical and research implications of these
findings are discussed.
PSYCHOLOGICAL IMPAIRMENT, TREATMENT SELECTION, AND ACCESS
P. M. Flynn, K. M. Broome*, and S. G. Craddock
National Development and Research Institutes, Raleigh, NC and *Institute of Behavioral
Research, Texas Christian University, Fort Worth, TX
Individuals accessing substance abuse treatment and selecting particular modes of treatment exhibit impairments
across multiple domains of functioning. particularly in the area of psychological functioning. Different treatment
modalities serve different clientele due to factors related to treatment program designs and client self-selection
elements. Early research has shown that level and type of impairment tend to vary by treatment type. Data from
the Drug Abuse Treatment Outcome Study (DATOS) were analyzed tO determine the sub-types, patterns, and rates
of psychological impairment and other key behaviors among clients selecting and accessing long-term residential,
outpatient drug-free, and short-term inpatient treatment modalities. Subjects were 10,010 clients interviewed at
admission to programs participating in DATOS; 66% were male, 47% African American, 13% Hispanic, with an
average age of 32.6 years. Stepwise logistic regression analyses were used to examine factors related to admission
to the three modalities. Findings included significant determinants of treatment access in community-based
treatment programs. Access to treatment in these programs can be explained in part by client factors such as
psychological impairment, substance dependencies, need for services, health insurance, criminal justice referrals and
status, and transportation barriers.
ACKNOWLEDGMENT:
Supported by NIDA grant U01-DA10377-3.
323
DOES CENTRALIZED INTAKE AFFECT CLIENT OUTCOMES?
J. Guydish, M. Chan, B. Tajima, and C. Ponath
Institute for Health Policy Studies, University of California, Sun Francisco
As part of the national Target Cities Demonstration Project, San Francisco implemented centralized intake in its
publicly-funded drug abuse treatment system. A key hypothesis driving the Target Cities project was that
standardized clinical assessment and referral procedures along with systematic efforts to assign clients to the most
appropriate treatment would yield improved outcomes. To test this hypothesis, clients who entered 6 treatment
programs through the centralized intake unit (CIU group, n=267) were compared to clients who entered the same
programs through usual routes (non-CIU group, n=200). Participants were interviewed al the time of admission,
and at 1 month and 12 month follow-up. Outcome measures included the seven composite severity scores from the
Addiction Severity Index (ASI). the Beck Depression Inventory, the Brief Symptom Index, and a measure of social
support. Preliminary findings reported here concern outcomes al 1 month follow-up only. At baseline, the CIU
group had greater severity of employment (t=-2.61. p < .01) legal (t=-2.01, p < .05) and psychological problems
(t=-2.37, p < .05). more psychiatric symptoms (t=-2.72, p < .01), and less social support (t=4.53. p < .001). The
CIU attracted and served a more severely disordered client population. At 1 month follow-up, both groups showed
significant improvement on ASI measures of legal, alcohol, and drug problems, and on measures of depression,
psychiatric symptoms, and social support. ANCOVA analyses controlling for baseline differences between groups
showed that level of improvemenl did not differ by group. This effort at systemic change may have resulted in
better access to treatment for the more severe client population, but did not result in better short-term (one month)
client outcomes.
ACKNOWLEDGMENT:
Grant no. U95-T100669.
The San Francisco Target Cities Project and evaluation are supported by CSAT
COERCION, MOTIVATION, AND CHANGE IN DRUG ABUSE TREATMENT
D. B. Marlowe, D. S. Festinger, K. C. Kirby, J. J. Platt, D. S. DeMatteo, G. R. Marczyk,
and M. A. Paninopoulos
Institute for Addictive Disorders, Allegheny University of the Health Sciences, Philadelphia,
PA
This study evaluated perceptions of coercive and noncoercive pressures to enter drug abuse treatment among 186
patients and their primary therapists in dual diagnosis inpatient (N = 61, 33%) intensive outpatient (N = 61, 33%)
methadone maintenance (N = 33, 18%), and detoxification (N = 31, 17%) programs. Interview responses were
tabulated according to a reliable coding procedure (Marlowe, et al., 1996). Results indicate that perceptions of
treatment-entry pressures differ significantly across settings (p < .0001); however, contrary to expectations,
outpatients reported significantly more coercive influences and there were no differences by gender or race.
Therapists’ and patients’ perceptions were highly discrepant (p < .0001) and patients’ perceptions were impressive
predictors of tenure, compliance, and outcome in treatment as well as readiness for change as measured by the
URICA. These data suggest that “coercion” should not be equated with residential treatment and that assessment of
treatment-entry pressures may have substantial prognostic value.
References:
Marlowe, D. B.; Kirby. K. C.; Bonieskie, L. M.; Glass, D. J.; Dodds, L. D.; Husband, S. D.; Platt, J. J.; and
Festinger, D. S. (1996). Assessment of coercive and noncoercive pressures to enter drug abuse treatment. Drug Alc
Depend 42: 77-84.
ACKNOWLEDGMENT: Supported by NIDA grant DA 10113.
324
FAILURE OF A FINANCIAL INCENTIVE TO REDUCE DRUG USE IN A METHADONE
MAINTENANCE PROGRAM
D. E. McMillan, J. E. Marshall, and T. Chivers
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences,
Little Rock, AR
Patients enrolled in the Substance Abuse Treatment Clinic, a methadone maintenance clinic at the University of
Arkansas for Medical Sciences, paid a weekly treatment fee of $17 to $62, depending on personal income. All
patients were screened each week on a day selected at random for the presence of abused drugs (amphetamines,
barbiturates, benzodiazepines, cannabinoids, cocaine, methaqualone, opiates, phencyclidine, propoxyphene and
methadone) in the mine. All patients were given a $5 reduction in their weekly treatment fee for any week that only
methadone was detected in their urine sample. They were also offered one week of treatment at no cost if they could
complete 25 consecutive weeks with detection of only methadone in their urine samples. Although many patients
received the fee reductions ($24,103 was the cost of the program during a 15-month period), there was no reduction
in the detection of these abused drugs in the urine. Generally, patients who were compliant remained compliant and
those who were not compliant remained not compliant. Subsequent interviews with patients who were not
compliant, suggested that $5/week was not sufficient to change their drug-taking behavior.
ACKNOWLECMENT:
Supported by the Arkansas Bureau of Alcoholism and Drug Abuse Prevention.
INCENTIVE PROGRAM FOR BENZODIAZEPINE-DEPENDENT METHADONE PATIENTS
SUSTAINS POST-DETOX ABSTINENCE
M. A. Chutuape, K. Silverman, and M. L. Stitzer
Department of Psychiatry and Behavioral Sciences,
Medicine, Baltimore, MD
Johns Hopkins University School of
This study examined whether incentives sustain abstinence following benzodiazepine inpatient detoxification.
Benzodiazepine-dependent patients maintained on 60-100 mg methadone first completed a 7-day inpatient
benzodiazepine detox. Patients then continued with outpatient methadone treatment, submitted urine samples 3
times weekly (M/W/F), and were randomized to either the Incentives (INC+) or No Incentives (INC-) condition.
INC+ patients chose either a methadone take-home or a $25 voucher for each drug-free (i.e., for opiate, cocaine, and
benzodiazepines) urine sample submitted. Following any drug-positive sample, patients were required to submit 3
consecutive drug-free mines to resume earnings. Drug use had no consequences for INC- patients. Fourteen
patients participated and were evaluated for 12 weeks post-detox. During the 4 weeks prior to detox, INC+ (N=7)
and INC- (N=7) patients submitled 91% and 86% drug-positive urines, respectively. Following detox, INC+ and
INC- patients submitted 10% and 77% overall drug-positive urines, respectively (p<.01). Furthermore, all INC+
patients (N=7) showed at least 4 weeks of sustained abstinence, with four showing greater than 8 weeks of sustained
abstinence during the 12-week evaluation (mean=8 wks). In contrast, almost all patients in the INC- group
sustained one week or less of continuous abstinence, whereas one INC- patient sustained at least 3 weeks of
abstinence (mean=1 wk; p<.01). These results demonstrate that providing incentives for drug-free urines are a useful
relapse prevention technique and dramatically sustain post-detox abstinence with benzodiazepine-dependent
methadone patients. Future studies are needed to determine whether inpatient treatment is an essential component
for the success of this program.
ACKNOWLEDGMENTS:
This research was supported by NIDA grants DA09258 and T32-DA07209.
325
REWARDING CANNABIS ABSTINENCE IN METHADONE TREATMENT
D. A. Calsyn and A. J. Saxon
Veterans Affairs Puget Sound Health Care System, and Department of Psychiatry and
Behavioral Sciences, University of Washington School of Medicine, Seattle, WA
Most methadone maintenance clinics do not routinely test urine specimens for cannabis, or have consequences
associated with its use. Two recent studies have indicated cannabis use is not associated with greater use of other
dsugs of abuse by methadone clients. Clinic staff may feel that such tolerance policies give the message that
cannabis use is sanctioned. Our clinic dealt with this dilemma by adding a requirement to the take home dose policy
that clients provide cannabis free urinalyses (UAs) to achieve twice a week pick up status (2x/wk). Prior to the
policy change the requirements for 2x/wk were: two years in treatment; six months negative UAs (except cannabis)
and involvement in constructive activity. The clinic announced the policy change 4/1/95 with an 11/1/95
implementation date. The policy change was evaluated by monitoring the UA records and take home sfatus of all
clients in treatment for the six months prior to implementation and one year after. At implementation 23 of the
120 clients (19%) had 2x/wk based on the previous criteria. Eleven of these- clients (47.8%) remained on 2x/wk
throughout the study. Of these 8 (72.7%) provided no cannabis positive UAs. Three (27.3%) had cannabis positive
UAs in the pre-implementation period, but none after. Five of 23 clients (21.7%) were inreased to three times a
week status during the implementation month due to cannabis positive UAs. One of these clients has subsequently
returned to 2x/wk by providing cannabis free UAs. No client who lost 2x/wk due to cannabis use provided a UA
positive for other drugs of abuse. Seven (30.4%) of the 23 were cannabis negative throughout the study period, but
lost their 2x/wk due to positive UAs for other drugs. Five of these subsequently regained 2x/wk. In summary, 4 of
8 clients (50%) on 2x/wk status who were using cannabis were able to discontinue their cannabis use in order to
maintain or regain 2x/wk.
ACKNOWLEDGMENT:
Supported in part by NIDA grant R01 DA08625.
INFLUENCE OF ALCOHOL USE M COCAINE ABUSE TREATMENT
M. Mengis, P. Maude-Griffin, D. Hartz, and S. Hall
Department of Psychiatry, University of California, San Francisco and the San Francisco VA
Medical Center, San Francisco, CA
Studies have reported high comorbidity of alcohol abuse in individuals with cocaine abuse or dependence, however it
has not been clarified whether alcohol use influences clinical and treatment response characteristics of cocaine abuse
or dependence disorders. This study addresses this question in 128 cocaine abusing adults who participated in a
randomized trial of cognitive behavioral vs. 12-step treatment. Subjects were assessed at baseline and weeks 4, 8, 12
and 26 on biologically-verified cocaine abstinence and a battery of psychometric measures. All subjects were crack
cocaine smokers; most were male (99%). African American (80%), unemployed (84%). and homeless or marginally
housed. Subjects were divided into three levels of alcohol use based on their self-reported frequency of drinking at
intake. Nondrinkers (17 % of subjects) denied any alcohol use in the thirty days prior to intake. Less than Daily
drinkers (48% of subjects) reported drinking at least once a week and as often as 2-6 times per week. Daily of More
drinkers (35% of subjects) reported drinking at least daily and as often as 4 or more limes per day. We hypothesized
that greater alcohol use in cocaine abusers would correlate with an increased alcohol, drug and psychiatric severity at
baseline; increased success with 12-step treatment, and overall worse outcome as measured by abstinence at 12 and
26 weeks. Preliminary results suggest that cocaine abusers who have greater levels of alcohol use have greater
alcohol and drug addiction severity at baseline. Level of alcohol use, did not interact with treatment condition or
significantly predict ability to achieve cocaine abstinence suggesting that alcohol drinking status is not a critical
prognostic factor in cocaine treatment outcome.
ACKNOWLEDGMENTS:
Development.
Supported by Dept. of Veterans Affairs, Health Services Research and
326
EFFECTS OF PERSONALITY ON TREATMENT COMPLIANCE AND DRUG USE IN
METHADONE PATIENTS
J. S. Wertz, R. K. Brooner, M. Kidorf, V. L. King, and K. B. Stoller
Johns Hopkins University School of Medicine, Baltimore, MD
This study evaluated the relationship between personality traits and treatment outcome in opiate abusers. New
admissions to methadone maintenance (n = 111) completed the NEO Personality Inventory Revised (NEO-PI R;
Costa and McCrae, 1985). Patients were randomly assigned to contingent (n = 58) or non contingent (n = 53)
treatment. Patients in both conditions were referred to escalating intensities of counseling based on recent drug use
and counseling attendance. In the contingent condition, continued methadone maintenance was linked to counseling
compliance and drug use, while in the control condition continued methadone maintenance was independent of
counseling and drug use. Weekly urinalysis results and counseling compliance were assessed over the first 90 days
of randomized treatment. Personality traits were associated with drug use but not counseling
Neuroticism correlated with both opioid (r = -.21, p < .05) and benzodiazapine (r = .27. p < .01) use, while
+conscientiousness was associated with benzodiazepine use (r = -.26, p < .01) use. No condition and personality
traits interactions were observed. Regression analyses showed that these variables did not significantly add to the
total chug use variance after controlling for baseline drug use. NEO-PI R personality traits appear to be modestly
related to drug use during treatment but do not add signiticantly to the predictive power of baseline drug use.
REFERENCES: Costa, P. T. and McCrae, R. R. The NEO Personality Inventory manual. Odessa, FL:
Psychological Assessment Resources, 1985.
VOUCHER-BASED REINFORCEMENT OF BRIEF COCAINE ABSTINENCE IN
METHADONE PATIENTS
E. Robles, K. Silverman, K. L. Preston*, G. E. Bigelow, and M. L. Stitzer
Johns Hopkins University School of Medicine, Baltimore, MD and *NIDA Intramural
Research Program, Baltimore, MD
Although voucher-based reinforcement has been effective in sustaining cocaine abstinence in methadone patients,
not all patients have initiated abstinence when offered voucher reinforcers. This ongoing study evaluates a procedure
that reinforces a brief period of abstinence (2 days) with one high-magnitude voucher to determine its effectiveness
in initiating cocaine abstinence in methadone patients. Study patients are told on Monday of the test week that they
will receive a $100 voucher if their urine on Wednesday indicates that they had abstained from cocaine. Patients were
considered cocaine abstinent if their urine benzoylecgonine concentration decreased by 50% from Monday to
Wednesday or if their Wednesday’s mine benzoylecgonine concentration was 300 ng/ml, the standard cutoff for
qualitative urine testing. Data from the test week were compared to equivalent periods in the weeks before and after
the test week. Thus far, 38 cocaine abusing methadone patients have completed the study. Significantly(p < 0.001)
more patients met the cocaine abstinence criterion during the week in which the abstinence reinforcement
contingency was in effect (87%) compared to the week before. (37%) and the week after (42%). Furthermore, almost
all patients (95%) decreased their benzoylecgonine concentration from Monday to Wednesday of the test week; in
contrast, only about half of the patients decreased from Monday to Wednesday of the weeks before (55%) and after
(52%) the test week. Analyses based on the standard qualitative test of cocaine abstinence ( 300 ng/ml) showed that
more patients were cocaine abstinent during the test week compared to the other two weeks, however, the differences
were not statistically significant. In conclusion, a high magnitude reinforcement ($100 voucher) contingent on a
brief period of abstinence (2 days) as assessed by changes in urine benzoylecgonine concentrations appears to be an
effective means of initiating abstinence in the vast majority of cocaine abusing methadone patients. This procedure
might be useful in increasing the proportion of patients who respond to subsequent long-term interventions.
ACKNOWLEDGMENTS: Supported by NIDA research grants P50 DA09258, K05 DAO0050, T32 DA07209.
321
METHADONE DOSE RESPONSE IN OPIATE DEPENDENT PATIENTS WITH COMORBID
COCAINE DEPENDENCE
S. M. Stine, B. E. Stanley, J. L. Scott, and T. R. Kosten
Yale University and VA Connecticut Healthcare System, West Haven, CT
A previous study comparing increasing and decreasing methadone (METH) dose contingency protocols indicated that
high dose (100mg or 120mg) may be effective in decreasing cocaine use in refractory patients (Stine et al. 1992).
That protocol had significant limitations (open study, few patients, behavioral contingency). Other studies described
cocaine induced opiate withdrawal-like symptoms in comorbid patients (Stine et al. 1992) and reported higher
correlation of withdrawal and cocaine use in patients on higher doses of both METH and buprenorphine suggesting
these symptoms may participate in reduced use at higher doses (Stine et al. 1994). The current study is a
randomized double-blind clinical trial comparing the effect of 40, 80, 120mg on opiate and cocaine use during 6
wks of maintenance after 6 wks of stabilization and dose adjustment. Subjects were METH treatment failures
(refractory cocaine abuse) and entered on 40 mg METH. Of 59 subjects enrolled, 3 in progress, results from 48 are
repotted. All 8 subjects not analyzed dropped out before beginning treatment. Mean age was 37±5.5, 66% males,
34% females, 57% Caucasian, 34% African American, 8% Hispanic. The primary outcome measures were cocaine
and opiate urine toxicologies. Other outcome measures were times and dollars cocaine used, cocaine craving, high,
other cocaine symptoms, opiate withdrawal and Beck Depression Inventory. Results from baseline through wk 13
were analyzed by repeated measures analysis of variance (RMANOVA). Cocaine use did not change significantly
with treatment. Opiate use did show a significant decrease with dose by time: F=1.80 df=13.46 p=0.039. Opiate
withdrawal symptoms also decreased: dose x time: F=2.140 df=13,46 p=0.010. Quality of cocaine high decreased
(dose x time: F=1.736 df=13.46 p=0.050) but no other cocaine measures changed significantly. We conclude
comorbid opiate and cocaine dependent patients may require higher doses of METH to decrease opiate use and
withdrawal symptoms, and these doses may also decrease cocaine high.
DIFFERENTIAL RESPONSE TO IV CARFENTANIL IN CHRONIC COCAINE USERS,
DEPRESSED PATIENTS, AND CONTROLS
R. Stauffer*, B. Bencheriff#, D. Gorelick*, R. Nelson*, G. Triesman#, N. Ilgin#, H. T.
Ravert#, W. B. Mothews#, J. L. Musachio#, R. F. Dannals#, and J. J. Frost#
#The Johns Hopkins Medical Institutions and *NIH-NIDA Division of Intramural Research,
Baltimore, MD
There is little human experimental data on the influence of chronic cocaine exposure on the acute response to
opiates. Some animal data suggest cross-sensitization between cocaine and opiates. We evaluated this by comparing
the side-effects experienced in response to an IV bolus of “C-carfentanil (CFN), a potent, specific synthetic muopioid agonist administered for positron emission tomography (PET) scanning to 14 chronic heavy cocaine users
(COC) (12 men, mean [SD] age 32.1 [3.8] years), 18 depressed patients (DEP) (8 men, age 38.6 [8.3] years), and 12
healthy controls (CTR) (8 men, age 46.8 [14.6] years). DEP and CTR groups had no self-reported history of illegal
drug use. The COC group had no opiate use within the prior 3 months. Potential opiate agonist effects (nausea,
vomiting, dizziness, itching, headache) were scored as present (1) or absent (0) during the scan itself (90 min) and
the following 90 min (possible total symptom count [SX CT] = 0-10). The COC group had a significantly lower
SX CT (0.6 [1.4]) than the DEP (1.9 [1.8]) or CTR (2.6 [2.2]) groups (p=0.02) and lower prevalence of subjects
with any symptom (29% vs 78% and 75%; p=0.01). There was no significant overall correlation between CFN dose
and total symptom count (rho=0.19, p=0.23), but CDC and CTR groups did receive lower CFN doses (0.045
[0.018] and 0.049 [0.011] µg/kg) than the DEP group (0.060 [0.017]; p=0.04). Reanalysis using only the 11 COC
and 12 DEP (and 12 CTR) subjects who received CFN doses of 0.03-0.07 ug/kg produced similar results (p’s=0.09;
all tests 2-tailed). These findings suggest that chronic cocaine use may reduce the acute response to mu-opioid
agonists, although the results are potentially confounded by any other significant group differences, e.g., prior
exposure to other drugs, age.
ACKNOWLEDGMENTS:
Supported by NIDA intramural funds and grant R01-DA 09479.
328
EFFICACY OF COGNITIVE-BEHAVIOHAL THERAPY FOR COCAINE-USING
METHADONE PATIENTS
S. Magura, A. Rosenblum, M. Palij, J. Foote*, L. Handelsman*, and B. Stimmel*
National Development and Research Institutes, Inc., New York, NY and *Mount Sinai
Medical School, New York, NY
Current cocaine-dependent methadone patients (by DSM-IIIR) were randomly assigned voluntarily to six months of
high intensity cognitive-behavioral therapy (5 X week individual and group) [N=140] or low intensity therapy (1 X
week group) [N=58]. All regular methadone clinic services were provided. Subjects were 57% male, 43% female;
53% Hispanic, 34% African-American, 13% white/other, mean age=38; 76% unemployed; mean methadone
dosage=68 mg. Therapy was completed by 61% of high intensity and 60% of low intensity patients. ANOVA with
repeated measures was conducted with patients trichotomized on severity of cocaine use at baseline, therapy
condition and therapy completion status as independent variables and cocaine use during four post-therapy follow-up
time periods as repeated dependent measures. Cocaine use at follow-up was measured by the percentage of cocainepositive urines during successive 12 week periods (25-36, 37-48, 49-60, and 61-72 weeks post-admission). using
endpoint data for all subjects. Lower severity of cocaine use at baseline and completion of either therapy were
associated with lower cocaine use at follow-up, but there was no difference between the high and low intensity
conditions. There, were two interaction effects: (a) Low cocaine severity patients improved more in the low intensity
condition, while mid- to high-severity patients improved more in the high intensity condition; (b) positive
outcomes for therapy completers relative to non-completers increased over time. Conclusion: Six months of
supplemental cognitive-behavioral therapy for dually addicted methadone patients had a good completion rate and
reduced cocaine use primarily for patients who completed therapy. High intensity as compared with low intensity
intervention was not superior overall, hut the results suggest that it may be cost-effective to match patients to
levels of treatment intensity based on their severity of cocaine use.
ACKNOWLEDGMENT:
NIDA Grant No. DA06959
PROCESS EVALUATION METHODS FOR 12-STEP AND REBT DAY TREATMENT
PROGRAMS
L. Winningham, P. Penn, E. Velten, and J. Parker
La Frontera Center, Inc., Tucson, AZ
This research evaluates and compares two intensive day treatment approaches, 12-Step and Rational Emotive
Behavior Therapy (REBT), for clients with dual diagnoses. We have devised three process evaluation methods for
monitoring adherence to program design and philosophy. These methods include: 1) a log system for measuring
program equivalence, and 2) two systems to monitor adherence to each of the treatment orientations. The methods
to be presented are transferable and could be utilized by similar programs. Both programs are designed to be the
same length and have the same number and types of groups and activities. The log system was developed for daily
and weekly -ding of data that may he used to compare program content and intensity. These logs capture data
that are quantitative (number and types of groups, translated into two databases) and qualitative (e.g., client
treatment progress and use of method). To monitor 12-Step and REBT program adherence, forms were developed
that can be used by an independent observer and/or by group leaders themselves. These forms evaluate whether the
major philosophies and techniques of the methods are utilized in the groups, if resource materials are available and
used, staff strengths and weaknesses, and whether the individual treatment plans and notes reflect use of the method.
ACKNOWLEDGMENT:
Research supported by NIDA grant RO1 DA08537 - 004.
329
MEDICATION TAKE HOME DOSES AND CONTINGENCY MANAGEMENT
J. M. Schmitz, H. M. Rhoades, R. Elk, and J. Grabowski
Substance Abuse Research Center, University of Texas - Houston
Two studies examined the effects of contingent take-home (TH) doses of methadone (Study 1) and fluoxetine (Study
2) for the treatment of opiate. and cocaine dependence, respectively. In Study 1, 32 methadone maintenance patients
were randomly assigned to one of two baseline TH groups: high frequency THs (2 clinic visits with 5 TH dose/wk)
or low frequency THs (5 clinic visits with 2 TH doses/wk). The 8-wk baseline period was followed by a 12-wk
contingency procedure when the HFTH schedule (2 visits/S THs) could be earned for submitting urines testing
negative for illicit drugs. The hypothesis that subjects in the preferred baseline condition (HFTH) would show
better contingent-reinforced responding (in order to avoid elimination of this condition) was partially supported by a
significant group by time interaction, indicating that the proportion of illicit drug use was lower in the HFTH
group during the first six weeks of contingency. Thereafter, the two groups showed comparable levels of
responding to the contingency. Drug screens at intake were related to outcome in that polydrug using methadone
subjects had an overall poorer response to the contingency than single-drug users. In Study 2, TH doses of
fluoxetine were used in a contingency management program for the treatment of cocaine dependence. Subjects
(n=81) were randomly assigned to 0, 20, or 40-mg fluoxetine, then began the 12-wk trial which included a 4-wk
non-contingency baseline period, a 6-wk take-home contingency period, and a 2-wk return to baseline period. All
subjects received the LFTH schedule during baseline periods. Results showed that the 40-mg group used less
cocaine during contingency than the other groups. There data suggest that the combination of fluoxetine and
environmental contingencies may produce benefit where neither alone, is sufficient. Results of both studies are
underscore the importance of behavioral and pharmacological treatment integration.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-6143.
HEALTH CARE NEED AND UTILIZATION: A COMPARISON OF INJECTION DRUG
USERS, OTHER CHRONIC DRUG USERS AND NON-USERS
D. D. Chitwood,* M. T. French,* D. C. McBride**, M. Comerford*, and L. R. Metsch**
Health Services Research Center, University of Miami, Miami, FL and **Andrews
University, Berrien Springs, MI
Purpose: To compare the need for care, treatment-seeking health care utilization, and the failure to receive needed
care among injection drug users (IDU), other chronic drug users (OCDU) and non-drug users (NDU). Methods:
Interview data from 1,078 African-American, Hispanic/Latino, and non-Hispanic white mate and female IDUs,
OCDUS, and NDUs recruited in Dade County, FL were analyzed to assess the need for care, utilization of care, and
failure to receive needed care. Eight independent demographic, health status, and drug use variables were entered into
three logistic regression models to determine independent factors associated with these outcomes. Results: Drug
use (IDU and OCDU), being female, having insurance, and poorer health were independently associated with need for
care. Non-use of drugs, having insurance, being female, and poorer health were independently associated with
utilization of treatment-seeking care. Drug use (IDU and OCDU), having insurance, and poorer health status were
independently associated with not receiving needed health care. Conclusions: Drug users have a demand for care,
are less likely to receive care, and are less likely to receive needed care than are non-users. Interventions are needed to
integrate chronic drug users into the health care system and to work with health care providers to increase their
sensitivity to the needs of drug users and to emphasize the importance of establishing a continuity of care.
330
“THE TRI-NET STUDY” ELECTRONIC TRACKING OF NATIONAL TRENDS IN
SUBSTANCE ABUSE TREATMENT
D. Carise, A. T. McLellan, H. Kleber*, and C Petro
Treatment Research Institute at The University of Pennsylvania and The Center on Addiction
and Substance Abuse at Columbia University*
The TRI-Net study is an ongoing, nationwide electronic system that provides standardized timely clinical and
administrative information on patients entering into substance abuse treatment programs. This presentation
describes the rationale, initial pilot testing and ultimate plans for this information network. Utilizing the Addiction
Severity Index (ASI), information is collected on the nature and severity of patients’ problems at admission, length
of treatment and type of discharge. A unique feature is made possible by the electronic format; ten supplemental
questions can be added via modem, based on issues of contemporary concern, and can be changed on a quarterly
basis. Four primary types of treatment programs are represented: methadone maintenance. therapeutic communities.
outpatient, and intensive outpatient abstinence oriented. In addition, drug court and DWI programs have been
piloted. In Phase, One, a pen-based computer system and software were developed and tested. During Phase Two,
nineteen programs in live major cities piloted the system, made suggestions regarding implementation, and changes
were implemented. These programs (5 intensive outpatient, 5 traditional outpatient, 4 inpatient, 3 methadone
programs, 1 drug court and 1 drunk driving program) continue to s-end data and provide feedback. Data transmission
via modem began in September of 1996, only non-identifying data are transmitted. The information will be in the
public domain. Phase Three has begun and involves expansion into approximately 100 additional programs in 25
cities. Sites are being randomly selected from the total population of treatment programs in the 26 SMSAs
represented, resulting in a representative sample of various types of treatment programs.
ACKNOWLEDGMENTS:
system funded by NIDA.
Current work supported by ONDCP. Pilot studies, including development of
EVALUATION OF COMMUNITY INTERVENTIONS: THE FIGHTING BACK MODEL
C. Winick, L. Saxe, and E. Reber
Social-Personality Psychology Program, City University of New York Graduate School, New
York, NY
Efforts to reduce substance use and harm have widened their focus in recent years from the individual who uses (or is
at risk to use) to increased emphasis on broad-based community programs, which seek to reduce substance use by
addressing the continuum of care surrounding substance users and potential users: prevention, early identification.
treatment, and aftercare. One of the most ambitious of these programs is Fighting Back (FB), a multi-year program
designed to foster community efforts to reduce demand for and abuse of substances in fourteen communities around
the U.S. In both FB and comparison communities, a set of outcome-oriented evaluation studies of the program is
measuring the changes over time in community-wide indicators of substance use, abuse, and harm. Four types of
studies are under way: (1) Surveys of adults and youth to address drug and alcohol use and attitudes; (2) Assessment
of social indicators of harm caused by substance abuse: (3) Ethnographic studies of the communities; (4) Systematic
tracking of program implementation in each community. Mid-project results validate some assumptions of the
program and demonstrate that some larger sites are focusing on areas that seem likely to produce substantive
changes. The complexity of the system surrounding substance abuse, however, argues that noticeable changes
require long-term efforts to alter both the physical and social environments.
ACKNOWLEDGMENT:
Supported by the Roben Wood Johnson Foundation.
331
LONGITUDINAL RISK-COHORT STUDY OF ONSET, COURSE, PREVALENCE AND
PREVENTION OF ILLEGAL DRUG ABUSE: DRUG USE PATTERNS FOR ASSESSING
THE COURSE OF DRUG USE
H. Kufner, J. Schumann, A. Duwe, K. Herbst, and G. Buhringer
IFT Institut fur Therapieforschung, Munich, Germany
Within an ongoing longitudinal study of risk-cohorts in Germany the purpose of the present analysis is to develop a
system of drug consumption patterns to assess the course of drug use for time windows of 12 months. The
following criteria should be fulfilled: (1) The data basis contains the CIDI with the criteria of DSM-IV diagnosis for
abuse and dependence. (2) Theoretically, a person should be able to change each drug use pattern within the time
window of 12 months. (3) Two dimensions should be regarded: frequency of use and consequences or problems in
relation to drug use assessed by DSM-IV criteria for abuse and dependence. (4) At least the use of hard drugs should
be summarized in the different drug use patterns. (5) The diagnostic drug use patterns should be validated by die selfallocation of the participants to different use categories. The suggested system of diagnostic use patterns consists of
six categories: (1) seldom use 1-11) in the last 12 months and no DSM-IV diagnosis of abuse and dependence (2)
regular use (12 - 100) and no diagnosis (3) heavy use and no diagnosis (4) seldom use and diagnosis of abuse or
dependence (5) regular use and diagnosis (6) heavy use and diagnosis. The frequency categories of CIDI can be
allocated to the frequency categories of the diagnostic drug use patterns. The results show a dominating accordance
between psychic dependence and heavy use with diagnosis for opiates (87%) and cannabis (83%). but only to a less
degree for cocaine users (in 58%). There is also a strong relationship between heavy use with diagnosis and physical
dependence with exception of cannabis use for which 25% of the persons with physical dependence have shown a
diagnostic use pattern of heavy use without DSM-IV diagnosis. The contingency coefficient care from 0.56 to 0.64
and for rank correlation (Spearman) from 0.43 to 0.62. Finally, several cluster-analyses with different predefined
numbers of clusters (SPSS: Quick Cluster) were carried out to find an empiric-statistical typology to support the
validity of the diagnostic drug use patterns. The four cluster solution seemed to be suitable for a plausible
interpretation.
THE INCIDENCE OF POLYSUBSTANCE USE IS GREATER AMONG COCAINE USERS
THAN NON-COCAINE USERS
S. L. Daniels, L. H. Lundahl, and S. E. Lukas
Neuropsychopharmacology Laboratory, McLean Hospital/Harvard Med. Sch., Belmont, MA
Although a large proportion of subjects recruited for drug abuse research studies are identified through responding to
newspaper advertisements, few studies have investigated their polydrug use profiles. This study was conducted to
determine the drug use profile of the typical subject who responded to the following advertisement:
Paid Volunteers, Healthy men and women,
ages 21-35, for cocaine/hormone related studies.
Blood sampling involved.
From 1990 to 1996 a total of 701 individuals responded to this advertisement and were screened using a series of
structured questionnaires inquiring about drug use, health status and demographic information. The subjects (62 %
male) ranged in age from 19 to 39 with a mean age of 25.7 years. Sixty-one % of the subjects reported a lifetime
history of cocaine use but only 3 % reported using cocaine exclusively. Use of LSD, amphetamine, psilocybin and
heroin in the cocaine using population was significantly more common than in the remaining 39 % who did not use
cocaine. The incidence of reported heroin use has increased in the past 1 to 2 years while only 7 % of the subjects
reported no illicit drug use at ah. These results suggest polysubstance use was significantly more common among
cocaine users than individuals who have never used cocaine.
ACKNOWLEDGMENTS:
NIDA grants DA03994, DA09657, and DA0115.
332
BEHAVIORAL ADAPTATION TO CHANGES IN REINFORCEMENT CONTINGENCIES BY
HUMANS: EFFECTS OF DRUG DEPENDENCE
S. D. Lane and D. R. Cherek
Dept. of Psychiatry and Behavioral Sciences, University of Texas Health Science Center,
Houston, TX
Two laboratory experiments investigated components of adaptation and self-control (e.g., response inhibition) in
subjects with a history of drug dependence. Experiment 1:12 subjects (n=6 per group) were exposed to conditions
with changing consequences. One group had a history of substance dependent: (SCID-II-NP), the other was a
matched control group. On day 1, subjects were required to wait 0.25 sec between responses (button presses) to earn
a monetary reward On day 2, without indication, subjects were required to wait 10 sec between each response.
Dependent measures included subjects’ response efficiencies (rewarded/total responses) and interresponse time
distributions. Three subjects in the drug-dependence group adjusted very poorly to the transition (p<.01). These
three subjects were all over age 35 and had long histories of substance use (>10 years): whereas other subjects either
had no use or much shorter use histories. The findings prompted Experiment 2, with 18 subjects (n = 6 per group),
All subjects were >35 years old. Group 1: dependence history, substance use 10 years; Group 2: dependence
history, use <5 years; Group 3: no dependence or abuse history. The high to low-rate transition procedure was
repeated from Exp 1. The general finding of Exp 1 was replicated, subjects with long drug dependence histories
(Group 1) showed little sign of adapting to the task requiring them to wait 10 sec between each response (p<.01).
In both studies, these subjects tended to perseverate on the previously established high-rate response pattern. We
suggest that our data measure a behavioral deficiency in adapting to contingencies that require self-controlled
responding (e.g., waiting) subsequent to a history of high-rate responding.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-03 166 and NIDA fellowship DA-05774.
REINFORCING EFFECTS OF DRUG/ETHANOL COMBINATIONS RELATIVE TO
ETHANOL ALONE
K. L. Shelton, M. J. Macenski, and R. A. Meisch
Department of Psychiatry and Beh. Sci., SARC, University of Texas Health
Science Center at Houston, Houston, TX
The reinforcing effects of combinations of ethanol and methadone or ethanol and cocaine were examined in 6 rhesus
monkeys. The monkeys had previously been trained to orally self-administer either methadone (n=4) or cocaine
(n=2) in daily 3-hr test sessions. Self-administration of either drug had declined over time such that none of the
subjects consistently self-administered methadone or cocaine in preference to concurrent water. However, when 0.2
mg/ml methadone or 0.2 mg/ml cocaine was combined with 1% (weight/volume) ethanol, both drug combinations
were consistently prefaced to concurrently available water. In the methadone group, the methadone+ethanol
combination was then compared to 1% ethanol over fixed-ratio values ranging from 1-32. At lower ratio values,
ethanol alone was preferred to the methadone+ethanol combination. At higher FR values, the combination was
preferred to ethanol alone. In the cocaine group, self-administration of a 0.2 mg/ml cocaine + 1% ethanol solution
was also compared to concurrently available 1% ethanol. Both animals also showed an increased preference for the
combination solution as fixed-ratio size increased. The results show that both ethanol+methadone and
ethanol+cocaine combinations will be orally self-administered by monkeys. The findings also suggest that work
requirement modifies preference for drug+ethanol combinations relative to ethanol alone.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA 08398, DA 04972 and DA 00159.
333
I.V. MORPHINE, AMPHETAMINE AND PENTOBARBITAL PRODUCE SIMILAR
DEGREES OF EUPHORIA IN MALES
L. H. Lundahl and S. E. Lukas
ADARC, McLean Hospital/Harvard Medical School, Belmont, MA
To determine whether drugs of three different classes produce similar profiles, the subjective/behavioral effects of
I.V. morphine, amphetamine, and pentobarbital were evaluated in eight healthy male volunteer drug users who
provided informed consent and resided on a Clinical Research Unit. On 10 separate days, each subject was
administered a different dose of morphine (5, 10, and 20 mg), amphetamine (5, 10, and 20 mg), pentobarbital (50,
100, and 200 mg), and placebo, in a double-blind, placebo-controlled design. Subjective drug responses were
collected at 60 and 15 minutes pre- and at 30, 60, 90, 120 and 180 minutes post-injection. Amphetamine and
pentobarbital produced significant elevations on the MBG Scale of the ARCI, and MBG Scale scores were
significantly higher after 200 mg pentobarbital than after 50 mg pentobarbital. Amphetamine produced a greater
number of discrete euphoric episodes compared to pentobarbital, and more euphoric events were reported after 200
mg pentobarbital than 50 mg pentobarbital. Latency to detect drug was shoes following 20, 10 and 5 mg
morphine. Duration of drug detection was greater after pentobarbital than morphine and amphetamine, with greatest
duration of drug detection reported after 200 mg pentobarbital. There were no drug-related differences in latency to
detect euphoria or duration of euphoria. These results indicate that the subjective reinforcing effects of iv.
morphine, amphetamine and pentobarbital have similar subjective profiles.
ACKNOWLEDGMENTS:
NIDA Grant DA00115.
METHODS FOR INCREASING FEMALE STUDY PARTICIPATION AND STUDYING
COCAINE ABSTINENCE
S. M. Evans, F. R. Levin, and R. W. Foltin
Columbia University and NYS Psychiatric Institute, New York, NY
Ten non-treatment seeking female cocaine smokers resided on a Clinical Research Center for 4-5 days, Cocaine selfadministration sessions occurred at 1200 and at 1600 on 2 consecutive days and participants could smoke up to 6
doses of 50 mg cocaine base each session. Participants immediately began a 2-week outpatient phase. They repotted
to the laboratory each morning, completed questionnaires, received clinical evaluations and provided a urine
specimen. Over the 2-day cocaine binge, women self-administered 20.4 out of a maximum of 24 possible doses.
Compared to the 1200 session, heart rate and blood pressure were significantly increased during the 1600 session.
Nine women completed the outpatient phase, attending 98% of appointments. Sixty-eight percent of urines
documented the absence of cocaine use and were reinforced with $40 in merchandise vouchers. Cocaine withdrawal
symptoms during the outpatient phase included increases in total scores on the Cocaine Withdrawal Questionnaire
and the Opiate Symptom Checklist and increases in ratings of “Miserable” and “Tired.” In contrast, scores on the
Beck Depression inventory decreased over time relative to admission. These results suggest that cocaine abstinence
symptoms are relatively mild in non-treatment seekers. Further, recruitment of female cocaine abusers can be
enhanced by short study lengths and reduced cocaine use can be reinforced in non-treatment seekers.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-08105 and NIH grant MOI-RR-00645.
334
LIMITED SEX DIFFERENCES IN RESPONSE TO SMOKED COCAINE IN HUMANS
R. W. Foltin, S. M. Evans, M. Haney, and M. W. Fischman
Columbia University and NYS Psychiatric Institute, New York, NY
The effects of repeated self-administration of smoked cocaine base were evaluated in 11 men and 9 women. Cocaine
self-administration sessions occurred at 1200 and again at 1600 on 2 consecutive days. During each session
participants could smoke up to 6 doses of 50 mg cocaine base (˜ a $3 “crack” vial in NYC). Baseline systolic and
diastolic blood pressure were higher in men than in women. The first cocaine dose increased HR and BP and ratings
of “High” and “Stimulated” similarly in both men and women. For example, HR was 98.1 + 2.2 bpm in men and
96.2 + 1.8 bpm in women, and ratings of “high” were 58.7 + 4.7 mm in men and 54.9 + 4.9 mm in women.
Women reported they would spend significantly less for that dose than men ($1.58 vs. $3.15), which may be related
to the fact that the women were less likely to buy their own cocaine. Men and women self-administered a similar
number (21.7 and 21.6) of doses. Although cocaine produced similar effects in men and women 4 min after each
dose, HR and BP remained elevated 20 min after the last dose of the session in women, but nor in men (e.g., HR
was 4 bpm above baseline for men and 11 bpm above baseline for women). Cocaine craving, estimated using
ratings of “I want cocaine,” also differed between men and women 20 min after the last dose: ratings were 6 mm
above baseline for men, but 9 mm below baseline for women. Other ratings of drug effects were similar, however,
after the last cocaine dose, despite higher cocaine plasma levels in women. Thus, smoking cocaine base pruduces
similar acute subjective effects in men and women, but prolonged cardiovascular effects in women, and different
effects on cocaine craving in men and women.
ACKNOWLEDGMENTS:
Supported by NIDA grant DA-08105 and NIH grant MOI-RR-00645.
GENDER DIFFERENCES IN HEROIN USE SEVERITY AMONG NON-INJECTING HEROlN
USERS
M. Miller, A. Neaigus, S. R. Friedman, X. Andrade, A. Atillasoy, G. Ildefonso, and D. C.
Des Jarlais*
National Development and Research Institutes, Inc., New York, NY and *Beth Israel Medical
Center, New York, NY
Introduction: Non-injecting users (NIUs) of heroin are an increasing proportion of heroin users. Little is known
about NIUs, particularly any gender differences that may exist. It is likely that gender differences in drug use
patterns and mental health that have been identified among injection drug users may also be found among NIUs.
Methods: Street recruited NIUs in New York City who reported that they had used heroin in the past 30 days, who
had never injected, and who were not currently enrolled in treatment were interviewed between March 1996 and April
1997 a part of a longitudinal study on transitions to injecting. This analysis is limited to 214 subjects for whom
urine toxicology results for opiate metabolites were available. Results: 77% of the sample were men. 23%
women, 35% were African American, 28% Latino. 30% While and 7% other race/ethnicity. The average age was
34.2 (sd 8.7). 59% of the subjects had a positive opiate toxicology result. Women were 2 times more likely to test
opiate positve than were men (OR=2.3, 95% Cl=1.2, 4.7). A positive opiate toxicology was significantly
associated with several self-reported measures of drug use severity including daily use (OR=8.8, 95% CI=4.6, 16.7),
use in the past 3 days (OR=24.9,95% CI=l2.4, 49.9), and the mean number of bags of heroin used in the past 30
days (59 vs. 19, p=.0001). Women were significantly more likely to have higher levels of psychological distress;
however, psychological distress was unable to adequately account for gender difference in heroin use severity.
Conclusion: It appears that among NlUs, the severity of heroin use is greater in women than in men.
Additionally, a positive opiate toxicology result appears to be a valid measure of heroin use severity.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-09920.
335
INTERCOLLEGIATE WOMEN ATHLETES, DRUG USE AND DRUG TESTING
R. H. Coombs and P. Issari
School of Medicine, University of California, Los Angeles, CA and Drug Abuse Research
Center, University of California, Los Angeles, CA
The drug-related attitudes and behaviors of female intercollegiate athletes and their views on drug testing were
assessed and contrasted with those of male athletes at a major university (division I). Few studies have examined
drug attitudes and behaviors among intercollegiate women athletes, and we could find only one study that assessed
college women athletes’ attitudes towards drug testing and compared attitudes towards drug testing by gender. Data
used in the present analysis were derived from two sources: a questionnaire completed anonymously by 500
intercollegiate athletes on 21 teams, who were required to participate in drug testing, and 45 minute m-depth tape
recorded interviews with a random sample of 57 of the 500 athletes. The questionnaire asked for demographic
information, personal drug use history, and general attitudes about appropriateness and usefulness of drug testing.
Results indicated that women student athletes preferred wine, and men beer; more women used coffee and over-thecounter drugs, and more men used tobacco/smokeless tobacco. Marijuana was the most commonly used illegal
substance among college athletes. Intercollegiate women held more positive attitudes regarding drug testing than
men and felt stronger about the importance of testing for all classes of drugs (p; chi-square tests). Only a minority
of male and female college athletes felt that athletes should be tested for the use of alcohol, tobacco, and prescription
drugs. The present findings have implications for drug education, counseling and drug testing programs as well as
policies and procedures in colleges and universities. Prevention and intervention efforts need to target both shared
and distinct characteristics of women’s and men’s behavior and attitudes towards substance use and drug testing for
more effective policies and programs.
FURTHER ANALYSIS OF HAIR COCAINE DATA SETS: CAN HAIR SERVE AS AN
AGGREGATE TREATMENT OUTCOME MEASURE?
P. R. Marques and A. S. Tippetts
National Public Services Research Institute, Landover, MD
The extent to which cocaine-hair analysis can be used to represent levels of exposure in a sample of users is not
settled. Hair is potentially of value as a long-term treatment outcome measure that could provide for more
objectivity than self-report. Relating hair results to a more widely accepted concurrent exposure measure allows for
an estimate of concordance. A perinatal research study provided an opportunity to study this in a sample of adult
women from the beginning of a treatment/case management intervention. As part of the study protocol, samples of
women’s hair and urine were collected every four months from baseline out to two years beyond intake for a total of
seven repeated measures by each method. Measurement of cocaine in hair and urine were performed by different
commercial laboratories, each blind to other’s results. A sample size of 160 were initially available, and with
attrition this declined to 82 in two years. The lost cases did not bias the sample toward lower-severity users as the
mean baselines for both urine and hair did not differ among the women who were either available or lost by 24 mo.
Dropping obviously had no bearing on concordance. Selecting on women who provided at least 6 of the 7
specimens of both hair and urine, a strong stable relationship was found within subjects for cocaine level estimates
derived from hair and urine measurement. Cocaine levels detected by the two methods were strongly correlated
across all 7 sampling periods (P<.001) with r values ranging from a low of .41 to a high of .66. Examination of
lag time between samples showed a significant linear decline in the strength of association as time between
successive periods increased, this was the case both within a method (hair to hair) and across the two methods (hair
to mine). The findings endorse hair as a useful AGGREGATE or cohort level estimate (especially as an alternative
to self-report), but have no bearing on the use of hair measures for specific samples as is required in forensics.
ACKNOWLEDGMENT: DA06379.
336
EFFECTIVENESS OF INTENSIVE CASE MANAGEMENT WITH SUBSTANCE ABUSING
WOMEN: A PROCESS EVALUATION OF THE MATES PROGRAM
L. Greenfield, V. Taliano*, and C. Small*
Institutes for Behavior Resources, Inc., and *Metropolitan Council of Governments,
Washington, DC
Hypothesis: Intensive Case Management (ICM) can be effective in decreasing alcohol and other drug (AOD) use.
increasing employment and improving physical health, mental health and social functioning. Procedures: The
DC Metropolitan Area Treatment Enhancement System (MATES) has provided ICM to more than 900 women.
Active Clients were assessed at intake and a median of 7 months post-intake with both the ASI (N=279) and SF36, a measure of health status and functioning, (N=203). AOD agency staff provided past 30-day urinalysis results
for N=209. Finally, terminated clients were compared for employment and criminal justice status between intake
and discharge using case manager reported data (N=516). Analysis: Percentages were compared over time using
the Cochran Q test. Results: Reductions in past 30 day AOD use were reported over time by 60% for alcohol,
70% for heroin, 65% cocaine and 68% marijuana. These results were consistent with urinalysis, as 9.6% of reported
test results were positive. For women with children below age 18, the percentage who lived with their children
increased over time by 16%. Client employment increased over time by 87%. Physical, social, role emotional and
mental health functioning scores on the SF-36 significantly increased, suggesting an improvement over time
relative to the general population. Conclusions: The results provide preliminary support for the treatment
effectiveness of the ICM services.
ACKNOWLEDGMENT: Supported by CSAT Grant or Cooperative Agreement Number: 5U95T100886-03.
MULTIPLE TREATMENT OUTCOMES FOR WOMEN ENROLLED IN OUTPATIENT
SUBSTANCE ABUSE TREATMENT
M. Comfort, G. Kumoraswamy, and K. Kaltenbach
Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA
Personal, social, and family outcomes were evaluated for 38 women enrolled at least 8 months in comprehensive
outpatient substance abuse treatment. Comparisons of self-reported outcomes assessed with the Psychosocial
History (Comfort and Kaltenbach, 1996) were conducted for intake to 4 months, 4 to 8 months, and intake to 8
months post admission. Significant declines occurred in self-reported 30-day substance use from intake to 8
months (p <.05). Increases in drug-free urine screens from the 1st to 4th months in treatment verified these reports
(p <.05). The number of substance using partners decreased from intake to 4 months, then increased from 4 to 8
months, although not to the level reported at intake (p <.05). Percentages of women taking prescribed psychiatric
medications showed an initial increase during the early months of treatment, followed by a decrease during later
months (p <.05).Perceived needsfor housing and financial assistance decreased across both assessment intervals (p
<.05). Financial assistance from partners/family doubled between intake and 4 months, then declined from 4 to 8
months (p <.05). Comparisons of the proportions of children per family who were living with their mothers
showed positive outcomes in family reunification between intake and 8 months in treatment ( p <.05). Reports of
family legal problems (e.g., child custody or support) increased from intake to 4 and to 8 months, suggesting
healthy acknowledgements of existing issues. These results demonstrate the value of assessing women’s multiple
needs and outcomes to effectively evaluate client progress and treatment efficacy.
ACKNOWLEDGMENT:
Partially funded by CSAT Grant# 5HD7 T100966-03.
337
N ACTIVITY SCALE AS A PROCESS MEASURE OF TREATMENT EFFICACY
C. Jean, M. Chawarski, J. Pakes, and R. Schoftenfeld
Yale University and The APT Foundation, New Haven, CT
Aims: To evaluate 1) whether patients treated with the Community Reinforcement Approach (CRA) engage in
different activity patterns compared to patients treated with 12-step facilitation drug counseling (DC), and 2) whether
greater involvement in pro-social activities leads to reduction in drug use. Methods: We developed an activity
duration scale (ADS) and compared weekly activities and cocaine use, as assessed by interviewers using the ADS and
the weekly drug use inventory, of cocaine-dependent pregnant and postpartum women treated for 12 weeks with
CRA (n=15) or DC (n=10) in a random-assignment clinical trial comparing these treatments. The intervieweradministered ADS assesses the number of hours per day over the past week spent in activities including
work/vocational; social and recreationaI with non-drug users; hobbies; 12 step recovery; spiritual/religious: and
interactions with drug-users. Results: Compared to DC, CRA is associated with greater increases in social
interactions with non-drug users (8.9 hrs/wk baseline to mean 13.1 hrs/wk during tx for CRA; 10.1 hrs/wk to 10.3
hrs/wk for DC) and in hobbies (9.6 hrs/wk to 12.5 hrs/wk for CRA; 6.5 hrs/wk to 7.5 hrs/wk for DC). Both CRA
and DC are associated with reductions in time spent with drug users. Patients were classified as abstinent >4 weeks
(n=7), 1-4 weeks (n=10), or never abstinent (n=8). Increased involvement in activities unreIated to drug use and
decreased time spent with drug users were associated with abstinence. Conclusions: CRA and DC may be
associated with differences in activity patterns, and activity patterns may be related to achievement of abstinence. A
revised version of the ADS has been developed to address problems identified in the original instrument, including
better definition of activity categories and specification of rating procedures.
AFTERCARE FOR WOMEN USING THE AFRICAN-AMERICAN CHURCH COMMUNITY:
AN EXPLORATORY STUDY
G. J. Stahler*; T. E. Shipley, Jr.*; I. Shandler**; C. Godboldte***; L. Ijoy***
J. Grannum*; E. Weiss*; and L. Simons
* TempIe University; **Diagnostic and Rehabilitation Center, Philadelphia, PA; ***Bridges
to the Community, Philadelphia, PA
The African-American Church community represents one of the most influential and powerful institutions within
the inner city but is usually not involved with the formal drug treatment system. This paper reports on the
pteliminary findings concerning a program that utilizes the African-American faith community to prevent relapse
among homeless crack cocaine using women with children. The Bridges program uses a coalition of AfricanAmerican churches to provide mentors and culturally-relevant educational and cultural programs in collaboration
with a residentiaI community-based treatment program. Church congregant volunteers are trained to be “community
anchor persons” (CAPs), providing clients with daily individual and group fellowship and companionship,
sponsorship and mentoring, as well as assistance with housing, child care, and other concerns. Because of funding
limitations, less than half of those eligible for assignment to a CAP actually became involved in the aftercare
program. This situation allowed for an unintended comparison group of clients who received residentiaI treatment
but did not receive the Bridges aftercare component. This paper describes the intervention, the client characteristics,
and a preliminary analysis of outcomes approximately six months following discharge from residential treatment.
In general, no differences were found between groups on outcomes at follow-up. However, both groups improved
significantly in terms of drug and alcohol use, HIV risk behaviors, residential stability, and mood. The lack of
differences may be due to a small sample size and the poor follow-up rate of the non-aftercare group. It is concluded
that using an aftercare program that utilizes mentors from the faith community as well as culturally-relevant
educational and group activities may represent a promising approach to maintaining long-term sobriety in the
community and merits further systematic investigation.
338
LABORATORY MEASURES OF AGGRESSION, IMPULSIVITY AND 5-HT FUNCTION IN
FEMALE PAROLEES
D. R. Cherek, S. D. lane, and F. G. Moeller
Human Psychopharmacology Laboratory, Dept. of Psychiatry and Behavioral Sciences,
University of Texas-Houston, Health Science Center
Thirty female parolees participated after giving their informed consent. Subjects were divided into a violent (n=10)
and nonviolent group (n=20)) based upon their criminal history. Subjects were excluded if screening indicated any
history of medical or psychiatric illness, or recent drug use detected by urine drug screen analysis. Subjects
participated for four days. Day 1 consisted of six 25 min sessions during which aggressive and escape responding
were measured using the Point Subtraction Aggression Paradigm. Day 2 consisted of up to 10 sessions which
employed an adjusting self-control procedure to measure impulsivi ty. Days 3 and 4 involved two neuroendocrine
challenge tests conducted in the University’s CRC. One day subjects were administered placebo and on the other
day, buspirone 0.4 mg/kg. To assess CNS serotonergic activity in these subjects serial measures of prolactin were
taken to determine the response to the challenge agent, buspirone. The violent and nonviolent groups differed
significantly on measures of aggressive responding, but female parolees responded much less than males parolees
(previous study). Impulsivity was not correlated with aggressive responding as it had been with male parolees. The
prolactin response data is being analyzed. Several psychometric measures were also administered. The behavioral
response data support the relationship between laboratory aggressive responding and violence history. With females
the behavioral measures of aggression and impulsivity were not correlated.
ACKNOWLEDGMENTS:
Supported by NIDA Grant DA03166-12 and CRC award RR-02558-11.
IMPACT OF VOUCHER INCENTIVES ON RESIDENTIAL LENGTH OF STAY AND
OUTPATIENT TREATMENT ATTENDANCE
D. Svikis, K. Silverman, N. Haug, and M. Stitzer
Johns Hopkins University School of Medicine, Baltimore, MD
Drug abstinence is particularly important for pregnant drug dependent women, as any illicit drug use cart he harmful
to both mother and fetus. In the present study, we examined the efficacy of escalating voucher reinforcement
schedules in retaining pregnant drug dependent women in treatment during the first 14 days (7 days residential
followed by 7 days intensive outpatient), when the risk of dropout is high. Subjects were randomly assigned to
escalating incentives or control groups. For subjects not in methadone maintenance (N=78), vouchers were given
daily contingent on treatment attendance ($5/Day 1 with $5 increase each subsequent day; total potential earnings
$525). For subjects in methadone maintenance (N=53), vouchers were given daily contingent on attendance (Days
1-7) or attendance and cocaine abstinence (Days 8-14). Vouchers bad no impact on premature dropout (AMA) from
residential care. For nonmethadone subjects who did not AMA, however, attendance was greater in the incentive
(mean 11.2 days) than control (mean 9.8 days) groups (p<.02). Similarly for methadone subjects who did not
AMA, attendance and abstinence were greater in the incentive (10.9 days) as compared to the control (9.5 days)
groups (p<.05). These data support the effectiveness of escalating voucher incentive schedules for improving
treatment attendance and drug abstinence in high-risk populations such as pregnant women.
339
PREDICTING TREATMENT NONCOMPLIANCE IN COCAINE DEPENDENT MOTHERS
II. M. Peitinati, J. R. Volpicelli, J. I. Filing, I. Markman, G. J. Luck, R. S. Trager, R. H.
Cooke, M. I. Andem, and C. P. O’Brien
Treatment Research Center, University of Pennsylvania, Philadelphia, PA
A major problem in treating crack-cocaine addiction is the patient’s noncompliance with coming to clinic visits which is especially true early in treatment, e.g. the first 6 weeks. Noncompliance is more likely for women became
they are, typically, single mothers of young children who have multiple psychosocial problems. The purpose of
this study was to identify pm-treatment characteristics that predicted treatment noncompliance in the first 6 weeks of
addiction treatment for 84 crack-cocaine dependent mothers, 18 years or older. who were either pregnant or had at
least one child less than 4 years old. Noncompliance was defined as failing to attend any treatment for 2 or more
weeks during the first 6 weeks. Using this definition. compliant and noncompliant female patient groups were
distinguished and logistic regression was applied to identify attrition predictors. Results revealed that the number of
high-risk sexual behaviors (i.e., HIV-related) these women had engaged in during the 6 months prior to entering
treatment was the best predictor of treatment noncompliance in the first 6 weeks of treatment. That is, the Sex Index
scores from the Risk for Aids Behavior (RAB) at treatment entry was 8.6 for noncompliers vs. 6.7 for compliers:
Wald = 5.43, df= 1, p< .05. The second predictor of treatment attrition (i.e., a trend) was the number of days of
reported cocaine use in the 30 days prior to entering treatment. That is, the number of days of cocaine use in the 30
days pre-treatment was 13.7 for noncompliers and 9.7 for compliers; Wald= 3.37, df=1, p=.07). Also, women with
both cocaine and significant alcohol use were more likely to drop out of treatment. However, there was a significant
correlation between number of days of cocaine use with the number of days of alcohol use in the 30 days prior to
treatment (r =0.44,
df= 83, p<.001). These findings have important implications for future efforts to improve
treatment compliance among this population in the initial weeks of treatment. In particular, women who engage in
high risk sexual behavior and have high levels of alcohol and cocaine use are more likely to drop out early in
treatment. Programs with a clinical focus on alcohol treatment may improve treatment retention.
This project is funded by NIDA grant #P50 DA09252.
ACKNOWLEDGMENT:
PREDICTORS OF TREATMENT OUTCOME FOR PREGNANT WOMEN
K. Kaltenbach, D. Rajogopal, and M. Comfort
Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, PA
This study examined client characteristics predictive of retention, abstinence, and service utilization for required
services and specialized services of pregnant women in outpatient and residential treatment. Retrospective data were
collected from the Psychosocial History (PSH), a structured clinical interview that is an expansion of the Addiction
Severity Index designed specifically to assess substance abusing women. The PSH was conducted at intake for 183
pregnant women admitted to outpatient (n=133) or residential (n=50) treatment. Factor analysis was used to reduce
42 predictor variables to 27 variables organized on 5 factors with composite scores created for the 5 factors.
Multiple regression procedures were used to determine client characteristics that predict treatment outcomes. In the
outpatient program, the strongest results were for Retention (p<.0001) and Required Services (p=.021). A variety of
factors accounted for the variance in Retention (multiple R2=.153). Utilization of Required Services was predicted
by low scores on the factor reflecting family reunification problems, parenting counseling needs, and unstable
housing (multiple R2=.069). For the residential program, early drug use coupled with low scores on the composite
of family history of drug and alcohol problems, psychiatric symptoms, need for prenatal and medical care and
history of family conflicts predicted greater abstinence (multiple R2=252, p=.017). These findings confirm there are
no simple predictors of outcome for pregnant women in treatment. Significant predictors were composites of
variables that span all aspects of women’s lives including medical and psychiatric needs, family and parenting
issues, housing, victimization and client’s perceived needs for treatment and assistance in all of these areas.
Supported by NIDA Grant DA 08903.
ACKNOWLEDGMENT:
340
TYPE A AND TYPE B CLUSTERS
TREATMENT-SEEKING WOMEN
IN PREGNANT
SUBSTANCE-DEPENDENT
N. A. Haug, D. S. Svikis, and R. K. Brooner
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, MD
Recent research has supported the validity of the Type A/Type B alcoholism typology (Babor et al., 1992) in other
drug abusing populations. Type As are characterized by less severe substance abuse, psychiatric and psychosocial
problems and fewer premorbid risk factors while Type Bs exhibit greater impairment in these areas. The present
study examined 238 opiate and/or cocaine dependent pregnant women admitted to a comprehensive drug treatment
program. Cluster analyses were performed using the K-means procedure with 8% of women classified as Type B and
92% classified as Type A. The two clusters were then compared on demographic, substance use and other psychiatric
and psychosocial variables using t-test and chi-square analyses. Type B women had a significantly higher incidence
of premorbid factors including family history of alcohol abuse, child Conduct Disorder, and an earlier age of onset of
substance dependence than Type A women. Type Bs also displayed greater substance abuse/dependence severity as
well as higher severity of psychosocial problems (medical, employment, family/social) and higher levels of
comorbid psychopathology. Unlike previous research, differences were found between the two subgroups for current
age (Type Bs older) and race (more Caucasian Type Bs). Study findings suggest the Type A/ Type B typology has
important implications for assessment and treatment of this high-risk population.
References available upon request from senior author.
ACKNOWLEDGMENT:
Supported by NIDA grant DA-09258.
PSYCHIATRIC SYMPTOMATOLOCY IN DRUG DEPENDENT PREGNANT WOMEN
P. Rutigliano 1 , N. Haug 2 , D. Svikis 2 , and M. Stitzer2
1
Allegheny University, Center City Campus, Philadelphia, PA and 2 The Johns Hopkins
University School of Medicine, Baltimore, MD
In substance dependent patients, psychiatric symptomatology has been associated with higher rates of treatment
dropout and drug relapse (Ward et al., 1981; Albott, 1982). Psychiatric comorbity has also been related to
unemployment. legal problems, marital distress, and lack of social support which have also been linked with
increased treatment dropout (Simpson and Joe, 1993). Treatment dropout has also been associated with drug use
severity (Stark and Campbell, 1988). Dropout becomes an even greater concern with pregnant women because drug
use during pregnancy is associated with low infant birth weight neonatal drug withdrawal, and other complications.
The present study characterized the psychiatric symptomatology in a sample of drug dependent pregnant women and
examined the relationship between psychiatric symptomatology and drug abuse severity. Subjects were 110 women
admitted to a comprehensive treatment program for pregnant women. Psychiatric distress was measured by the
Symptom Checklist 90-Revised (SCL-90-R) and alcohol and drug abuse were measured by the Addiction Severity
Index (ASI). Results indicated that 74% scored positive on at least one of the 9 subscales on the SCL-90-R upon
admission to the program. Consistent with previous research (Schaefer et al., 1987, Stark et al., 1988) those
designated as positive on the SCL-90-R for Somatization, Depression, and Anxiety had higher severity ratings on
the drug subscale of the ASI when compared to those negative on the SCL-90-R for the 3 of subscales (p=0.003,
p=0.006, and p=0.004, respectively). Given that psychiatric comorbidity is most prevelant for drug abusing
populations (Smith et al., 1992; Montoya et al., 1994; Johnson et al., 1996). it is important that upon admission
these symptoms be assessed so that appropriate intervention may be taken.
341
CONTINUITY OF DRUG USE PATTERNS AMONG HIGH RISK WOMEN
C. L. Raskind-Hood, M. E. Lynch, and C. D. Coles
Human and Behavior Genetics Lab, Dept. of Psychiatry, Emory University School of
Medicine, Atlanta, GA
Postnatal drug use among mothers who have used drugs prenatally is of particular concern not only due to increased
risk to the woman’s health but also because of the negative impact on her caregiving capacity. Continuity of drug
use after the baby’s birth was examined over a 24-month period in a sample of 119 women whose primary drug was
either alcohol or cocaine. Multiple samples (n=51 at 6-months, n=42 at 24-months) of low SES, urban,
predominantly African-American women were drawn from a larger study. At 6-months postpartum, 82% of this
sub-sample reported continued substance use. One hundred percent of those reporting alcohol as their primary drug
continued, while 60% of those reporting cocaine as their primary drug continued. At 24-months postpartum, 57%
reported use. 80% of those reporting alcohol as their primary drug continued to use, while among those reporting
cocaine as their primary drug, the percentage was 27%. These data indicate significant behavior differences
depending upon their primary drug of choice. Only a minority of women received drug treatment/intervention (16%
at 6-months, and 10% at 24-months). The majority of mothers at both 6- and 24months reported that their children
were home during their most recent drug and/or alcohol use. Although many demographic, social, and emotional
factors were assessed, no predictors for continued drug use were identified, except for the primary drug of choice.
PARENTING SKILLS QUESTIONNAIRE-REVISED (PSQ-R): TEST-RETEST RELIABILITY
M. Velez, W. Kissin, L. Jansson, C. McCormick, J. Cohen, I. Montoya*, and D. Svikis
The Center for Addiction and Pregnancy, Johns Hopkins Bayview Medical Center and
*University of Antioquia School of Public Health
Parenting training programs are part of comprehensive substance abuse treatment for women. No instrument has
been validated in this population to measure parenting knowledge. The purpose of this study was to determine the
test-retest reliability of the Parenting Skills Questionnaire-Revised (PSQ-R). The PSQ-R is a 31 self-report truefalse-l don’t know questionnaire developed to evaluate parenting knowledge in 3 different domains: infant care, child
development, and drug abuse during pregnancy. The questionnaire was first administered to 45 pregnant or
postpartum women upon entering substance abuse treatment, and administered a second time (with item order
changed) 5 to 10 days later. Preliminary results showed moderate test-retest agreement for true and false items
(average kappa = 0.51, p < .05 for 27 of 31 items), and the average percent item agreement was 87.65. These
results suggest that the PSQ is a good tool to assess knowledge and beliefs among substance abusing women and to
measure changes in knowledge following parenting training within this population.
342
COMPARISON OF MORPHINE AND METHADONE MAINTENANCE IN PREGNANT
OPIATE ADDICTS
P. Etzersdorfer, C. Fischer, H. Eder, R. Jagsch, K. Schmidl-Mohl, and W. Gombas
Clinical Department of General Psychiatry, University of Psychiatry, Vienna, Austria
A majority of studies demonstrate the advantage for mother and child in using methadone maintenance in pregnant
opiate addicts. It is also proven, that infants born to methadone maintained mothers are more severely affected in
their neonatal withdrawal syndrome as infants with an intrauterin exposure to heroin. Over a period of 50 months.
the drug-addiction out-patient clinic in Vienna investigated 52 pregnant opiate addicts in administering during
pregnancy either methadone or slow-release morphine. The subjects (mean age: 26 years, mean duration of
pregnancy before starting maintenance treatment: 19 weeks) were consecutively enrolled in an open study design.
The oral opioid at the time of delivery was in 50% of the subjects methadone (mean daily dosage 45 mg), in 43%
morphine (mean daily dosage 340 mg) and 7% were successfully detoxified and drug free. The mean birth weight in
the methadone group was 2850g, in the morphine group 2880g. No significant differences occurred in comparing
the mean duration of withdrawal syndrome in the newborns, 16 days in the methadone group and 20 days in the
morphine group. No significant correlation between withdrawal syndrome and mean daily dosage of methadone (r =
0.53, p = 0.2) and morphine (r = 0.39, p = 0. 14) could be found. Born substances are safe during pregnancy and
yield to a comparable out-come in regard to birth-weight of the birth-weight and neonatal withdrawal syndrome.
INCREASED SENSlTIVlTY TO LONG-TERM CONSEQUENCES OF EARLY EXPERIENCE
FOLLOWING GESTATIONAL COCAINE EXPOSURE IN RATS
J. Campbell, K. Snyder, M. Silveri, N. Katovic, and L. P. Spear
Center for Developmental Psychobiology, SUNY - Binghamton, Binghamton, NY
This experiment is part of our ongoing work examining the impact of gestational cocaine exposure on later stressor
responsivity. Rat offspring were derived from Sprague-Dawley dams receiving subcutaneous injections of 40
mg/kg/3cc cocaine hydrochloride (COC40) on gestational days 8-20, non-treated (NT) control dams, and dams mar
had been exposed to substantial undernitrition (NC) during pregnancy. Some litters of offspring were examined in a
non-invasive study of heart rate at 16 days of age (requiring approximately 5 hr of separation from me home nest),
whereas other litters received no early experience. In adulthood, animals received either 0.1 or 9 daily exposures to
a 15 min foot shock session (1mA, 1 sec; VI 30 sec), with all animals receiving a 5 min open field (OF) test 24 hr
after the last manipulation. A number of behavioral alterations were seen in COC40 offspring, with me nature of
these alterations being dependent on the early postnatal experience of the animals. COC40 offspring that did not
have the early experience exhibited less immobility during their first exposure to the foot shock and in subsequent
OF testing. as well as more OF locomotion man corresponding NT offspring, replicating previous findings (Molina
et al., 1994). In contrast. COC40 offspring given the early experience exhibited an opposite pattern, showing
increased immobility and reduced OF locomotion. These dramatic effects of early experience were not seen in NT
and NC offspring, despite substantial undernutrition as indexed by notable birth weight reductions in NC offspring.
ACKNOWLEDGMENTS:
Supported by NIDA grant R01 DA04478 and grant K02 DA00140.
343
LATE ABSTRACTS
DEVELOPMENT OF NEW SCALES TO ASSESS CHANGE IN THE ADDICTION
SEVERITY INDEX.
A. I. Alterman, P. A. McDermott, L. S. Brown*, D. Metzger, T. C. Cook, and M. J.
Rutherford
University of Pennsylvania, Phila. Pa. and *Addiction Research and Treatment Center,
Brooklyn, NY
Analyses were performed to construct and confirm the validity of new conjoint intake and 6-month follow-up scales
for the Addiction Severity Index. Using a diverse sample (N=1,008) of methadone maintenance, cocaine, and alcohol
dependent patients, a multistage scaling strategy identified 5 psychometrically integral addiction problem scales.
Exploratory item and components analyses, confirmatory oblique item clustering, and secondarder factor analysis
verified that the sales comprised relatively little common variance and that each retained a substantial amount of
unique and reliable variance. Resulting scales (psychiatric, drug, alcohol, family, and legal problems, respectively)
were highly internally consistent and structurally stable overall. at intake and follow-up, and across gender, age,
ethnicity, and substance abuse categories. Concurrent and predictive validity were supported for clinical subsamples
based on urine toxicology, criminal records, comorbid psychopathology, and personality indices. Baseline to
follow-up changes on the new scale were associated with demographics and types of substance dependence.
Advantages of the new scales are discussed, including provision of computer code for calculating normalized intake
and follow-up standard scores and predicted change scores for use in clinical practice and treatment outcome research.
ACKNOWLEDGMENTS:
Supported by NIDA Center Grant # DA05186, NIDA Grant # DA-05858, and the
Department of Veterans Affairs.
PSYCHOSTIMULANTS DIFFERENTIALLY AFFECT DOPAMINE TRANSPORTER
ACTIVITY
A. E. Fleckenstein, R. R. Metzger, D. G. Wilkins, J. W. Gibb, and G. R. Hanson
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT
Methamphetamine (METH) and several related analogs cause reactive oxygen species formation in vivo, and reactive
oxygen species decrease dopamine transporter (DAT) activity in vitro. Hence, effects of administering METH or
other pyschostimulants on DAT activity were investigated. A single administration of METH caused a rapid, but
3
reversible, decrease in Vmaxof [ H]dopamine uptake, as assessed in rat stiatal synaptosomes. This phenomenon was
independent of the well-characterized, long-term neurotoxic effects of this stimulant, and was not caused by residual
METH introduced by the original in vivo treatment. Administration of related psychostimulants such as
methylenedioxymethamphetamine (MDMA), methcathinone or p-chloroamphetamine likewise rapidly decreased
DAT activity. In contrast, cocaine administration had no effect on [3H]dopamine uptake. These data demonstrate
significant differences in the response of DAT to psychostimulants, and may have important implications regarding
the role of oxidative events in the physiological regulation of dopaminergic neurons.
ACKNOWLEDGMENTS:
Supported by NIDA grants DA-05780, DA-04222 and DA-00869.
344
DISCRIMINATIVE STIMULUS EFFECTS OF SELF-ADMINISTERED ETHANOL IN RATS
M. J. Macenski and K. L. Shelton
Department of Psychiatry and Behavioral Sciences, University of Texas - Houston Health
Science Center, Houston, TX
Five rats were trained to discriminate 1000 mg/kg ethanol from saline injected i.p. 15 minutes prior to a 15 minute
drug discrimination session. An ethanol dose response curve (100-1560 mg/kg ethanol) was completed. Complete
substitution occurred at the training and higher doses. Subsequently, rats were trained to self-administer a 10%
ethanol (w/v) solution. Discrimination and ethanol self-administration (SA) days were then alternated. On
discrimination days, rats were injected with 1.0 g/kg ethanol or saline, placed into SA chambers for 15 minutes and
then into the discrimination chamber for testing. On SA days, animals were allowed to SA ethanol for 15 minutes,
then given a sham injection and returned to the chamber for 15 minutes. Three tests were completed to examine
substitution of SA ethanol and water for the trained i.p. dose. First, rats SA ethanol (mean intake = 1017 mg/kg),
wee given a sham injection, and tested in the discrimination procedure. Full substitution (80% ethanol lever
responding) of SA for i.p. ethanol was observed. Second, rats SA water, were given a sham injection, and were
tested in the discrimination procedure. Water SA resulted in 20% ethanol-level selection. A redetermination of
1000 mg/ml ethanol and saline i.p. injections reveled the training dose continued to control ethanol discrimination.
Thirds, rats were allowed to SA 0.1 ml of 10% w/v ethanol prior to a discrimination session. and here was no
substitution for i.p. ethanol. Finally, rats were allowed repeated access to water and response rates declined to
minimal levels, indicating that ethanol was functioning as a reinforcer. These data suggest that the internal
stimulus effects of self-administered ethanol are similar to stimulus effects of i.p. experimenter administered
ethanol.
A CATALYTIC ANTIBODY AGAINST COCAINE ELIMINATES ITS REINFORCING
EFFECTS IN RATS
G. Winger, D. W. Landry, C. Cabrera, and J. H. Woods
University of Michigan, Ann Arbor, Ml and *Columbia University, New York, NY
Rats were conditioned to press a lever for sweetened condensed milk, and maintained on a fixed-ratio 5 time-out 20 s
schedule of reinforcement Intravenous catheters were then implanted; subsequently, lever presses delivered 0.3
mg/kg/inj cocaine under the same schedule for 1 hr daily sessions. When drug-reinforced responding was stable,
saline was substituted for cocaine on occasion until responding was reduced and occurred predominantly in the early
portion of the session. When the catalytic antibody, 15A1O, previously described by Yang et al. (1996) was
administered prior to a session in which cocaine was available, the pattern of responding maintained by cocaine
resembled that maintained by saline. Thus, this catalytic antibody can function in vivo to reduce the reinforcing
effect of cocaine in rats.
Reference:
Yang, G., Chun, J., Arakawa-Uramoto, H., Wang, X., Gawinowicz, M.A., Zhao K., and Landry, D.W. Anticocaine antibodies: a synthetic approach to improved antibody diversity. J.Amer. Chem. Sec. (19%) 118, 25,
5881-5890.
ACKNOWLEDGMENTS:
Supported by USPHS Grant DA 03228 and the Counterdrug Technology
Assessment Center at the Office for National Drug Control Policy.
345
BIOLOGICAL EVALUATION OF COMPOUNDS FOR THEIR PHYSICAL
DEPENDENCE POTENTIAL AND ABUSE LIABILITY. XXI. DRUG EVALUATION
COMMITTEE OF THE COLLEGE ON PROBLEMS OF DRUG DEPENDENCE (1997)
A. E. Jacobson, Biological Coordinator, Drug Evaluation Committee, CPDD
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, MD
PURPOSES OF THE DRUG EVALUATION COMMITTEE (DEC)
As previously noted (Jacobson 1997), the contemporary DEC is a direct descendent of the original analgesic
testing program of the Committee on Drug Addiction of the National Research Council, National Academy of
Sciences. It has only been within the past 20-25 years that the purposes and activities of DEC could be
distinguished from those of CPDD. Within the past year DEC has reorganized to become an independent
consortium of researchers which acts as the arm of the CPDD involved with drug testing and research. DEC
activities are reported to the Chair of the the newly established Liaison Committee for Drug Evaluation and
Testing.
DEC work now encompasses methodological research and physical dependence potential and abuse liability
testing of drugs with analgesic, stimulant, and depressant actions. The work is done as a free public service to
the pharmaceutical industry, university researchers, and governmental organizations in the U.S. and abroad, and
the WHO. Researchers engaged in the work have grants or contracts from the National Institute on Drug
Abuse, NIH, and some of DEC organizational expenses are paid by the CPDD. The DEC public service sets
the CPDD apart from all other scientific membership organizations. Questions regarding this testing service
can be addressed to the Biological Coordinator of DEC (fax: 301-402-0589, e-mail: aej@helix.nih.gov).
Publication of the data gathered by DEC generally occurs within three years from receipt of sample, both in
the NIDA Monograph (e.g., Aceto et al. 1997; English et al. 1996; Woods et al. 1997), as well as in various
journals (Aceto et al. 1996; Aceto et al. 1989; May et al. 1994).
DEC MEMBERS
Members of DEC are those individuals who are presently associated with the Analgesic and
Stimulant/Depressant Testing Programs. At this time, the DEC Members are: Drs. Mario Aceto and Louis
Harris from the Medical College of Virginia Virginia Commonwealth University, James Woods, Gail
Winger, and John Traynor from the University of Michigan, Ted Cicero (DEC Chair) from Washington
University, St. Louis, Arthur E. Jacobson (DEC Biological Coordinator) from NIDDK, NIH, Charles France
from Louisiana State University, Bill Woolverton (DEC Recording Secretary) from the University of
Mississippi, and the Chair of the CPDD Liaison Committee for Drug Testing and Evaluation (James Smith,
Bowman Gray School of Medicine, ex officio).
Membership in DEC is available to anyone who has the expertise and resources to carry out drug testing, and
who is the principal investigator on a grant/contract. This drug testing must complement or extend existing
drug testing programs, and the principal investigator must consider DEC drug testing as a priority for them.
Their inclusion into DEC is gained by majority vote of the voting members of DEC.
STATISTICS
The sources and number of compounds released for publication from 1992 - 1997 can be seen in Fig. 1. In
1997, pharmaceutical industry once again became a major source of samples for evaluation (19%), and most of
the industrial groups were foreign. The university sources (45%) were all domestic. and the governmental
sources were, mostly, NIDA, with some drugs from NIDDK researchers. Additional data on four compounds
346
were obtained by the stimulant/depressant testing groups. The total number of compounds released for
publication this year was somewhat less than the number released last year, as shown in Fig. 1, but there are
several very interesting drugs (see Experimental Observations section), one of which is in phase III clinical
trials for intractable pain untreatable by morphine. The sources for the examined drugs are considerably more
disparate than was observed last year, although no drugs came from non-profit institutions.
EXPERIMENTAL OBSERVATIONS
Table 1 lists the names and assigned NIH and CPDD numbers of the compounds examined this year, and notes
the specific table number where they appear. Tables 2 - 9 present the structures and a summary of the
biological activities of compounds evaluated as analgesics, as obtained from work at the Medical College of
Virginia, VCU, and the University of Michigan (Aceto et al. 1998; Woods et al. 1998) and additional work
on CPDD 0007, 0032, 0042, and 0044 (France et al. 1998) from the Stimulant/Depressant group is
summarized in Table 10. The compounds in Tables 2 - 9 are grouped according to their molecular structure
(e.g., endoethano- and ethenooripavines, 4,5-epoxymorphinans, 6.7-benzomorphans, etc.) in order to facilitate
recognition of the relationship between their molecular structure and biological activity.
In Table 2. the DEC work is shown on the very potent endoethenoorpipavine, etorphine (NH 8068), and the
even mom potent endoethanooripavine, NIH 10846, dihydroetorphine, the latter having been sent to DEC by
the NIDA Medications Development Division. Both drugs are many-fold more potent than morphine as
antinociceptives. The dihydroetorphine has considerably greater affinity for the µ-opioid receptor than
etorphine, and is more potent in vivo. Since both self-administration and drug discrimination indicate that
10846 is likely to show abuse liability in man, unless its clinical efficacy is considerably better than currently
used analgesics it will probably not he clinically useful as an analgesic. NIH 10846 might have utility as
medication for drug abuse; it will probably be well-liked by heroin addicts, and withdrawal from the drug
might be physically easier than from methadone. It is not, however, a particularly long-acting drug.
341
Selective, potent, opioid agonists and antagonists would be useful both as therapeutic agents and as tools for
the exploration of opioid receptor systems. Such drugs are known, if not well-utilized as yet, for the the µ-,
and perhaps -opioid receptors: less well known am drugs for the -opioid system. There is debate about
whether the -opioid receptor acts independently, or interacts with the µ-receptor, or both, and whether an
extremely selective -agonist would show physical dependence potential or abuse liability. Both a -agonist
(NIH 10821) and antagonist (NIH 10822) were examined by DEC, and are shown in Table 3. It is interesting
to note that neither drug displays an antinociceptive (or narcotic antagonist) effect in mice (sc administration),
similar to our findings for other known -ligands such as SNC 80 (NIH 10815 (Jacobson 1996)), nor do they
suppress the morphine abstinence syndrome in monkey single-dose suppression assays, unlike µ-ligands,
Even more interesting is their inability to displace [3H]-etorphine from rat cerebral membrane preparations.
However, the actual affinity and selectivity of the -antagonist was shown in specific opioid receptor assays.
NIH 10822 was found to be have high affinity for the -opioid receptor and the µ/ ratio was found to be 37,
and
was 88. Lastly, in Table 3, NIH 10875, was shown in 1930 to be a weak antinociceptive agent in the
HP assay. Its binding affinity was determined, and it was found to be selective for µ-opioid receptors: its
affinity is somewhat better than that of codeine, its isomer.
A series of N-substituted normetazocines were examined and the data are shown in Tables 4 and 5. It is
surprising to note that the effect of various substituents on the nitrogen atom in this (or any other) class of
analgesics is in large measure still quite unpredictable, although in vivo and in vitro data on many of them
have been experimentally obtained (May et al. 1994). Of particular interest in Table 5 is the (+)-enantiomer,
NIH 10898, which has weak antinociceptive activity and does not suppress morphine abstinence in the
monkey single-dose suppression assay. Unfortunately, it appears to have convulsant actions. The (-)
normetazocine NIH 10884 is a fairly potent antinociceptive agent, also without much effect in the SDS assay.
However, like many N-substituted normetazocines, it also has high affinity at the -receptor.
The remaining compounds examined, in Tables 6, 7, 8, and 9 have molecular structures which do not tit into
well-known analgesic classes. (-)-Eseroline (NIH 10820, in Table 6) was reexamined for pharmaceutical
industry and found to be a morphine-like antinociceptive which was fairly ineffective at displacing 3Hetorphine from opioid receptors; interaction with selective receptor assays was not measured. Several
compounds (NIH 10833, 10838, 10839, 10840, 10841, and 10867, in Tables 6 and 7) were examined for the
NIDA Medications Development Division as potential treatment agents, and -conotoxin (NIH 10887, Table
8) was sent to us by pharmaceutical industry. That drug was noted by the submitter to be an extremely potent
intrathecal analgesic. DEC found it to have a little antinociceptive activity sc or iv and it does not appear to
have affinity for any of the opioid receptors, except weak affinity for the -receptor. It would not be predicted
to have physical dependence potential or abuse liability of the opioid-type from our self-administration and
drug discrimination tests. The conotoxin family of toxins come from the cone snail and it was recently noted
that the disulfide links confer its rigidity and a characteristic shape allowing the toxin to nestle in a particular
channel or portion of a specific CNS receptor (Ackerman 1997). The -conotoxin which DEC evaluated is a
synthetic peptide which was developed as a potential treatment for intractable pain, for those unresponsive to
morphine It is in phase HI clinical trials (Ackerman 1997).
In Table 10, new work is shown on four compounds which were previously evaluated by the
Stimulant/Depressant Group (CPDD 0007, 0032, 0042, and 0044; methaqualone, flunitrazepam, zipeprol, and
-hydroxybutyric acid, respectively). These data are from drug discrimination studies at Louisiana State
University (France et al. 1998). Comparative data from previous work with these compounds are also listed in
that Table. the procedures used, and the complete data, will be published this year in a separate
Stimulant/Depressant Group report (France et al. 1998).
NOTES FOR TABLES 2 - 9
Rounded numbers are used; precise values and details of the procedures are given in the MCV (Aceto et al.
1998) and UM (Woods et al. 1998) reports.
348
1) Antinociceptive reference data:
Morphine ED, (confidence limits): Hot Plate = 0.8 (0.3-1.8); Phenylquinone = 0.23 (0.20-0.25); Tail-Flick =
5.8 (5.7-5.9)
Tail-Flick Antagonism vs. morphine (naltrexone AD50= 0.007 (0.002-0.02); naloxone AD50 0.035 (0.010.093)).
2) In Vitro - Subtype selective binding affinity using monkey brain cortex membranes. Selectivity for µ,
and -opioid receptors determined with [3H]-DAGO, [3H]-p -Cl-DPDPE and [3H]-U69,593, respectively.
349
TABLE 1. NIH NUMBERS, CHEMICAL NAMES, TABLE NUMBER, AND EVALUATING GROUP
8068
Etorphine.HCl
TABLE #Evaluator
2-MCV
10820
(-)-Eseroline (L)-ascorbate
6-MCV/UM
10821
3-O-Methyloxymorphindole hydrocloride
3-MCV/UM
10822
3-O-Methylnaltrindole
3-MCV/UM
10833
N-[(R,S)-2-Benzyl-3[(S )(2-amino-6-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester methyl sulfite
6-MCV/UM
10838
2-Phenyl-1,3-propanediol dicarbamate (Felbamate)
6-MCV/UM
10839
3,5-Dimethyltricyclo[3.31.13,7]decan-1-amine
6-MCV/UM
10840
1-Aminocyclopropane carbolic acid (ACPC)
7-MCV/UM
10841
D-Phenylalanine
7-MCV/UM
10846
Dihydroetorphine hydrocloride
2-MCV/UM
10860
(-)-5,9 Dimethyl-2-heptyl-2'propionoxy-6,7-benzomorphan hydrocloride
4-MCV/UM
10864
(-)-5,9 -Dimethyl-2'-hidroxy-2-(2-hydroxyethyl)-6,7-benzomorphan
4-MCV/UM
10867
7-Nitroindazole
10869
(-)-2-Cyanomethyl-5,9
dimethyl-2'-hydroxy-6,7-benzomorphan
hydrocloride
4-MCV/UM
10870
(+)-2-Cyanomethyl-5,9
-dimethyl-2'hydroxy-6,7-benzomorphan
hydrochloride
4-MCV/UM
10871
(-)-2-(5-Chloropentyl)-5,9 -dimethyl-2'hydroxy-6,7-benzomorphan hydrochloride
4-MCV
10874
7-Benzoyl-2-piperidinomethyl-1,6-benzodioxane hydrochloride
7-UM
10875
Pseudocodeine
3-UM
10884
2R,5R,9R-(-)-2-(3-Cyanopropyl)-5.9
NAME
NIH#
fumarate
(Memantine)
oxalate
7-MCV/UM
hydrocloride
dimethyl-2'-hydroxy-6,7-benzomorphan
5-MCV/UM
TABLE 1. CONTINUED - NIH NUMBERS, CHEMICAL NAMES, TABLE NUMBER, AND EVALUATING GROUP
NIH#
TABLE #Evaluator
5-MCV
NAME
10885
2S,5S,9S-(+)-2-(3-Cyanopropyl)-5,9
10886
(±)-Isonicotine oxalate
8-MCV/UM
10887
w-Conotoxin MVIIA (reduced cyclic (1-16), (8-20), (15-25) - SNX-111)
8-MCV/UM
10895
(-)-Isonicotine
8-MCV/UM
10896
(+)-Isonicotine oxalate
10897
2R,5R,9R-(-)-2-(6-Chlorohexyl)-5,9
dimethyl-2'-hydroxy-6,7-benzomorphan
hydrochloride
5-MCV
10898
2S ,5S ,9S -(+)-2-(6-Clorohexyl)-5,9
-dimethyl-2'-hydroxy-6,7-benzomorphan
hydrochloride
5-MCV
10899
2-Methyl-5-(3-pyridyl)morphan
10900
11-[6-Hydroxy-6-(3-trifluoromethyl)piperidin-1-yl]-2-methyl-6,11-dihydrodibenz[b,e]oxepine
dimethyl-2'-hydroxy-6,7-benzomorphan
oxalate
8-MCV/UM
9-UM
oxalate
fumaric
sulfuric
acid
9-MCV
9-MCV
10901
11-(6-Hydroxy-6-phenylpireridin-1-yl)-2-methyl-6,11-dihydrodibenz[b,e]oxepine
10902
11-[6-Hydroxy-6-(3-trifluoromethylphenyl)piperidin-1-yl]-2-dihydrodibenz[b,e]oxepine
acid
10903
11-(6-Hydroxy-6-phenylpiperidin-1-yl)-2-hydroxymethyl-6,11-dihydrodibenz[b,e]oxepine
9-MCV
CPDD
0007
CPDD
0032
CPDD
0042
CPDD
0044
Methaqualone
10-S/D:LSU
Flunitrazepam
10-S/D:LSU
Zipeprol
dihydrochloride
10-S/D:LSU
Hydroxybutyric acid sodium salt
10-S/D:LSU
fumaric
acid
9-MCV
TABLE 2. ENDOETHENO- AND ENDOETHANOORIPAVINES
ANTINOCICEPTIVE/ANTAGONIST ASSAYS
IN VITRO
(MOUSE ED50/AD50, sc, mg/kg)
NIH # Hot Plate Phenylquinone Tail Flick Tail Flick Binding Affinity, nM Mouse Vas Deferens
(EC50, nM (% twitch
Antagonist
inhibition))
c
b
a
µ
=
0
.
6
;
=1.13
0.002
8068 0.00096 0.0004
Inactive
MONKEY
Substitution-for-Morphine
(sc, mg/kg)
Complete substitution
( ˜ 2000x morphine)
10846 0.0002
0.0002
0.00015 d Inactive
µ=0.088; = 2 . 5 4
=0.197
0.34 (100) [antagonized Complete substitution
by naltrexone]
( ˜ 2000x morphine)
a) Previously reported, with high physical dependence capacity noted in Substitution-for Morphine assay (Deneau and Seevers 1964).
b) Tail flick assay with nor-BNI or naltrindole antagonism: µ-selective and devoid of for activity. Extended duration in
morphine-dependent animals. Low pA2 (0.09) suggests multiple drug properties.
c) Previously reported (displacement of 3H-sufentanil and 3H-DPDPE, [(Woods et al. 1997), see p 400]).
d) Naloxone AD50 = 0.04
e) Rat Infusion (Substitution-for-Morphine): suppression less than with morphine; Rat Infusion (Primary Physical Dependence): withdrawal
milder than morphine, but same behavioral signs; Monkey primary physical dependence: µ-like withdrawal syndrome, but body weight
constant; Self-administration (monkey): >460x heroin, >20,000x codeine.
TABLE 3. 4,5-EPOXYMORPHINANS
IN VITRO
ANTINOCICEPTIVE/ANTAGONIST ASSAYS
(MOUSE ED50/AD50, sc, mg/kg)
NIH # Hot Plate Phenylquinone Tail Flick Tail Flick Binding Affinity,
Mouse Vas Deferens
(EC50, nM (% twitch inhibition))
Antagonist nM
3
H-etorphine>6000
10821 Inactive Inactive
Inactive
Inactive
1300 (100) [antagonized
MONKEY
Substitution-for Morphine
(sc, mg/kg)
Partial substitution (20)
by naltrexone]a
10822 Inactive
Inactive
Inactive
Inactive
3H-etorphine>6000
-
µ = 6 6 . 4 ; =1.8;
No substitution, possible
exacerbation of withdrawal (4,16)
=158
-
10875
00003
-
431b
-
c
µ = 427; = >6000; 14800 (63)
-
=>6000
a) Typical -agonist.
b) Determined in 1930 at NIDDK, MH.
c) Very weak agonist with unusual activity at µ-opioid receptors (naltrexone decreased maximum response without shift in concentration-effect
curve).
TABLE 4. 6,7-BENZOMORPHANS
10860:
10864:
10869:
10871:
R1 = OCOEt, R2= (CH2)6CH3
R1 = OH, R2 = (CH2)2OH
R1 = OH, R2 = CH2CN
R1 = OH, R2 = (CH2)5Cl
ANTINOCICEPTIVE/ANTAGONlST ASSAYS
IN VITRO
(MOUSE ED50/AD50, sc, mg/kg)
Binding Affinity, nM Mouse Vas Deferens
NIH # Hot Plate Phenylquinone Tail Flick Tail Flick
(EC50, nM (% twitch
Antagonist
inhibition))
Inactive
10860 5.5
3.13
0.31
µ=28.2, =47,
No effecta,b
=47.5a
Inactive
Inactive
µ=41, =316, =16
10864 Inactive Inactive
1290 (68) Slight antagonism)
by naltrexone; weak -agonist
(sc and icv)
Inactive
µ=166, =574, =69
11.6
1.52
10869 8.5
1720 (83)
10870 Inactive
6.0
Inactive
Inactive
10871 3.6
0.5
0.84
Inactive
µ=4490,
=1310
-
=>6000,
7930 (35); not antagonized by
naltrexone
-
MONKEY
Substitution-for-Morphine
(sc, mg.kg)
No substitution (2-12);
convulsant, lethal
No substitution (3,12)
Complete substitution
[0.25x morphine]
Complete substitution (1)k
Complete substitution
a) Previously reported ((Woods et al. 1997) - see p 416).
b) Unusual agonist decreased magnitude of twitch, but did not suppress it at any concentration. Very weak, non-selective, antagonist.
c) Severe ataxia; possible -opioid.
TABLE 5. 6,7-BENZOMORPHANS (CONTINUED)
ANTINOCICEPTIVE/ANTAGONIST ASSAYS
IN VITRO
(MOUSE ED50/AD50, sc, mg/kg)
Mouse Vas Deferens
NIH # Hot Plate Phenylquinone Tail Flick Tail Flick Binding Affinity, nM
Antagonist
(EC50, nM (% twitch
inhibition))
10884
1.1
0.1
0.36 a
Inactive
µ=6.5,
=21.6,
=0.34 42.7 (100)
MONKEY
Substitution-for-Morphine
(sc, mg/kg)
Non-dose-dependent
10885 Inactive
Inactive
Inactive
Inactive
-
[antagonized by naltrexone]
Non-dose-dependent
10897 1.59
0.67
2.03
Inactive
-
-
Partial substitution (2,8)b
10898 Inactive
6.32
11.56
Inactive
-
-
No substitution (3,12);
convulsions at 12 mg/kg.
a ) High naloxone AD50 = 0.28, and effects in monkeys suggest heterogenous opioid properties.
b) Nearly suppresses morphine-withdrawal, potency>morphine; appears µ-opioid-like.
TABLE 6. MISCELLANEOUS
IN VITRO
ANTINOCICEPTIVE/ANTAGONIST
ASSAYS
(MOUSE ED50/AD50, sc, mg/kg)
NIH # Hot Plate Phenylquinone Tail Flick T a i l F l i c k Binding Affinity, nM Mouse Vas Deferens
(EC50, nM (% twitch
Antagonist
inhibition))
MONKEY
Substitution-for-Morphine (sc.)
mg/kg)
10820 3
0.3
2.4 b
Inactive
1600 (3H-etorphine]
3.9 (49) [Antagonized by
naltrexone]
10833 -
-
39 (iv);
-
µ=2100, =>6000,
=>6000
977 (23) [Not antagonized Solvent-like partial substitution
(iv)
by naltrexone]
µ=>6000, =>6000,
=>6000
670 (29) [Not antagonized No substitution (3,15)
by naltrexone]
ip inactivec
10838 Inactive
Inactive
Inactive
Inactive
10839 Inactive
15.1
Inactive
Inactive
µ=>6000,
=>6000
=>6000,
47 (35) [Not antagonized
by naltrexone]
Complete substitution (2.5-10)
No substitution (2,8)d
a) Previously reported (Aceto et al. 1987)
b) High naloxone AD50= 0.16; pA2: not typical opioid agonist non-competitive or non-equilibrium steady slate. No antagonism with norBNI.
c) Drug has no acute or chronic effect on morphine’s ED50.
d) No exacerbation of withdrawal. Excitability seen in tail flick and phenylquinone assays; some signs suggest PCP-like behavior in monkeys.
TABLE 7. MISCELLANEOUS (CONTINUED)
ANTINOCICEPTIVE/ANTAGONIST ASSAYS
IN VITRO
(MOUSE ED50/AD50, SC, mg/kg)
Mouse Vas Deferens
NIH # Hot Plate Phenylquinone Tail Flick Tail Flick Binding Affinity, nM
(EC50, nM (% twitch
Antanonist
inhibition))
10840 Inactive
Inactive
Inactive
Inactive
µ=>6000,
=>6000,
=>6000
10841
Inactive Inactive
Inactive
Inactive
µ=>6000,
Inactive
Inactive
Inactive
µ=>6000,
=>6000,
7.4
-
µ=>6000,
=>6000
a
3290 (34) [Not antagonized by No substitution (5,25)
185 (56) [Not antagonized by
No substitution (9,45)b
naltrexone]
=>6000,
=>6000
10874
Substitution-For-Morphine
(sc, mg/kg)
naltrexone]
=>6000
10867 Inactive
MONKEY
1500 (47) [Not antagonized by naltrexone]
=>6000,
21 (100) [Not antagonized by No substitution (5,40)
naltrexone]
a) A single (200 mg/kg) dose had no effect When a 200 mg/kg sc was given for 4 days and the monkeys placed in withdrawal, followed by
another 200 mg/kg sc dose, neither substitution nor exacerbated withdrawal was observed.
b) No exacerbation of withdrawal. Rat Infusion (Substitution-for-Morphine): no substitution. Heroin discrimination: no attenuation of heroin
disciminitive stimulus.
TABLE 8. MISCELLANEOUS (CONTINUED)
H-Cys-Lys-Gly-Lys-Gly- Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-SerCys-Arg-Ser-Gly-Lys-Cys-NH2 cyclic (1-16), (8-20), (15-25)-tris(disulfide)
10887 [ -Conotoxin MVIA (reduced)]
ANTINOCICEPTIVE/ANTAGONIST
NIH # Hot Plate Phenylquinone Tail Flick
10886 Inactive 3.2
Inactive
IN VITRO
ASSAYS
3.16
17.7 (iv)
Binding Affinity, nM
Mouse Vas Deferens
(EC50, nM (% twitch
inhibition))
Inactive
µ=>6000, =>6000,
Very weak antagonist at µ, No substitution (3,12)
-
µ=>6000,
=>6000
10895 Inactive 3.8
Inactive
Substitution-for-Morphine
(sc, mg/kg)
Tail Flick
Antagonist
and possibly
=>6000
10887 -
MONKEY
Inactive
-
=>1190,
4.8 (100) [Not antagonized by
Partial substitution
naltrexone]
(0.25,1)a
Partial substitution
(non-dose related)
10896
Inactive
1.63
Inactive
Inactive
-
No substitution (2.5,10)
a) Self-administration: no reinforcing effect; drug discrimination (naltrexone-saline): did not attenuate discrimination of morphine withdrawal.
TABLE 9. MISCELLANEOUS (CONTINUED)a
10900: R1 = CF3, R2 = CH3
10901: R1 = H, R2 = CH3
10902: R1 = CF3, R2 = CH2OH
10903: R1 = H, R2 = CH2OH
ANTINOCICEPTIVE/ANTAGONIST ASSAYS
IN VITRO
(MOUSE ED50/AD50, sc, mg/kg)
NIH # Hot Plate Phenylquinone Tail Flick Tail Flick Antagonist Binding Affinity, Ki, nM
10899 -
-
-
-
µ=>1175, =>10000,
MONKEY
Substitution-for Morphine (sc, mg/kg)
-
=>10000
10900 Inactive Inactive
Inactive a Inactive
-
Non-dose related suppression of
withdrawal
10901 -
7.6
Inactivea
Inactive
-
10902 0.98
1.13
12.86b’c
Inactive
-
10903 2.2
0.6
1.11 d
Inactive
-
a) Also, orally with 20 or 40 min pretreatment: inactive
b) Possible pro-drug in mouse.
c) Naloxone AD50: 0.12 (high - suggests heterogenous activity)
d) Also, orally with 20 min pretreatment 1.0 mg/kg; 40 min pretreatment: 0.98 mg/kg.
Complete substitution (0.2x morphine)
Complete substitution - morphine-like
TABLE 10. EVALUATION OF STIMULANT/DEPRESSANT DRUGS
CPDD#
0007
Discriminative Stimulus Effects In Monkeys, Monkey SelfComparison To Flumazenil & Triazolam (sc)a Administration (iv)
No benzodiazepine agonist or antagonist Reinforcer b
action
Monkey Drug Discrimination
(Intragastric)
Substitutes for pentobarbitalb
Reinforcer in 1/3 monkeysc Pentobarbital-trained: 100% Drug-appropriate responding
0032
Benzodiazepine-like agonist potency similar
to triazolam
0042
No benzodiazepine agonist or antagonist
action
at 0.3-1.0 mp/kgc
Reinforcer in methohexital- Pentobarbital-trained: No drug-appropriate responding
and alfentanil-trained
Amphetamine-trained: No drug-appropriate respondingd
monkeysd
0044
No benzodiazepine agonist or antagonist
action
Did not maintain behavior.
No reinforcing effecte
a)
b)
c)
d)
e)
See Stimulant/Depressant report (France et al. 1998)
Previously reported (Jacobson 1988a; Jacobson 1988b; Johanson 1986)
Previously reported (Jacobson 1991; Patrick et al. 1992; Winger et al. 1992)
Previously reported (English et al. 1996)
Previously reported (Jacobson 1997)
Pentobarbital-trained: No drug-appropriate responding
Amphetamine-trained: Maximum of 50% drug-appropriate
responding, probably not dose-related; may have weak
amphetamine-Iike subjective effectse
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Jacobson, A. E.: Biological Evaluation of Compounds for their Physical Dependence potential and Abuse
Liability. XX. Drug Evaluation Committee of the College on problems of Drug Dependence. Inc.
(1996). In: L. S. Harris, ed. Problems of Drug Dependence, 1996, pp. 323-337, NIDA Research
Monograph 174, Washington, D.C., 1997.
361
Johanson, C. E.: Stimulant Depressant Report In: L. S. Harris, ed. Problems of Drug Dependence, 1985, pp.
98-104, NIDA Research Monograph 67, Washington, DC, 1986.
May, E. L.; Aceto, M.D.; Bowman, E. R.; Bentley, C.; Martin, B. R.; Harris, L. S.; Medzihradsky, F.;
Mattson, M. V.; and Jacobson, A. E. Antipodal -N-Alkyl (Methyl-Decyl)-N-Normetazocines (2’Hydroxy-5,9 -methyl-6.7-benzomorphans): In Vitro and In Vivo Properties. J Med Chem 37:34083418, 1994.
Patrick, G. A.; Harris, L. S.; Nader, M. A.; Woolverton, W. L.; Winger, G.; and Woods, J. H.: Progress
Report From the Testing Program for Stimulant and Depressant Drugs (1990). In: L. S. Harris, ed.
Problems of Drug Dependence 1991, pp. 604-624, NIDA Research Monograph 119, Washington,
D.C., 1992.
Winger, G.; Woods, J. H.; Patrick, G. A.; Powell, L. J.; Harris, L. S.; Nader, M. A.; and Woolverton, W.
L.: Progress Report From the Testing Program for Stimulant and Depressant Drugs (1991). In: L. S.
Harris, ed. Problems of Drug Dependence, 1991, pp 625-639. NIDA Research Monograph 119,
Washington, DC, 1992.
Woods, J. H.; Medzihdky, F.; Smith, C. B.; Butelman, E. R.; and Winger, G. D.: Evaluation of New
Compounds for Opioid Activity (1996). In: L. S. Harris, ed. Problems of Drug Dependence 1996, pp.
396-420, NIDA Research Monograph 174, Washington, D.C., 1997.
Woods, J. H.; Traynor, J.; Butelman, E. R.; and Winger, G. D.: Evaluation of New Compounds for Opioid
Activity (1997). In: L. S. Harris. ed. Problems of Drug Dependence 1997, NIDA Research Monograph,
Washington, D.C., 1998, in press.
362
DEPENDENCE STUDIES OF NEW COMPOUNDS IN THE RHESUS MONKEY, RAT AND
MOUSE (1997)
M. D. Aceto, E. R. Bowman, L. S. Harris, and E. L. May
Department of Pharmacology and Toxicology, Medical College of Virginia
Virginia Commonwealth University, Richmond, VA
All compounds, except etorphine, dihydroetorphine, NIH 10917 and 10918 were unknown to us when submitted by
Dr. Arthur Jacobson, Laboratory of Medicinal Chemistry, NIDDK, NIH. These studies were conducted under the
auspices of the Drug Evaluation Committee in association with of the College on Problems of Drug Dependence.
See summary of new data in Table 1.
Dependence-Liability Studies in Rhesus Monkeys
Substitution-for-Morphine (SDS) Test. Male and female rhesus monkeys (M. mulatta) weighing 2.5-7.5 kg were.
used, and they received 3 mg/kg, s.c., of morphine•SO4 every 6 h. All the animals had received morphine for at
least 3 months and were maximally dependent on morphine (Seevers and Deneau 1963). A minimal 2-week
recuperation period was allowed between tests. At least 3 monkeys/dose were used. The assay (Aceto and coworkers, 1977 and 1978) was initiated by a subcutaneous injection of the test drug or control substances (morphine
and vehicle) into animals in a group that bad not received morphine for 14-15 h and showed definite signs of
withdrawal. Each animal was randomly chosen to receive one of the following treatments: a) a dose of the
compound under investigation; b) morphine control, 3.0 mg/kg; and c) vehicle control, 1 ml/kg. The animals were
scored for suppression of withdrawal signs during a 2.5-h observation period. The observer was “blind” regarding
the choice of treatments. At the end of the study, the data were grouped according to dose and drug. The mean
cumulative score ± SEM was calculated and the data illustrated in figure form. If indicated the data were analyzed
using the Kruskal-Wallis Anova and posthoc Mann-Whitney U-Tests.
Precipitated-Withdrawal (PPT-W) Test. This evaluation was done under the same conditions as described above,
except that the animals were administered a test compound 2-3 h after the last dose of morphine. These animals
were not in withdrawal. Naloxone•HCI (0.05 mg/kg, s.c.) served as the positive control.
Primary-Physical-Dependence (PPD) Study. Drug-naive monkeys were medicated with drug, using escalating dose
regimens, periodicahy challenged with naloxone or placed in abrupt withdrawal. They were observed for overt
behavioral signs during drug administration and when they were challenged with antagonist or abruptly withdrawn
from the drug.
Rat-Infusion Studies
The continuous-infusion method was reported by Teiger (1974) and certain modifications are indicated as follows.
Rats were anesthetized after which each was fitted with a specially prepared cannula which was passed
subcutaneously from the nape of the neck to the lateral side of the lower abdomen and then inserted into the
peritoneal cavity. The cannula was anchored at both ends with silk sutures and attached to a flow-through swivel
mechanism which allowed the animal to move about in the cage and eat and drink normally. The swivel was
connected to a syringe which was attached to a syringe pump. The animals received 7-10 ml of solution every 24
h. Occasionally, when deemed necessary, as with cocaine, infusions were given via the right jugular vein.
Substitution-for-Morphine (SM) Test. The rats received morphine•SO4 (50 mg/kg/24 h on the first day, 100
mg/kg/24 h on the second day, and 200 mg/kg/24 h from days 3 and 4). Then, a test drug was substituted for 2
days. The morphine controls received an infusion of sterile water for injection. The animals were observed for
changes in body weight and for behavioral-withdrawal signs for 0.5 h at 6, 24, 48, 72 and/or 96 h after stopping the
infusion of morphine.
363
Table 1. SUMMARY OF NEW DATA
Table 1. SUMMARY OF NEW DATA
(continued)
NIH No.
Chemical Name or
Generic Class
T F
10903
10917
10918
4-Piperidinol
(+)-Pyrroloisoquiniline1
(-)-Pyrroloisoquinoline2
T o,q
Tr
T
MOUSE
HP
TFvsM P P Q
T
T
T
T
T
T
T
T
T
pA2
SM
RAT
PPD
SDS
MONKEY
PPt-W
PPD
T
T=TEST PERFORMED
a
Special interaction study of NIH 8068 and antagonist subtypes in mouse TF test. bSpecial time-course study in mouse TF test. cSpecial naloxone vs
ED80 of NIH 10820 in TF test. dSpecial Nor-binaltorphimine (NlH 10588, kappa antagonist, vs ED80 of NIH 10820 in TF test. eSpecial intravenous
study in mouse TF test. fNIH 10841 and morphine given simultaneousiy in mouse TF test. gSpecial chronic NIH 10841 (i.v.) plus morphine (s.c.) in
mouse TF test. hSpecial chronic NIH 10841 (s.c.) plus morphine (s.c.) in mouse TF test. iSpecial naloxone vs ED80 of NIH 10846 in TF test. jSpecial
time-course study of morphine and NIH 10846 in mouse TF. test. kSpecial interaction study of NM 10846 and opioid antagonists subtypes in mouse TF
test. lSpecial preliminary study-repeated dose-suppression, abrupt and precipitated withdrawal. mSpecial naloxone vs ED80 of NIH 10897 in mouse TF
test. n,oSpeciai oral pretreatment of mice with NIH 10900 in TF test. pSpecial naloxone vs ED80 of NIH 10902 in mouse TF test. qSpecial naloxone vs
ED80 of NIH 10903 in mouse TF Test. rSpecial naloxone vs ED80 of NIH 10817 in TF test. sSpecial mecamylamine vs ED80 of NIH 10817 in mouse
PPQ test. tSpecial mecamylamine vs ED80 of NIH 10817 in HP test. 1(+)-Bridged Nicotine. 2(-)-Bridged Nicotine.
Primary-Physical-Dependence (PPD) Study. The rats received test compound, as specified above, for 4-6 days and
then, were placed in abrupt withdrawal and observed for overt behavioral signs.
Mouse-Antinociception Tests
Male mice, weighing 20-30 g, were used. All drugs were dissolved in distilled water or in the vehicle indicated and
injected subcutaneously (s.c.). At least three doses were tested and 6-10 animals per dose were used. When
applicable, ED50’s were calculated by using computerized probit analysis. The results obtained with reference
compounds are summarized in Table 2. Occasionally, when requested, drugs were given orally or i.v. and the
pretreatment tunes are indicated in the text.
Tail-Flick (TF) and (TF vs M) Assays. The procedure and modifications were described (D'Amour and Smith, 1941
and Dewey et al., 1970 and 1971) in the literature. Briefly, the mouse’s tail was placed in a groove which contained
a slit under which was located a photoelectric cell. When the heat source of noxious stimulus was turned on, the
heat focused on the tail, and the animal responded by flicking its tail out of the groove. Thus, light passed through
the slit and activated the photocell which, in turn, stopped the recording timer. The heat source was adjusted to
produce tail flick of 2-4 s under control conditions. Mice were injected with drug or vehicle and tested 20 m later.
In the assay for antagonism of the antinociceptive effect, the potential antagonists were administered 10 m before
the agonist, and evaluation occurred 20 m later.
Phenylquinone Abdominal-Stretching (PPQ) Assay. The procedure was reported previously (Pearl and Harris,
1966). The mice were injected with test drugs and 10 m later received 2.0 mg/kg ip of a freshly prepared
paraphenylquinone (PPQ) solution. The mice were then placed in cages in groups of two each. Ten minutes after
the PPQ injection, the total number of stretches per group were counted over a 1-m period. A stretch was
characterized by an elongation of the mouse’s body, development of tension in the abdominal muscles, a-d
extension of the forelimbs. The antinociceptive response was expressed as the percent inhibition of the PPQinduced stretching response.
Hot-Plate (HP) Assay. The method was also reported previously (Eddy and Leimbach, 1953 and Atwell and
Jacobson, 1978). The hot plate was held at 55°C. Mice were placed on the hot plate and activity was scored if the
animal jumped or licked its paws after a delay of 5 s or more, but no more than 30 s beyond the control time.
366
Table 2
Comparative Data (ED50, mg/kg s.c.) [95% C.L.] of Selected Standards in 4 Mouse Agonist-Antagonist Tests
Drug
Tail-flick
Pentazocine
15% at 10.0
Cyclazocine
17% at 1.0 a
0.03
(0.02-0.78)
Nalorphine•HCl
None at 10.0
2.6
(0.7-1.0)
Naloxone•HCl
None at 10.0
0.04
(0.0-0.09)
No Activity
----
Naltrexone•HCl
None at 10.0
0.007
(.002-0.02)
No Activity
----
Morphine•SO 4 b
1.92
(0.89-4.14)
Codeine•PO 4
Meperidine•HCl
----
8.37
(4.59-15.27)
Tail-flick
Antagonist
18
(12-26) (1.0-2.5)
Phenylquinone
1.7
0.01
(0.005-0.03)
0.6
(0.03- 1.44)
Hot-Plate
13% at 30.0
25% at 9.0
13% at 30.0
Inactive
0.4b
(0.2-0.8)
0.85
(0.39-1.86)
Inactive
8.25
(5.12-13.29)
6.4
(2.4-16.8)
Inactive
----
4.6
(1.18-11.7)
a
Mice were ataxic at 3.0 and 10.0 mg/kg but there was no further increase in reaction time
ICR - Harlan-Sprague-Dawley Inc.
b
Calculation of Apparent pA2. Using the tail-flick assay, the apparent pA2 and 95% confidence limits were
calculated using Schild and constrained plots as described in Tallarida and Murray (Manual of Pharmacologic
Calculations with Computer Programs, 2nd ed., Springer Verlag, NY., 1987).
Briefly, mice were pretreated with vehicle or various doses of antagonist followed 10 m later by an injection of
agonist. The mice were tested 30 m after receiving the antagonist. Dose-response lines for antinociception were
plotted using at least 3 doses of each opioid agonist in the presence of vehicle or one of the selected doses of
antagonist. ED50s were, estimated according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther.,
96.399, 1949). Bach dose ratio (x) was calculated by dividing the ED50 of the opioid in the presence of a given
dose of antagonist by that of the agonist alone. Log (x-1 ) was plotted against the negative logarithm of the molar
dose of the antagonist. At least 3 logs (x-1) were plotted. The pA2 values for the antagonist were calculated from
the point of intersection of the regression line with the abscissa. See Table 3 for summary of results.
367
Table 3. Apparent pA2 valuesa using the mouse tail-flick assay
Treatment
Antagonist/Agonist
Schild Plot
pA2 (95% C.L.) Slope
Constrained Plot
pA2 (95% C.L.)
1) Naloxone/Morphine
7.2 (7.0-7.4)-1.2
7.3 (7.1-7.6)
2) Nalmefene/Morphine
8.0 (7.6 - 8.3)-1.1
8.0 (7.7 - 7.6)
3) Naltrexone/Morphine
7.7 (4.9 - 10.5)-0.8
7.6 (7.1 - 8.3)
4) (-)Quadazocine/Morphine
6.8 (6.7 - 7.0)-0.9
6.8 (6.1 -0 7.6)
5)
Naloxone/Sufentanil
7.0 (6.9 - 7.1)-1.0
7.0 (6.9 - 7.0)
6) Naloxone/Sufentanil
7.0 (6.5 - 7.5)-1.0
7.0 (6.8 - 7.1)
7) Naloxone/Mirfentanil
7.6 (7.3 - 8.0)-1.7
7.2 (6.9 - 7.5)
5) Naloxone/(-)-Nicotine
5.3 (5.3-5.3)-0.5
7.0 (6.9 - 7.0)
9) Naloxone/U-50,488
6.6 (6.3 - 6.9)-1.1
7.2 (6.9 - 7.5)
6.6 (6.3 - 7.0)
kappa agonist
6.1 (5.6 - 6.6)-1.2
6.2 (5.9 - 7.3)
11) (-) Quadazocine/NIH 10672
6.2 (6.1 - 6.2)-1.7
6.7 (6.6 - 6.8)
12) nor BNI/NIH 10672
6.5 (5.9 - 7.0)-1.3
6.6 (5.9 - 7.3)
13) Mecamylamine/(-)-Nicotine
6.6 (6.2 - 6.9)-0.9
6.5 (6.4 - 6.6)
10) Naloxone/NIH 10672
selective kappa agonist
a
Negative logarithm of the molar concentrations of antagonist required to produce a two-fold shift of the agonist
dose-response curve the the right. Competitive antagonism can be assumed when slope = -1. pA2 provides a
measure of the relative potency and affinity of the antagonist. When the slope differs significantly from unity, this
may indicate non-equilibrium conditions, interactions with multireceptors, receptor sensitization, precoupling
mechanisms, or multiple drug properties. With a costrained plot, the slope of the regression line is restricted to
slope = -1.
Special Intracerebroventricular Tail-Flick and PPQ Assays. In order to develop an in-vivo agonist and antagonist
model to correlate with the in vitro binding data of the various opioid receptor types (mu, kappa and delta), we chose
the mouse Tail-Flick and PPQ tests and a variety of routes of administration. The intracerebroventricular (i.c.v.)
route was chosen to accomodate the fact that no delta agonist is available which is active by peripheral mutes of
administration.
368
NIH 8068 Etorphine•HCI
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 0.002 (0.001 - 0.004)
2) TF vs. M - Inactive
3) PPQ - 0.0004 (0.00002 - 0.0009)
4) HP - 0.001 (0.0004 - 0.003)
5) Naloxone vs NIH 8068 in Tail-Flick Test (Apparent pA2).
The naloxone pA2 estimate for etorphine of 6.5 (6.5 - 6.5) with a slope of - 0.9 is lower than obtained for
morphine (7.2) and fentanyl (7.0). When the slope is constrained to - 1, the pA2 is 6.45 (6.33 - 6.57).
6) Interaction of opioid agonist and antagonist subtypes in the mouse T.F. Test.
The data indicate that etorphine is a selective mu agonist devoid of kappa and delta activity (see Table 1).
Table 1. The interaction of NIH 8068 (etorphine) with selective opioid antagonists subtypes in the mouse T.F.
test.
7) Time Course.
As shown in Table 2, etorphine has a rapid onset of action and relatively short duration of action. The half-life
estimate is 40 m. The half life of morphine is approximately 2 hr.
Table 2. Time-course study for etorphine tail-flick ED80s in the mouse tail flick assay
Pretreatment Time (min)
% Inhibition of Nociception ± SEM
20
40
60
90
82 ± 12
66 ± 18
18 ± 8
4±4
369
NIH 8068 (Continued)
MONKEY DATA
(SDS)
Etorphine dose-dependently substituted completely for morphine with a potency range of 1.500 to 6,000 times that
of morphine sulfate. Etorphine acted promptly and, at the high dose, duration of action was at least 2.5 h.
Comment: In the mouse etorphine behaved essentially as a short-acting-selective mu agonist. In the morphinedependent monkey in withdrawal, etorphine completely substituted for morphine suggesting that it had mu agonist
properties. However, the duration of action was longer in a state of opioid dependency
NIH 10820 (NIH 10398) (-)-Eseroline (L)-ascorbate
MOUSE DATA - ED50 OR AD50, mg/kg/s.c.
(95% C.L.) or % change
1) TF - 2.4 (1.2 - 4.5)a
2) TF vs. M - Inactive at 1.0. 10.0 and 30.0a
3) PPQ - 0.3 (0.1 - 0.7)a
4) HP - 3.0 (1.5 - 6.0)a
5) Special: Naloxone vs ED80 of 10820 in TF AD50 = 0.16 (0.05 - 0.55)
6) Special: Naloxone-NIH 10820 pA2 = 6.9 (4.2 9.6) Slope - 0.33 (see Fig Naloxone-NIH10820)
Fig Naloxone-NIH 10820. Naloxone vs NIH 10820 apparent pA2.
370
NIH 10820 (Continued)
7) Special: Nor-binaltorphimine (NIH 10588, kappa antagonist) vs ED80 of 10820 in TF (0% antagonist at
1.0, 10.0, 30.0 and 60.0 mg/kg).
MONKEY DATA
(SDS)
NIH 10820 dose dependently substituted completely for morphine at 2.5 and 10.0 mg/kg (see Fig MH 10820)
Comment: This compound was originally studied in the mouse for antinociceptive properties the results of this
study are in accord with those reported earlier (see NIDA Monog. 76, 1986).
The fact that this compound was reported not to bind to mu receptors and yet showed in vivo mu activity prompted
the additional studies. The pA2 is similar to that obtained with naloxone/morphine interaction. However, the slope
of the regression was less than unity suggesting a non competitive or nonequilibrium steady state. In addition, NIH
10820 was devoid of kappa agonist properties.
Fig NIH 10820 Results of single-dose substitution of NIH 10820 for morphine in dependent monkeys in
withdrawal.
371
NIH 10821 3-O-Methylmorphindole•HCl
MOUSE DATA - ED50 OR AD50, mg/kg/s.c.
(95% C.L.) or % change
1) TF - Inactive at 1.0, 10.0 and 30.0
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0
3) PPQ - 0% at 1.0, 17% at 10.0 and 23% at 30.0
4) HP - 13% at 1.0, 25% at 10.0 and 38% at 30.0
MONKEY DATA
(SDS)
As shown in the figure (NIH 10821), apparently it suppressed withdrawal. However, the results are equivocal
because the number of subjects per dose was only 2. Drug supply was exhausted. The solution had a garlic-like
odor.
Comment: The results in monkeys contrast sharply with those observed in mice, Because of limited supplies a
definitive study in monkeys was not possible.
Fig NIH 10821. Results of single-dose suppression of NIH 10821 for morphine in morphine-dependent monkeys
in withdrawal.
372
NIH 10822 3-O-Methylnaltrindole•fumarate
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
1) TF - Inactive at 1.0, 10.0 and 30.0
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0
3) PPQ - 6% at 1.0, 14% at 10.0 and 23% at 30.0
4) HP - 13% at 1.0, 25% at 10.0 and 38% at 30.0
MONKEY DATA
(SDS)
At doses of 4 and 16 mg/kg, NIH 10822 did not substitute for morphine. Instead, there appeared to be a nonsignificant trend indicating exacerbation of withdrawal (see Fig. NIH 10822). Vehicle was 10% hydroxypropylcyclodextrin in sterile water.
Comment: This compound does not display remarkable pharmacological properties in the assays tested.
Fig NIH 10822. Results of single-dose substitution of NIH 10822 for morphine in morphine-dependent monkeys in
withdrawal.
373
NIH 10833 N-[(R,S)-2-Benzyl-3[(S)(2-amino-4-methylthio)butyldithiol]-1=oxopropyl]-L-phenylalanine
ester methyl sulfite
benzyl
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
1) TF - ( i.v.) - 39.0 (13.9 - 85.0) at 30.0 increased
locomotor activity and 60.0 Straub taila
TF- ( i.p.) 15% at 60.0, 20% at 120 and 54% at
200.0a
a
Vehicle 3% Tween 80 in saline
b
Eyelid ptosis at 60.0 and 120.0
MONKEY DATA
SDS - Special i.v. study
NIH 10833 was dissolved in a minimal amount of dimethylsulfoxide (DMSO). Sterile saline was added, quantum
sufficiat, to obtain the desired final volume of 3 ml. The solution was injected into a saphenous vein over a 40-60
second interval. During the first 30-m observation period, some of the monkeys receiving NIH 10833 vocalized as
if getting relief (calling) and began eating. However, they also retched and vomitted. An examination of the data
illustrated in (figure NIH 10833) suggested that NIH 10833 exacerbated withdrawal. However, the DMSO vehicle
controls suppressed two important withdrawal signs termed rigid abdominal muscles and vocalization when palpated.
As a result, the control cumulative score was low.
Comment: The results in the mice suggest that given i.v., NIH 10733 produced signs indicative of opioid action
(Straub tail and increased locomotor activity). However, the different behavioral signs obtained after i.p.
administration suggest that it was rapidly metabolized. Although some indications for opioid action were noted in
monkeys, the effect was fleeting and was not reflected in the cumulative scores. Finally, DMSO may have some
actions of its own.
374
NIH 10833 (Continued)
Fig NIH 10833. Results of single-dose. substitution of NIH 10833 for morphine in morphine-dependent monkeys
in withdrawal.
NIH 10838 2-Phenyl-1.3-propanediol
dicarbamate
(Felbamate)
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
Subcutaneously
1) TF (s.c.) - Inactive at 1.0, 10.0 and 30.0a
2) TF vs. M (s.c.) - Inactive at 1.0, 10.0 and 30.0a
3) PPQ (s.c.) - 6% at 1.0, 14% at 10.0 and 6% at
30.0
4) HP (s.c.) - 13% at 1.0,10.0 and 30.0a
Intravenously
1) TF (i.v.) - 15% at 1.0, 2% at 10.0 and 8% at
30.0 a
2) TF vs. M (i.v.) - Inactive at 1.0, 10.0 and 30.0a
3) PPQ (i.v.) - Inactive at 1.0, 20% at 10.0 and
34% at 30.0
a
Vehicle-5% hydroxypropyl- -cyclodexhin in saline
375
NIH 10838 (Continued)
MONKEY DATA
(SDS)
Inactive at 3 and 15 mg/kg s.c. (See Fig NIH 10838).
Comment NIH 10838 appears to be avoid of antinociceptive activity in the mouse and neither substituted for nor
exacerbared withdrawal in morphine-dependent monkeys in withdrawal. Apparently, NIH 10838 lacks opioid
properties.
Fig NIH 10838. Results of single-dose substitution of NIH 10838 for morphine in morphine-dependent monkeys
in withdrawal.
376
NIH 10839 3,5-Dimethyltricyclo[3.3.1.13,7]decan-1-amine
(Memantine)
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
1)
2)
3)
4)
TF (s.c.) - Inactive at 1.0, 10.0 and 30.0a
TF vs. M (s.c.) - Inactive at 1.0, 10.0 and 30.0b
PPQ (s.c.) - 15.1 (11.2 - 20.5)
HP (s.c.) - Inactive at 1.0, 10.0 and 30.0c
a
Mice were extremely excited and jumping at 10.0
and 30.0. Test latencies (MPEs) were shorter than
control latencies.
b
Increased locomotor activity and Straub tail at 10.0
and 30.0. Clonic convulsions in 1 of 6 mice at
30.0. Also, tremors and ataxia noted.
c
At 30.0 mg/kg ataxia increased locomotor activity
and Straub tails were noted. Latencies (MPEs)
where shorter than control.
MONKEY DATA
(SDS)
As shown in the accompanying fig., NIH 10839 did not substitute for morphine or exacerbate withdrawal at doses
of 2 and 8 mg/kg. A number of signs designated slowing, ataxia, chewing, eyelid ptosis, disorientation, walking in
circles were noted at both doses.
Comment: It is unlikely that NIH 10839 has mu or kappa-like properties. The drug displays prominent CNS
effects in mice and monkeys. Some of the signs noted in monkeys suggest PCP-like behavior.
Fig NIH 10839. Results of single-dose replacement of NIH 10839 for morphine in morphine-dependent monkeys
in withdrawal.
377
NIH 10840 1-Aminocydopropane carboxylic acid (ACPC)
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
1) TF - Inactive at 1.0 10.0 and 30.0
2) TF vs. M - Inactive at 1.0 10.0 and 30.0
3) PPQ - Inactive at 1.0, 10.0 and 30.0
4) HP - Inactive at 1.0, 10.0 and 30.0
MONKEY DATA
SDS
Study 1: At doses of 5 and 25 mg/kg, NIH 10840 neither suppressed nor exacerbated withdrawal (see Fig NIH
10840 ). No overt behavioral effects were seen at these doses.
Study 2: A single dose of 200 mg/kg s.c. was without effect in an abruptly withdrawn morphine-dependent
monkey. The dose was administered at 2 sites. Drug supply exhausted.
Comment: NIH 10840 does not display remarkable mu opioid suppressive properties in the monkey at 5 or 25
mg/kg. In the dose range tested in the mouse, NIH 10840 did not demonstrate antinociceptive properties.
Fig NIH 10840. Results of replacement of NIH 10840 for morphine in morphine-dependent monkeys in
withdrawal.
378
NIH 10841 D-Phenylalanine
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
1) TF (i.v)a - Inactive at 1.0, and 30.0, 14% at 10.0
(s.c.) Inactive at 1.0, 10.0 and 30.0
2) TF vs. M (i.v.)a - Inactive at 1.0, 10.0 and 30.0
(s.c.) Inactive at 1.0, 10.0 and 30.0
3) PPQ (i.v)a - 14% at 1.0, 11% at 10.0 and 23% at
30.0
(s.c.) 9% at 1.0 and 10.0, 51% at 30.0 and 37% at
30.0
4) HP (i.v.)a - Inactive at 1.0, 10.0 and 30.0
(s.c.) 13% at 1.0, 10.0 and 30.0
a
Vehicle-Sterile Saline
MOUSE DATA - ED50 OR AD50, mg/kg
(95% C.L.) or % change
1) TF (s.c.) - Inactive at 1.0, 10.0 and 30.0a
2) TF vs. M (s.c.) - Inactive at 1.0, 10.0 and 30.0a
3) PPQ (s.c.) - 9% at 1.0 and 10.0, 51% at 30.0,
37% at 60.0 a
4) HP (s.c.) - 13% at 1.0, 10.0 and 30.0a
a
Vehicle - Sterile water
Special Mouse Data
Special acute and chronic interaction studies of NIH 10841 with morphine in the tail-flick test.
A) Acute NIH 10841 (i.v.) Plus Morphine (s.c.)
Mice were given 30 mg/kg of NIH 10841 followed 10 min later by morphine. Latency measurements were
conducted 20 min later (see Fig NIH 10841 Mouse Acute Treatment) .
B) Chronic (3 day) NIH 10841 Plus Morphine (s.c.)
Mice were given NIH 10841 i.v. or vehicle once a day for 3 days. On the third day, NIH 10841 was given 10 min
before morphine. Results were obtained 20 min later.
As shown in the figure (Fig NIH 10841 Mouse Chronic Treatment (i.v.), chronic treatment with NIH 10841
caused a suppression of morphine’s dose-response curve.
C) Chronic (3 days) NIH 10841 (s.c.) Plus Morphine (s.c.)
Essentially, the same procedure as described in B above was followed. except NIH 10841 was given subcutaneously
Results obtained are shown in Fig NIH 10841 Mouse Chronic Treatment (s.c.)
379
The results are consistent, but not as pronounced as those reported in B above.
Fig NIH 10841. Mouse Acute Treatment. Results of study on the effect of acute treatment of mice with NIH
10841 prior to receiving morphine. Note lack of suppression of morphine dose-response curve.
Fig NIH 10841. Mouse Chronic Treatment (i.v.). Results of study on the effect of chronic treatment of mice with
NIH 10841 prior to receiving morphine. Note suppression of morphine dose-response curve.
380
NIH 10841 (Continued)
Fig NIH 10841. Mouse Chronic Treatment (s.c.). Results of study on the effect of chronic treatment of mice with
NIH 10841 prior to receiving morphine. Note suppression of morphine dose-response curve.
MONKEY DATA
SDS
The data did not demonstrate or indicate that NIH 10841 suppressed withdrawal in morphine-dependent monkeys (see
Fig NIH 10841). Neither did it show significant exacerbation of withdrawal at either 9 or 45 mg/kg. Vehicle was
10% hydroxypropyl- -cyclodextrin in water.
Comment: It appears that given chronically, NIH 10841 suppressed morphine’s antinociceptive action. The action
appears non-competitive. The intravenous route is the most effective. Apparently, NIH 10841, per se, was without
significant opioid effect in the mouse and monkey studies.
381
NIH 10841 (Continued)
Fig NIH 10841. Results of study in which NIH 10841 was substituted for morphine in morphine-dependent
monkeys in withdrawal
NIH 10846 Dihydroetorphine•HCl
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 0.00015 (0.00006 - 0.0004)a
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0a,b
3) PPQ - 0.0002 (0.00005 - 0.0008)
4) HP - 0.0001 (0.00005 - 0.0003)a
a
5% hydroxypropyl- -cyclodextrin in water
At 10 and 30 mice convulsed and lost their righting reflex
b
1. Special Test: Nalxone AD50 vs ED80 of NIH 10846 in TF = 0.04 (0.01 - 0.08)
2. Special Time-Course Study: Dihydroetorphine’s half-life (in Table 1) is estimated to be 40 min.
382
NIH 10846 (Continued)
Table 1. Time-course study for the ED80 of NIH 10846 in the tail-flick test.
% Inhibition of Nociception ± SEM
Pretreatment Time (min)
77 ± 13
41 ± 10
4±2
1 ± 0.8
20
40
60
90
3. Special Test: Naloxone vs DHE pA2 in TF = 6.65 (5.79 - 7.51) Slope - 0.93. When the slope is constrained to
- 1, the pA2 is 6.5 (6.3 - 6.8).
In mice DHE and etorphine have similar and short durations of action compared with morphine. The apparent pA2s
for naloxone versus DHE or ET are also similar to but lower than that calculated for morphine (see Table 3 in
Introduction).
4. Interaction of opioid agonist and antagonist subtypes in mouse T.F. test
Table 1. The interaction of NM 10846 (dihydroetorphine) (DHE) with selective opioid antagonists subtypes in the
mouse T.F. test.
383
NIH 10846 (Continued)
MONKEY DATA
A. SDS
NIH 10846 dose-dependently substituted for morphine at doses of 3 x 10-5 and 15 x 10-5 mg/kg. There was a
subjective feeling that the onset of action was slightly delayed. Duration appeared similar to that of morphine.
Potency estimates is at least 20,000 x morphine. Some drowsiness, slowing, and sagging were noted at the high
dose.
Comment: The drug has a profile of activity commonly associated with mu agonists. The potency is impressive.
Activity was noted in the potency range of 20.000 to 100.000 x morphine. Comments regarding primary physical
dependence in monkeys may be found under PPD below.
MONKEY DATA
B. PPD
Initially, dihydroetorphine produced the usual agonist behavioral signs asssociated with the administration of opiates
to non tolerant subjects such as body sag, ataxia, slowing, ptosis, and scratching. Because dihydroetorphine had a
relatively short duration of action, the frequency of injections was increased from every 6 h to 6 times a day on
weekdays (at 6, 10 and 12 a.m. and 2.6 and 12 p.m.). On day 8, when the dose had been raised to 1,200 ng/kg, one
monkey lost consciousness for a brief period. The following day, 2 monkeys lost consciousness briefly. As a result,
the dose was reduced to 600 ng/kg at the noon injection. Fewer agonist signs were noted at the lowered dose
indicating some tolerance had developed.
On day 16, approximately 2 h after the 6 AM injection of DHE, the monkeys were challenged with naloxone (0.05
mg/kg/s.c.). This dose would normally precipitate a severe withdrawal syndrome in morphine-treated monkeys
receiving 3 mg/kg every 6 4 for at least 90 days (Aceto et al., 1977). However, naloxone was ineffective. One-half h
later, the dose of naloxone was raised by a factor of 10 and the monkeys were challenged again. As described in
Table 4, a very mild withdrawal syndrome developed. Nevertheless, two critically important withdrawal signs were
not seen; namely, rigid abominal muscles and vocalization associated with palpation of the abdomen. We concluded
that only a very mild degree of physical dependence had developed. After the precipitated withdrawal test was
conducted, dihydroetorphine was given and the dose was raised to 900 ng/kg. The usual agonist signs were recorded
The following day the dose of DHE was raised to 1,200 ng/kg and maintained at that level until day 21 when loss
of consciousness was again observed in 2 monkeys. The dose was reduced to 900 ng/kg for the remainder of the
study. Agonist signs were noted throughout this period.
On day 31, the monkeys were again challenged with a very high dose (0.55 mg/kg s.c.) of naloxone. Only a very
mild withdrawal syndrome was elicited. DHE was abruptly withdrawn (Abrupt Withdrawal) on day 41 and the
animals were evaluated for signs of withdrawal. Again, very mild withdrawal behavior was noted. Sixteen h after
abrupt withdrawal (day 42), dihydroetorphine (900 ng/kg) was again administered and 0.5 4 later, the monkeys were
challenged for the third time with naloxone (0.55 mg/kg s.c.). Wet-dog shakes were elicited in only 1 of 5 subjects.
Interestingly, during the 0.5 h-observation period, some DHE agonist signs were still evident. Throughout the study
no remarkable body weight changes were observed (Data not shown.).
384
NIH 10846 (Continued)
MONKEY DATA (Preliminary Study)
C. Chronic Replacement of DHE for Morphine and Subsequent Abrupt and Precipitated Withdrawal Studies
NIH 10846 was substituted for morphine in 3 maximally-dependent monkeys for 7 days. It substinned completely
for morphine during this interval at a dose of 0.00006 mg/kg 4 x per day. Fifteen h after DHE was withdrawn,
some abstinence signs were apparent (see Table 4). However, the incidence and number of abstinence signs are
considered low. One day later, 2 h after DHE (0.00006 mg/kg), the monkeys were challenged with a dose of 0.05
mg/kg of naloxone, a dose which would have precipitated a full-blown abstinence syndrome. Few signs (as shown
in table) were observed during a 1/2 h observation period. The monkeys wee challenged a second time with a
double dose of naloxone (0.1 mg/kg) and again only a few abstinence signs were noted. Additionally, at the end of
the experiment the monkeys were again treated with the usual regimen of morphine (3.0 mg/kg) some of the
animals were scratching. The results suggest that DHE alters the course of tolerance and physical dependence on
morphine and may be useful in the therapy of opioid abuse in human addicts.
Table 4. Signs observed in three morphine-dependent monkeys IN whom NIH 10846 was substituted for 7 days and
then subjected to precipitated withdrawal.
a
Denotes number responding of possible 3. It should be noted that one monkey expired
six days after experiment was completed On gross necropsy the monkey appeared to have abnormal kidneys.
b
Naloxone 0.05 mg/kg as initial dose.
Naloxone 0.10 mg/kg after 1/2 hr.
Numbers in parentheses denote total number of signs observed during 2.5 h observation
of abrupt withdrawal and during 30 m precipitated withdrawals 1 and 2.
NM 10860 (-)-5.9 -Dimethyl-2-heptyl-2’-propionoxy-6,7-benzomorphan.HCl
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 3.13 (1.55 - 6.30)a
2) TF vs. M - Inactive at 1.0. 10.0 and 30.0a
3) PPQ - 0.31 (0.07 - 1.3)a
4) HP - 5.5 (3.5 - 8.8)a
a
Vehicle - 2.5% Hydroxypropyl- -cyclodextrin in water
385
NIH 10860 (Continued)
MONKEY DATA
(SDS)
As shown in Figure NIH 10860, this compound produced a dose-related but non-significant reduction in withdrawal
signs at 2 and 8 mg/kg. One monkey convulsed and died 5 m after receiving 12 mg/kg. Vehicle was 10%
hydroxypropyl- -cyclodextrin in water.
Comment: Results in mice suggest an opioid profile of activity. Because the drug produced convulsions and was
lethal, higher doses were not investigated in me monkey. Perhaps this compound is a delta agonist.
Fig NIH 10860. Results of study involving the substitution of a single dose of NIH 10860
in morphine-dependent monkeys in withdrawal.
NIH 10864 (+)-5,9 -Dimethyl-2’-hydroxy-2-(2-hydroxyethyl)-6,7-benzomorphanoxalate
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - Inactive at 1.0, 10.0 and 30.0a
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0a
3) PPQ - Inactive at 1.0, 14% at 10.0 and 26% at 30.0a
4) HP - 13% at 1.0, 25% at 10.0 and 20% 30.0 a
a
Vehicle - 2.5% hydroxypropyl- -cyclodextrin
in water
386
NIH 10864 (Continued)
MONKEY DATA
(SDS)
NIH 10864 neither substituted for morphine nor exacerbated withdrawal at doses of 3 and 12 mg/kg (see Fig NIH
10864). Vehicle was 10% hydroxypropyl- -cyclodextrin in water.
Comment: Apparently, NIH 10864 was without significant opioid effect in me mouse and monkey studies.
Pig NIH 10864. Results of study involving the substitution of a single dose of NIH 10864 in morphine-dependent
monkeys in withdrawal.
NIH 10867 7-Nitroindazole
(7-Nitro-1H-indazole)
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF- 6% at 1.0, 1% at 10.0 and 4% at 30.0 a
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0a
3) PPQ - Inactive at 1.0, 46% at 10.0 and 51% at 30.0a
4) HP - Inactive at 1.0, 13% at 10.0 and 25% at 30.0a
a
Vehicle - 20% hydroxypropyl- -cyclodextrin-15%
Tween 80 in water
387
NIH 10867 (Continued)
MONKEY DATA
(SDS)
Not tested Drug supply exhausted
Comment: NIH 10867 is not active antinociceptively and apparently lacks opioid properties.
NIH 10870 (+)-Cyanomethyl-5.9a-dimethyl-2’-hydroxy-6,7-benzomorphan.HCl
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 5% at 1,6% at 10 and 12% at 30a
2) TF vs. M - Inactive at 1, 10 and 30
3) PPQ - 6.0 (4.2 - 8.4)b
4) HP - Inactive at 1 and 10, and 30a,b,c
a
Loss of righting reflex al 30
ataxia at 10,
c
popcorn convulsions (6 of 8) and difficulty in
breathing in all; at 30, 1 of 8 died.
b
MONKEY DATA
(SDS)
NIH 10870 produced a dose related and significant reduction in withdrawal signs at 0.25 and 1.0 mg/kg (see Fig
NIH 10870). However, suppression at the higher dose was accompanied by the signs designated as slowing,
ataxia and eyelid ptosis. In addition, in the preliminary study, in one monkey receiving a cumulative dose of 5.5
mg in 45 min, profuse salivation and severe ataxia were noted.
Comment: The results in the mouse and monkey are at variance. In the monkey, kappa opioid activity is
suspected.
388
NIH 10870 (Continued)
Fig NIH 10870. Results of study in which NIH 10870 was substituted for morphine in morphine-dependent
monkeys in withdrawal,
NIH 10871 (-)-2-(Chloropentyl)-5,9 -dimethyl-2’-bydroxyd,7-benzomorphan•HCl
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 0.84 (0.43 - 1.63)
2) TF vs. M - inactive at 1, 10 and 30
3) PPQ - 0.5 (0.25 - 1.0)
4) HP - 3.6 (2.3 - 5.8)a
a
Vehicle - 5% Hydroxypropyl- -cyclodextrin in water
Straub tails and increased locomotor activity at 6
and 10
b
389
NIH 10871 (Continued)
MONKEY DATA
(SDS)
NIH 10871 significantly suppressed withdrawal for about 90 m at the high dose (see Fig NIH 10871). Onset was
rapid and offset was short Vehicle was 10% hydroxypropyl- -cyclodextrin in water.
Comment: The profile of activity for NIH 10871 in mice and in monkeys was typical of a morphine-like drug.
Fig NIH 10871. Effects of NIH 10871 acutely substituted for morphine in dependent monkeys in withdrawal.
NIH 10884 (-)-2-(3-Cyanopropyl)-5,9a-dimethyl-2’hydroxy-6,7-benzomorphan
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 0.36 (0.18 - 0.72)a
2) TF vs. M - Inactive at 1, 10 and 30a
3) PPQ - 0.1 (0.05 - 0.27)a
4) HP - 1.1 (0.37 - 3.4)a
a
Vehicle was lactic acid in water.
390
NIH 10884 (Continued)
Special Test: Naloxone AD50 vs NIH 10884 ED80 in TF = 0.28 (0.12 - 0.67)
MONKEY DATA
(SDS)
A non dose-related reduction of withdrawal signs (see Fig NIH 10884) accompanied by jaw sag, ataxia, salivation
and sagging in some of the monkeys at the high dose was the signature of NIH 10884. However, the drug did not
completely substitute for morphine.
Comment: The relatively high naloxone AD50 in mice and the results in monkeys suggest heterogenous opioid
properties.
Fig NIH 10884. Results of study involving the single-dose substitution of NIH 10884 for morphine in morphinedependent monkeys in withdrawal.
NIH 10885 (+)-2-(3-Cyanopropyl)-5,9a-dimethyl-2’hydroxy-6,7-benzomorphan
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - Inactive at 1,13% at 10,9% at 0a
2) TF vs. M - Inactive at 1, 10 and 30a
3) PPQ - 3% at 1.9% at 10 and 60% at 30a
4) HP - Inactive at 1, 10 and 30a
a
Vehicle - 1 drop Lactic acid + water
391
NIH 10885 (Continued)
MONKEY DATA
(SDS)
As shown in Fig NIH 10885. at doses of 4 and 16 mg/kg, NIH 10885 non-dose dependently attenuated withdrawal.
At both doses, behavioral signs designated jaw sag, slowing and ptosis were noted. Salivation was also observed at
the high dose.
Comment: The mouse data and monkey data suggest that NIH 10885 is devoid of opioid properties. The
attenuation of withdrawal signs is probably associated with nonspecific CNS/and autonomic properties. Vehicle
was dilute HCl in water.
Fig NIH 10885. Results of study in which single doses of NIH 10885 were substituted for morphine in morphinedependent monkeys in withdrawal.
NIH 10886 (±)-Isonicotin•oxalate
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - Inactive at 1 and 10, 17% at 30
2) TF vs. M - Inactive at 1.10 and 30
3) PPQ - 3.24 (1.18 - 8.89)
4) HP - Inactive at 1 and 10.25% at 30
392
NIH 10886 (Continued)
MONKEY DATA
(SDS)
As indicated in Fig. NIH 10886, at doses of 3.0 and 12.0 mg/kg, NIH 10886 neither substituted for nor exacerbated
withdrawal. The number of withdrawal signs seen with the vehicle controls were abnormally low.
Comment: The results obtained with NIH 10886 provide little evidence that it has opioid properties. Slight
activity was noted in the paraphenylquinone and hot plate tests at 30 mg/kg.
Fig NIH 10886. Results of study in which NIH 10886 in single doses was substituted for morphine in morphinedependent monkeys in withdrawal.
NIH 10887
-Conotoxin MVIIA (reduced, cyclic (1-16), (8-20), (15-25))
H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-CysSex-Arg-Leu-Met-Tyr-Asp-Cys-Cys-DirGly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2
cyclic (1-16), (8-20), (15-25)-tris(disulfide)
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 17.7 (11.0-28.2)a Intravenously
2) TF vs. M - Not Tested
3) PPQ - 3.16 (1.0 - 9.7)a Intravenously
4) HP - Not Tested
a
Clonic convulsions and eyelid ptosis at 20 and 30
393
NIH 10887 (Continued)
MONKEY DATA
(SDS) Intravenuously
NIH 10887 produced a dose-related reduction of withdrawal signs (see Fig NIH 10887). However, it never
substituted completely for morphine. Drug supply precluded testing higher doses. Additionally, eyelid ptosis was
noted in all monkeys at both doses and jaw sag was seen in one monkey receiving the high dose. Vehicle was
sterile saline solution.
Comment: There is insufficient data to characterize this drug. It may have opioid properties.
Fig NIH 10887. Results of study involving single-dose substitution of NIH 10887 for morphine in morphinedependent monkeys in withdrawal.
NIH 10895 (-)-Isonicotine•dioxalate
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 3% at 1.8% at 10 and 32% at 30a
2) TF vs. M - Inactive at 1, 10 and 30
3) PPQ - 3.80 (1.99 - 7.30)
4) HP - Inactive at 1.38% at 10 and 38% at 30
a
Mobility diminished at 10 and 30.
394
NIH 10895 (Continued)
MONKEY DATA
(SDS)
As shown in the figure, NIH 10895 produced a non-dose related attenuation of withdrawal signs. The effect was not
remarkable.
Cornment: NIH 10895 did not provide results indicative of opioid properties. The only biological activity noted
was in the paraphenylquinone antinociceptive test.
Fig NIH 10895. Results of a study involving the single-dose substitution of NIH 10895 for morphine in
morphine-dependent monkeys in withdrawal.
NIH 10896 (+)-Isonicotine•oxalate
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 3% at 1, 11% at 10 and 64% at 30a
2) TF vs. M - Inactive at 1, 10 and 30
3) PPQ - 1.63 (0.57 - 4.70)
4) HP - Inactive at 1, 13% at 10 and 13% at 30
a
Mobility diminished at 10 and 30
395
NIH 10896 (Continued)
MONKEY DATA
(SDS)
NIH 108% neither substituted for morphine nor examined withdrawal at doses of 2.5 and 10.0 mg/kg (see Fig
NIH 108%).
Comment: Except for some antinociceptive activity in the pataphenylquinone test, the results with NIH 10896 in
mice and monkeys were not rermarkable. This compound produced little evidence regarding opioid activity.
Fig NIH 108%. Results of single-dose substitution of NIH 10896 for morphine in morphine-dependent monkeys
in withdrawal.
NIH 10897 (-)-(6-Chlorohexyl)-5.9 -dimethyl-2’-hydroxy-6,7-benzomorphan•HCl
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 2.03 (1.16 - 3.57)
2) TF vs. M - Inactive at 1, 10 and 30a,b
3) PPQ - 0.67 (0.33 - 1.35)a
4) HP - 1.59 (0.87 - 2.92)
a
Vehicle - 5% hydroxypropyl- -cyclodextrin in
water.
At 10 mg/kg decreased locomotor activity.
396
NIH 10897 (Continued)
Special Test: Naloxone AD50 vs ED80 of NIH 10897 in TF = 0.02 (0.01 - 0.04)a
MONKEY DATA
(SDS)
Both doses appeared equally effective in nearly suppressing withdrawal in morphine-dependent monkeys (see Fig
NIH 10897). At the high dose, ataxia slowing, and pale faces were noted. Lower doses might provide a dose
response relationship. The compound acts quickly and has a duration of action at least as long as that of morphine.
Potency cannot be determined on the basis of the data available. However, it is probably greater than that of
morphine.
Comment: Based on the results in mice and monkeys, it is concluded that NIH 10897 appears to have mu-opioid
properties.
Fig NIH 10897. Results of study involving the substitution of single doses of NIH 10897 for morphine in
morphine-dependent monkeys in withdrawal.
397
NIH 10898 2S ,5S ,9S -(+)-2-(6-Chlorohexyl)-5-9 -dimethyl-2’-hydroxy-benzomorhan•HCl
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - 11.56 (4.00 - 33.37)a
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0a
3) PPQ - 5.32 (2.92 - 9.68)
4) HP - Inactive at 1.0, 38% at 10.0 and 50% at 30.0a
a
5% hydroxypropyl- cyclodextrin in water
MONKEY DATA
(SDS)
This compound did not substitute for morphine (see Fig NIH 10898) at doses of 3 and 12 mg/kg. At the high dose,
2 monkeys convulsed. The convulsions were quickly terminated using pentobarbital (30 mg, i.p.). The vehicle
was 10% hydroxypropyl- -cyclodextrin in water.
Comment: Although some antinociception was observed in the mouse, mu opioid activity was probably not a
significant factor in either species.
Fig NIH 10898. Results of study involving the substitution of NIH 10898 for morphine in morphine-dependent
monkeys in withdrawal.
398
NIH 10900 11-[4-Hydroxy-4(3-triflouromethylphenyl)-piperidin-1-yl]-2-methyl-6,11-dihydrobenz[b,e]oxepine
sulfuric acid
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
A. Subcutaneously
1) TF - Inactive at 1.0, 10.0 and 30.0
B. Subcutaneously
1) TF vs. M - Inactive at 1.0, 10.0 and 30.0
2) PPQ - 9% at 1.0, 23% at 10.0 and 39% at 30.0
3) HP - Inactive at 1.0, 10./0 and 30.0
C. Orally (20 min pretreatment)
1) TF - 7% at 1.0, 14% at 10.0 and 12% at 30.0
D. Orally (40 min pretreatment)
1) TF - 7% at 1.0, 14% at 10.0 and 57% at 30.0
MONKEY DATA
SDS
As shown in the Figure NIH 10900, the drug produced a non-dose-related suppression of withdrawal signs. It
should be noted that the results of the high dose are not significantly different from those of vehicle (7%
hydroxypropyl- -cyclodextrin in water). The small number of subjects preclude a definite conclusion in this study.
Insufftcient supplies prevented additional testing.
Comment: The results suggest that NIH 10900 has a delayed onset of action in the mouse. Possibly, it is a pro
drug. Taken together, these results in both species indicate weak, if any, mu opioid activity.
399
NIH 10900 (Continued)
Fig NIH 10900. Results of study involving the substitution of single doses of NIH 10900 for morphine in
morphine-dependent monkeys in withdrawal.
NIH 10901 11-(4-Hydroxy-4-phenylpiperidin-l-yl)-2-methyl-6,11-dihydrodibenz[b,e]oxepine
fumaric
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
A. Subcutaneouslya
1) TF - Inactive at 1.0, 10.0 and 30.0
B. Subcutaneouslya
1) TF vs. M - Inactive at 1.0, 10.0 and 30.0
2) PPQ - 7.6 (3.7 - 15.4)
3) HP - Inactive at 1.0, 10./0 and 30.0
C. Orally (20 min pretreatment)
1) TF - 5% at 1.0, 9% at 10.0 and 45% at 30.0
D. Orally (40 min pretreatment)
1) TF - 0% at 1.0, 8% at 10.0 and 25% at 30.0
a
2.5% Hydroxypropyl- cyclodexodextrin in water
400
acid
NIH 10901 (Continued)
MONKEY DATA
(SDS)
Because drug supply was exhausted, a complete evaluation could not be conducted. The results shown in the figure
suggest that NIH 10901 substituted for morphine. Onset was slow and duration of action was 90-120 min. Potency
was estimated at 1/5 that of morphine. Vehicle was 10% hydroxypropyl- -cyclodextrin in water.
Comment: NIH 10901 does not show significant antinociceptive activity in the TF or HP tests when given s.c.
Neither does it show remarkable activity when given orally with pretreatment times of 20 or 40 min. Some
antinocicepcive activity was observed in the PPQ test. Possible opioid activity is suggested in the morphinedependent monkey.
Fig NIH 10901. Results of replacement study involving NIH 10901. Single doses of NIH 10901 were substituted
for morphine in morphine-dependent monkeys in withdrawal.
401
NIH 10902 11-[4-Hydroxy-4-(trifluoromethylphenyl)piperidin-l-yl]2-hydroxymethyl]2-hydroxymethyl-6,11 dihydrodibenz[b,e]oxepine fumaric acid
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
A. Subcutaneously
1) TF - 12.86 (6.28 - 26.33)
2) TF vs. M - Inactive at 1.0, 10.0 and 30.0
3) PPQ - 1.13 (0.45 - 2.88)
4) HP - 2.4 (1.1 - 5.0)
B. Orally a (20 min pretreatment)
1) TF - 1.0 (0.4 - 2.5)
C. Orally a (40 min pretreatment)
1) TF - 0.98 (0.28 - 3.40)
a
Vehicle - 5% hydroxypropyl- -cyclodextrin in water
Special Test: Naloxone AD50 vs ED80 of NIH 10902 in TF = 0.12 (0.06 - 0.24)
MONKEY DATA
(SDS)
As shown in Fig NIH 10902, this compound dose-dependently substituted for morphine. Onset was rapid and
duration of action was at least 2.5 h. At the high dose, the signs scratching, sagging, slowing, salivation and
yawning were noted. Vehicle was 10% hydroxypropyl- -cyclodextrin.
Comment: The compound appears to be a pro drug in the mouse. The relatively high AD50 for naloxone coupled
with salivation in the monkey suggested that NM 10902 may possess heterogenous opioid activity.
402
3NIH 10902 (Continued)
Fig NIH 10902. Results of single-dose substitution of NIH 10902 for morphine in morphine-dependent monkeys
in withdrawal.
NIH 10903 11-(4-Hydroxy-4-phenylpiperidin-l-yl)-2-hydroxymethyl-6,11-dihydrodibenz(b,e]oxe-pine fumaric
acid
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
A. Subcutaneously a
1) TF - 1.1 (0.45 - 2.76)
B. Subcutaneouslya
1) TF vs. M - Inactive at 1.0, 10.0 and 30.0
2) PPQ - 0.6 (0.4 - 1.0)
3) HP - 2.2 1.2 - 4.2)
C. Orallya (20 min pretreatment)
1) TF - 1.0 (0.45 - 2.5)
D. Orallya (40 min pretreatment)
1) TF - 0.98 (0.28 - 3.40)
a
15% Hydroxypropyl- cyclodcxtrin in water
403
NIH 10903 (Continued)
Special Test: Naloxone AD50 vs ED80 of NIH 10903 in TF = 0.06 (0.03 - 0.12)
MONKEY DATA
(SDS)
As shown in the Figure NIH 10903, this drug dose-dependently substituted completely for morphine in the dose
range of 0.2 to 0.8 mg/kg s.c. Onset was prompt and offset was about 2 h. Potency is estimated as 3 x that of
morphine. Eyelid ptosis was noted in one monkey at the high dose. Vehicle was 25% hydroxypropylcyclodextrin in water.
Comment: Given subcutaneously or orally and at 20 min or 40 min before testing, NIH 10903’s effects are the
same. The naloxone AD50 and the results in monkeys suggest that NIH 10903 is a mu agonist and its potency in
monkeys is approximately 3 x that of morphine.
Fig NIH 10903. Results of study involving the substitution of single doses of NIH 10903 for morphine in
morphine-dependent monkeys in withdrawal.
404
NIH 10917 (+)-2,3,3a,4,5,9b-Hexahydro-1-methyl-1H-pyrrolo[3,2-h]-isoquinoline•HBr (+)-Bridged Nicotine
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
Special: 5 mm Pretreatment
1) TF - 4.1 (1.7 - 9.8)
2) TF vs. M - Inactive at 0.1, 1.0 and 10.0b
3) PPQ - 1.6 (0.6 - 4.1)
4) HP - 3.1 (1.6 - 6.0)
a
Convulsions at 10.0 and 20.0 mg/kg
Convulsions at 10.0 mg/kg
b
Special Tests: 1) Naloxone AD50 vs ED80 of NIH 10917 in TF: 2% at 0.1, 24% at 0.3, 62% at 1.0, 37% at 3.0
and 41% at 10.0.
2) Mecamylamine AD50 vs ED80 of NIH 10917 in PPQ: 0% at 5 and 10.0 mg/kg.
3) Mecamylamine AD50 vs ED80 of NIH 10917 in HP: 0% at 1.0 and 10.0 mg/kg.
MONKEY DATA
(SDS)
Not tested.
Comment: This is a (+)-“bridged nicotine” with antinociceptive properties similar to those of nicotine. However,
mecamylamine was ineffective in suppressing antinociception in the TF and PPQ tests.
NM 10918 (-)-2,3.3a,4,5,9b-Hexahydro-1-methyl-1 H-pyrrolo[3,2-h ]-isoquinoline-2HBr (-)-Bridged Nicotine
MOUSE DATA - ED50 OR AD50
(95 % C.L.) (mg/kg or % change)
1) TF - Inactive at 1.0 and 10.0; 8% at 30.0
2) TF vs. M 3) PPQ - 11% at 1.0, 14% at 10.0 and 57% at 30.0
4) HP - 0% at 1.0, 13% at 10.0 and 38% at 30.0
MONKEY DATA
(SDS)
Not tested.
Comment: Surprisingly, this (-)-“bridged nicotine” did not show antinociceptive activity. See NIH 10917 the (+)enantiomer.
405
ACKNOWLEDGMENTS:
This study was was supported by contracts DA 3-8200 and DA 5-8059 from the National Institute on Drug Abuse.
We also acknowledge the expert assistance of Susan M. States, Larry D. Hughes and Zhen Ji.
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Seevers, M.H. and Deneau, G.A. Physiological aspects of tolerance and physical dependence. In: Root, W.S. and
Hofman, F.G., eds. Physiological Pharmacology, Vol. I. New York: Academic Press, 1963. pp. 565-570.
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Tallarida, R.J. and Murray, R.B. Manual of pharmacological calculations with computer programs. Second
Edition: New York: Springer-Verlag, 1987. pp. 53-56.
Teiger, D.G. Induction of physical dependence on morphine, codeine, and meperidine in the rat by continuous
infusion. J Pharmacol Exp Ther, 190:408-415, 1974.
407
EVALUATION OF NEW COMPOUNDS FOR OPIOID ACTIVITY (1997)
J. H. Woods, F. Medzihradsky, C. B. Smith, G. Winger, and J. R. Traynor
Department of Pharmacology, University Michigan Medical School, Ann Arbor, MI
This report contains information on opioid abuse liability evaluations on compounds that have been submitted to the
Drug Evaluation Committee of the College and released for publication by the submitters. The information obtained
can involve both in vitro evaluation in opioid binding assays and smooth muscle preparations. In addition, the
compounds may be evaluated for discriminative and reinforcing effects. Analgesic and respiratory function assays are
also possible. These behavioral assessments are conducted in rhesus monkeys. Each of these assays is described below.
Usually when limited information is provided (e.g., in vitro assessment only), it is because the sample provided by the
submitter was insufficient to carry out further evaluation.
The evaluation of new compounds by the programs at the University of Michigan and the Medical College of Virginia
is coordinated by Dr. Arthur E. Jacobson, Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health,
Bethesda, MD. The compounds, which come originally from pharmaceutical companies, universities, government
laboratories, and international organizations are submitted to Dr. Jacobson.
At the UM and MCV laboratories, drug samples arrive from Dr. Jacobson with only the following information: (1) an
identifying NIH number, (2) molecular weight, (3) solubility information and (4) a recommended starting dose. After
the evaluation is complete and the report submitted to Dr. Jacobson, the submitter is requested to release the chemical
structure to include with the evaluation data in the ANNUAL REPORT. The submitter has up to three years before
release of the structure is required. When the structure is released all of the data on the compound are reported herein
DRUG DISCRIMlNATION IN RHESUS MONKEYS
We currently use three groups of monkeys to test the discriminative stimulus effects of submitted drugs: one of these
groups discriminates the administration of the agonist ethylketazocine (EKC); a second group discriminates the µ
agonist alfentanil or fentanyl; a third group is treated daily with morphine and discriminates the opioid antagonist
naltrexone.
The procedures used with the EKC-trained monkeys have been described by Bertalmio et al. (1982). The monkeys are
removed from their home cages each day and seated in primate restraining chairs. These chairs are placed in chambers
equipped with two response levers, several stimulus lights and a cup to receive Noyes, banana-flavored pellets. These
monkeys are required to make 100 consecutive responses on the correct one of the two levers and receive ten 300-mg
food pellets. The right lever is correct if they were given a subcutaneous injection of 0.0032 mg/kg EKC immediately
prior to the start of the cycle. The left lever is designated correct if they were given a sham injection before the start
of the cycle. Each cycle lasts 15-min and consists of an initial 10-min black out period followed by a period of as long
as 5 min, during which a blue light is illuminated in the chamber and the monkey can respond for food. If the food
pellets are delivered before the 5 min period is completed, the lights are extinguished for the remainder of this time.
Typically, a daily session consists of several 15 min cycles. During a training session, if EKC is given, it is given on
the penultimate cycle of that session. Responding on the drug-appropriate lever is reinforced during that cycle and on
the subsequent, final cycle of the day. These last two cycles may be preceded by from zero to four sham cycles on a
training day. A training session of six sham cycles is also scheduled from time to time.
With this type of multiple, discrete-cycle training, the animals can be tested with a cumulative dosing procedure. On
a test session, the first cycle is preceded by an injection of saline, and prior to subsequent cycles, increasing, cumulative
doses of the test drug are administered. One hundred consecutive responses on either lever are reinforced throughout
the test session. The test drug is administered in increasing doses until the monkey either responds on the drug-
408
appropriate lever, the response rate falls to less than half of the saline-control rate, or six cycles are given. In the latter
situation, it is assumed that the selected dose range is too low, and the test is continued at higher doses on the next test
session. Each test session is preceded and followed by a training session. The criterion for satisfactory performance
must be met on each training session that is followed by a test session. This criterion is that at least 90% of the
responses during each cycle of a training session must be on the injection-appropriate lever, either sham or EKC.
The procedure for the alfentanil-trained monkeys is similar, but not identical. These are are also named and tested
in a discrete, multiple-cycle procedure. The main difference between the alfentanil procedure and the EKC procedure
is that the alfentanil monkeys are required to make 20 rather than 100 responses, and they receive a single pellet for
correct responses. They can receive as many as 10 pellets during the 5-min, food-availability period of each cycle, but
each pellet is delivered after 20 responses. Because in this procedure, monkeys can switch from one lever to another
following the delivery of food. an additional criterion is added for satisfactory performance. In addition to making 90%
or more of their responses on the correct lever, the monkeys must make fewer than 20 responses on the incorrect lever
prior to delivery of the first food pellet of each cycle. Tests of the discriminative stimulus effects of submitted drugs
in the alfentanil-trained monkeys are also done using a cumulative dosing procedure with dosing criteria identical to
those used in the EKC-trained monkeys.
The procedure for studying discriminative stimulus effects in morphine-treated monkeys has been described previously
(France and Woods, 1989). Daily sessions are comprised of a 10-min time out during which lever presses have no
programmed consequence and a 5-min response period during which green stimulus lights are illuminated and signal
the activation of a schedule of stimulus-shock termination. Sessions consist of between two and six discrete. 15-min
cycles with each cycle. Under these experimental conditions electric shock is scheduled to be delivered to the subject’s
feet every 15 seconds; monkeys can terminate the lights and postpone scheduled shocks for 30 seconds by pressing five
times consecutively (i.e., fixed-ratio 5) the lever appropriate for the solution administered during the first minute of the
time out (left lever, saline; right lever, naltrexone). Monkeys receive an injection of saline (0.1 ml/kg) or drug (0.01
mg/kg naltrexone) during the first minute of each time out. On drug training days a single injection of naltrexone is
administered during one tune out and for that cycle and all subsequent cycles on that day only responding on the right
lever postpones shocks. A variable number of saline cycles (0-5) precede the naltrexone cycle and on some days saline
is administered during the time out of all cycles. Under these conditions monkeys switch their response choice from
the saline lever to the naltrexone lever with complete generalization occurring in all three subjects at a dose of 0.01
mg/kg. Responding on the naltrexone lever is accompanied by other behavioral effects indicative of opioid withdrawal
(e.g., irritability, miosis, salivation). Moreover, when saline is substituted for the daily injection of 3.2 mg/kg of
morphine monkeys respond predominantly on the naltrexone lever and show directly observable signs of withdrawal;
the discriminative stimulus and other effects produced by morphine abstinence are reversed by some opioid agonists
(e.g., alfentanil; France and Woods, 1989; France et al., 1990).
For test sessions increasing doses of drug are administered during the first minute of consecutive time outs and five
consecutive responses on either lever postpone shocks. In monkeys that receive 3.2 mg/kg of morphine 3 hours earlier,
increasing doses of a test compound are administered up to doses that produce an average of at least 80% responding
on the naltrexone lever or to doses that disrupt responding and result in the delivery of electric shock. Drugs that do
not substitute for naltrexone (i.e., precipitate withdrawal) are also studied for their ability to reverse responding on the
naltrexone lever in morphine-abstinent (i.e., withdrawn) subjects. Test compounds are studied using a cumulativedosing procedure in morphine-abstinent monkeys up to doses that reverse completely responding on the naltrexone lever
(<20%) or to doses that disrupt responding. Some compounds that substitute for naltrexone also are studied for their
capacity to prevent the effects of cumulative doses of opioid agonists. Monkeys that receive saline three hours earlier,
rather than the daily injection of morphine, receive saline (control) or a single injection of test compound during the first
cycle and increasing doses of agonist (alfentanil or morphine) during subsequent cycles. Agonists are administered up
to doses that produce a switch from the naltrexone lever to the saline lever or to doses that disrupt responding and result
in the delivery of electric shock.
409
THERMAL ANALGESIA IN RHESUS MONKEYS
The tail withdrawal procedure used to study analgesic effects of test compounds in rhesus monkeys has been described
previously (Dykstra and Woods, 1986). Monkeys are restrained loosely at the neck and arms while seated in Plexiglas
primate chairs. For tests of tail withdrawal latency, the lower 10-12 cm of the shaved tail is immersed in a thermos
containing water at 40°, 50°, or 55° C and the latency until the tail is withdrawn from the thermos is recorded for each
monkey at each temperature. When the tail is not withdrawn within 20 seconds (cut-off latency) the experimenter
removes the thermos and a latency of 20 seconds is recorded. Experimental sessions begin with several exposures to
40°C water. Four or five monkeys are tested consecutively and the time between tail immersions for individual
monkeys is 5 minutes. Generally, 40° C water does not produce tail withdrawal in rhesus monkeys (Dykstra and
Woods, 1986); however, if a monkey fails to keep its tail in 40° C water for 20 seconds on at least 3 of 4 immersions,
that animal is not tested further for that particular session. In a subsequent pre-test component, tails are immersed in
40°, 50°, and 55° C water. The order in which the three temperatures are presented is varied among subjects. If the
latencies for tail withdrawal in the pre-test component are at or near 20 seconds for 40° C water and less than 5 seconds
for 55° C water, monkeys receive the test compound. The test is identical to the pre-test, except that monkeys receive
s.c. injections of drug 10 minutes prior to tail immersion. The time between immersions for individual subjects is 5
minutes or fess and the order in which temperatures are presented varies among subjects and across cycles. The
interinjection interval typically is 30 minutes and between four and six doses are studied in a single experiment using
the cumulative dosing procedure. For some studies a single dose of an opioid antagonist is administered prior to the
test compound and for other studies a single dose of test compound is administered prior to increasing doses of a µ (e.g.,
alfentanil) or (e.g., U-50,488) opioid agonist.
RESPIRATORY STUDIES IN RHESUS MONKEYS
The effects of test compounds on ventilatory function are studied in rhesus monkeys breathing air or 5% CO, in air
(France and Woods, 1990; Howell et al., 1988). Monkeys are restrained at the neck and waist while seated in a Plexiglas
primate chair. Normal air or 5% CO, in air is delivered at a rate of 10 l/min into a sealed helmet placed over the
subject’s head. Changes in pressure within the helmet are measured and recorded by a transducer and a microprocessor,
and are transformed according to known standards to frequency of respiration (f) in breaths/minute and to tidal volume
(VT) in ml/inspiration. Data are recorded continuously during 23-minute exposures to air alternating with 7-minute
exposures to CO,. The last 3 minutes of exposure to CO, are used for data analyses and are compared to the last 3
minutes of exposure to air only. Increasing doses of drug are administered during the first minute of consecutive time
outs so that the interinjection interval is 30 minutes. For some studies a single injection of an opioid antagonist is
administered prior to increasing doses of a test compound and for other studies a single injection of test compound is
administered prior to cumulative doses of a standard compound (e.g., alfentanil).
SELF-ADMINISTRATION BY MONKEYS
Tests of self-administration determine the ability of the drug to maintain responding in monkeys trained to self-inject
codeine. Each of at least three monkeys is studied with saline as a negative control and a number of doses of the test
compound until a maximum rate of responding was obtained or until, in the absence of evidence of a reinforcing effect,
observable changes in behavior are produced by the compound.
The schedule of intravenous drug delivery is a fixed-ratio 30; when a light above a lever is illuminated, the 30th
response produce an intravenous drug injection accompanied by another light that is illuminated during drug delivery.
After each injection, a 45 sec timeout period occurs. A component of the session ends after 20 injections have been
received or 25 min have passed, whichever occurs first. Different doses of the drug are available during each of four
components of a session. Other procedural details are given in Winger et al. (1989).
410
DISPLACEMENT OF RADIOLABELED LIGAND BINDING
Details of the binding assay based on the displacement of 3H-etorphine in rat brain membranes have been described
previously (Medzihradsky et al., 1984). Briefly, aliquots of a membrane preparation from rat cerebrum are incubated
with 3H-etorphine in the presence of 150 mM NaCI, and in the presence of different concentrations of the drug under
investigation. Specific, i.e., opioid-receptor-related interaction of 3H-etotphine is determined as the difference in binding
obtained in the absence and presence of an appropriate excess of unlabeled etorphine. The potency of the drugs in
displacing the specific binding of 3H-etorphine is determined from log-probit plots of the data. See table I for
representative results with different opioids.
TABLE I
EC50‘s of representative opioids for displacement of 0.5 nM 3H-etorphine from rat brain membrane, and inhibition of
the twitch of the mouse vas deferens preparation.
Compound
DPDPE
U50,488
Fentanyl
DAMGO
Etorphine
(-)Cyclazocine
Naltrexone
Bremazocine
UM 1071R**
Sufentanil
(-)SKF 10047
Ethylketazocine
Ketazocine
Morphine
DSLET
Dextrorphan
BINDING*
EC50 (nM)
MVD
5.52
6.29
36.2
23.9
0.37
0.53
0.63
1.42
1.55
1.60
3.93
6.60
14.1
23.6
43.0
<6000
37.1
81.3
0.0068
11.9
___
0.29
___
4.43
11.6
1.18
395
1.71
1010
* In the presence of 150 mM NaCl.
** IR-5R-9R-2”R-5,9-dimethyl-2’-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan
hydrochloride
To enhance the characterization of novel opioids, we are also investigating their selectivity in binding to µ-, -, and
opioid receptors in membranes from monkey brain cortex. Thus, we are now providing Ki values of the tested
compounds in displacing the following radiolabeled opioid ligands:
etorphine (nonselective, reflects opioid character).
sufentanil or Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAMGO); (µ selective),
[D-Pen2-D-Pen5]enkephalin (DPDPE; selective),
U-69,593 ( selective).
Using the receptor-specific assays, we have described the selectivity of various established opioids in brain membranes
of different species (Clark et al., 1988). The selection of monkey brain as the tissue for the selective binding assays
strengthens the correlation between this in vitro assessment and the behavioral evaluation of the tested compounds. In
411
the ANNUAL REPORT, the results of the selective binding assays are listed under “Binding in monkey brain cortex.”
See table II for representative results with different opioids in rat and monkey brain.
ISOLATED, ELECTRICALLY-STIMULATED MOUSE VAS DEFERENS PREPARATION
The development of new, highly selective antagonists such as the reversible receptor antagonist norbinaltorphimine
(Smith et al., 1989) and the competitive receptor antagonist ICI-174864 have made possible the evaluation of
selectivity of opioid agonists and antagonists by use of the mouse vas deferens preparation. Male, albino ICR mice,
weighing between 25 and 30 g, are used. The mice are decapitated, the vasa deferentia.
TABLE II
Inhibition of radiolabeled sufentanil, DPDPE and U69,593 binding in rat and monkey brain. In membranes from rat
cerebrum and monkey brain cortex, the inhibition of specific equilibrium binding of 0.5 nM [3H]sufentanil, 1.5 nM
[3H]DPDPE and 1.5 nM [3H]U69,593 by five different concentrations of the listed compounds was investigated in the
presence of 150 mM NaCl (modified from Clark et al., 1988).
Compound
[3H]Sufentanil
EC50 (nM)
[3H]DPDPE
13.2
1.25
31.4
6.99
1.29
6.37
0.60
1.07
1 .19
576
121
58900
7720
7230
38000
690
45.0
422
43.9
7.48
14.3
1.13
1.12
1.12
16.5
1.05
59.0
6.44
13100
13400
1.18
18900
10700
81.1
4.21
17000
[3H]U69,593
Rat cerebrum
DAMGO
Sufentanil
Morphine
-FNA
-CNA
Naloxone
Etorphine
Buprenorphine
Bremazocine
Superfit
DSLET
ICI-174,864
DPDPE
U50,488
U69,593
Monkey cortex
Sufentanil
DPDPE
U69,593
>10000
>10000
8.41
removed, and 1.5 cm segments are suspended in organ baths which contain 30 ml of a modified Kreb’s physiological
buffer. The buffer contains the following (mM): NaCl, 118; KCl, 4.75; CaCl2, 2.54; MgSO4, 1.19; KH2PO4, 1.19;
glucose, 11; NaHCO3, 25; pargyline HCl, 0.3; and disodium edetate, 0.03. The buffer is saturated with 95% O2 - 5%
CO, and kept at 37° C. The segments are attached to strain gauge transducers and suspended between two platinum
electrodes. After a 30-min equilibration period, the segments are stimulated once every 10 sec with pairs of pulses of
412
2 msec duration, 1 msec apart and at supramaximal voltage. See table III for potencies of representative agonists,
The following antagonists are studied: naltrexone MCI, ICI- 174864 [N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH] and
norbinaltorphimine. The antagonists are added to the organ baths 15 minutes before the determination of cumulative
concentration-effect relationships for the various agonists. See table III for the potencies of different competitive
antagonists studied in relation to prototypic agonists. EC50‘s are calculated by probit analysis, and pA2 values are
determined to assess relative potencies of antagonists.
All drugs which are submitted for evaluation are studied in the following manner: 1) the submitted drug is tested on
the vas deferens preparation in the absence and in the presence of a concentration of naltrexone sufficient to block µ,
and receptors. 2) If the submitted drug inhibits the twitch and its actions are blocked by naltrexone, it is evaluated
further in the absence and presence of ICI-174864 and norbinaltorphimme used in concentrations at which these
antagonists are selective for and receptors, respectively. 3) If the submitted drug is a partial agonist or devoid of
agonistic activity at opioid receptors, it is evaluated further as an antagonist against the following agonists: sufentanil
(µ selective), DSLET ( selective) and U50,488 ( selective). If the submitted drug has antagonistic activity against
any or all of the receptor-selective agonists or upon any of the other preparations used in the Drug Evaluation Unit, the
type of antagonism (competitive, noncompetitive, irreversible) is determined. For further details of the procedure and
for a description of experiments in which -funaltrexamine was used see Smith (1986). Drugs studied in the preparation
prior to 1987 were evaluated with the protocol reported in the 1985 Annual Report.
TABLE III
Potencies of antagonists assessed in the mouse vas deferens
pA2 values* determined with three agonists
Sufentanil (µ)
U50,488 ( )
DSLET ( )
Antagonist
Naltrexone
Naloxone
Cyprodime
Nalbuphine
Naltrindole
ICI-174,864
8.76
7.99
7.41
7.23
7.71
<5.00
7.74
6.90
6.15
6.31
7.38
<5.00
7.41
7.35
5.98
5.76
9.44
7.90
*The pA2 value is the negative logarithm of the molar concentration of antagonist necessary
to shift the agonist concentration-effect curve to the right by a factor of 2-fold.
413
SUMMARY OF TESTS PERFORMED
The compounds which were evaluated at the University of Michigan during the past year, and the individual tests which
were performed are shown in table IV. Also shown are dates of Reports to the Biological Coordinator, Dr. A.E.
Jacobson, in which results are reported.
TABLE IV
SUMMARY OF TESTS PERFORMED
* Date report was submitted to CPDD Biological Coordinator. MCB = Monkey Cortex Binding
414
NIH 10820
(-)-Eseroline (L)-ascorbate
(Also see 10398, 1986 Annual Report)
DISPLACEMENT OF [3H]ETORPHINE BINDING
EC50 of 1604 nM in the presence of 150 nM NaCl.
MOUSE VAS DEFERENS PREPARATION
Condition
EC50 (nM)
Maximum Response
(%)
Control
3.89 ± 0.40
49.2 ± 3.9
Naltrexone ( 100 nM)
3.87 ± 0.72
37.3 ± 0.8
Shift (x-fold)
n
3
1.0
3
Second Phase
Maximum Response (%)
Condition
EC50 (µM)
Control
3.88 ± 0.62
55.7 ± 3.0
Naltrexone (100
nM)
4.74 ± 1.73
23.3 ± 2.9
Shift (x-fold)
n
3
1.2
3
SUMMARY
NIH 10820 had very low affinity in the binding assay. In the electrically-stimulated mouse vas deferens preparation,
NIH 10820 decreased the magnitude of the twitch in concentrations of 0.1 nM to 100 µM. Naltrexone, 100 nM, did
not shift either phase of the NIH 10820 concentration effect curve but did decrease the maximum response. Thus, NIH
10820 did not display characteristics typical of opioid agonists. In concentrations up to 10 µM, NIH 10820 was devoid
of antagonist activity at µ, , and receptors.
* * *
NIH 10821
3--O-Methyloxymorphindole.HCl
DISPLACEMENT OF [3H]ETORPHHINE BINDING
EC50 of >6000 nM (19% inhibition) in the presence of 150 mM
NaCl.
415
NIH 10821 (continued)
MOUSE VAS DEFERENS PREPARATION
Condition
Maximum Response (%)
EC50 (µM)
Control
1.29 ± 0.26
100
Naltrexone (100 nM)
9.48 ± 2.12
100
ICI 174.864 (100 nM)
5.83 ± 1.09
Nor-BNI (10 nM)
2.13 ± 0.43
Shift (x-fold)
n
9
1.4
3
99.2 ± 0.8
4.5
3
100
1.7
3
SUMMARY
NIH 10821 had little opioid activity in the binding assay. In concentrations of 10 nM to 100 µM, NIH 10821 decreased
the magnitude of the twitch of the electrically stimulated moose vas deferens preparation. Both naltrexone (100 nM,
a µ-opioid selective receptor antagonist) and ICI 174864 (100 nM, a -opioid receptor antagonist) shifted the NIH 10821
concentration-effect curve to the right. Neither antagonist decreased maximum responses to this drug. Norbinaltorphimine (10 nM, a -opioid receptor antagonist) did not shift the NIH 10821 concentration-effect curve
significantly. Thus, NIH 10821 had characteristics typical of a -opioid receptor agonist.
*
*
*
3-O-Methylnaltrindole.fumarate
NIH 10822
DISPLACEMENT OF [3H]ETORPHINE BINDING
EC50 of >6000 nM (38% inhibition) in the presence of 150 mM
NaCI.
MONKEY CORTEX BINDING (nM)*
µ-receptor:
-receptor:
-receptor:
66.4
1.8
158.0
MOUSE VAS DEFERENS PREPARATION
NIH 10822 was insoluble.
*For this assay 0.6 N HCl, 10% ethanol,
and 28% DMSO were used as vehicle.
416
NIH 10833
N-[(R,S)-2-Benzyl-3[( S)(2-amino-4-methyithio)butyldithiol]-1oxopropyl]-Lphenylalanine benzyl ester methyl sulfite
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
2100
0% inhibition at 6000 nM
42% inhibition at 6000 nM
MOUSE VAS DEFERENS PREPARATION
Condition
EC50 (nM)
Control
977.3 ± 350.0
Naltrexone (100 nM)
1565.3 ± 103.5
Maximum Response (%)
Shift (x-fold)
23.1 ± 1.3
25.0 ± 0.6
n
3
1.6
3
SUMMARY
NIH 10833, in concentrations of 100 nM to 30 µM, slightly decreased the magnitude of the twitch of the
electrically stimulated mouse vas deferens preparation. This response was not blocked significantly by
naltrexone. In a concentration of 30 µM, NIH 10833 was devoid of antagonist activity at µ, and
receptors. In the monkey cortex binding assay, NIH 10833 was active in displacing the ligand at the µ site
only at high concentrations.
* * *
2-Phenyl-1,3-propanediol dicarbamate (Felbamate)
NIH 16838
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
417
5% inhibition at 6 µM
0% inhibition at 6 µM
7% inhibition at 6 µM
NIH 10838 continued
MOUSE VAS DEFERENS PREPARATION
Condition
EC 5 0 (nM)
Maximum Response (%)
Control
670.1 ± 15.6
29.7 ± 3.3
659.4 ± 33.7
28.5 ± 3.7
Naltrexone (100 nM)
Solubility: 3 mM in H2O
Shift (x-fold)
n
3
1.0
3
SUMMARY
NIH 10838, in concentrations ranging from 100 nM to 30 µM, slightly decreased the magnitude of the twitch of the
electrically stimulated mouse vas deferens preparation. This response was not blocked significantly by naltrexone. In
the monkey cortex binding assay, NIH 10838 had insignificant affinity for the binding sites.
* * *
NIH 10839
3,5-Dimethyltricyclo[3.3.1.1 3,7]decan-1-amine
(Memantine)
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
21% inhibition at 6 µM
0% inhibition at 6 µM
9% inhibition at 6 µM
MOUSE VAS DEFERENS PREPARATION
Maximum Response (%)
Condition
EC 5 0 (nM)
Control
47.7 ± 7.1
34.8 ± 3.5
Naltrexone (100 nM)
57.2 ± 8.1
26.7 ± 1.1
Shift (x-fold)
n
3
1.2
3
Solubility: 3 mM in H2O
SUMMARY
NIH 10839, in concentrations ranging from 10 nM to 3 µM, slightly decreased the magnitude of the twitch of the
electrically stimulated mouse vas deferens preparation. This response was not blocked significantly by naltrexone. In
the monkey cortex binding assay, NIH 10839 had insignificant affinity for the binding sites.
418
NIH 10840
1-Aminocyclopropane carboxylic acid (ACPC)
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
1% inhibition at 6 µM
2% inhibition at 6 µM
3% inhibition at 6 µM
MOUSE VAS DEFERENS PREPARATION
Condition
EC 5 0 (µM)
Control
3.29 ± 1.41
33.8 ± 8.1
2.56 ± 1.60
28.5 ± 10.2
Naltrexone (100 nM)
Solubility: 3 mM in H2O
Maximum Response (%)
Shift (x-fold)
n
3
0.8
3
SUMMARY
NIH 10840, in concentrations ranging from 1 µM to 30 µM, slightly decreased the magnitude of the twitch of the
electrically stimulated mouse vas deferens preparation. This response was not blocked significantly by naltrexone.
Higher concentrations could not be evaluated because of an insufficient supply of the drug. In the monkey cortex
binding assay, NIH 10840 had insignificant affinity for the binding sites.
*
NIH 10841
*
*
D-Phenylalanine
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
0% inhibition at 6 µM
3% inhibition at 6 µM
2% inhibition at 6 µM
MOUSE VAS DEFERENS PREPARATION
Condition
Control
Naltrexone (100 nM)
SOL: 3 mM in H2O
EG50 (nM)
Maximum Response (%)
185.5 ± 35.2
55.8 ± 2.9
182.1 ± 16.7
46.9 ± 1.1
Shift (x-fold)
n
3
1.0
3
SUMMARY
NIH 10841, in concentrations of 10 nM to 30 µM slightly decreased the magnitude of the twitch of the electrically
stimulated mouse vas deferens preparation. This response was not blocked by naltrexone. NIH 10841, at a concentration
of 30 µM, was devoid of significant antagonist activity at µ, and -opioid receptors. In the monkey cortex assay, NIH
10841 had insignificant effects.
419
NIH 10846
Dihydroetorphine.HCl
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
0.088
2.54
0.197
MOUSE VAS DEFERENS PREPARATION
Condition
EC50 (nM)
Maximum Response (%)
Control
0.34 ± 0.06
100.0
Naltrexone (100 nM)
2.84 ± 0.56
100.0
ICI-174864 (100 nM)
0.43 ± 0.20
Nor-BNI (10 nM)
0.51 ± 0.10
Shift (x-fold)
n
9
8.3
3
100.0
1.3
3
100.0
1.5
3
SUMMARY
NIH 10846, in concentrations ranging from 1 nM to 100 mM, decreased the magnitude of the twitch of the electrically
stimulated mouse vas deferens preparation. Naltrexone, 100 nM, shifted the NIH 10846 concentration-effect curve to
the right. Neither nor-binaltorphimine (a -opioid receptor antagonist) nor ICI-174864 (a -opioid receptor antagonist)
shifted the NIH 10846 concentration-effect curve significantly. None of the antagonists decreased maximum responses
to NIH 10846. Therefore, in the mouse vas deferens preparation, NIH 10846 acted as an extremely potent µ-opioid
receptor agonist. In the monkey cortex binding assay, NIH 10846 also had quite high affinity and some selectivity for
the µ recognition site.
*
NIH 10867
*
*
7-Nitroindazole (7-nitro-1H-indazole)
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
420
0% inhibition at 6 µM
0% inhibition at 6 µM
0% inhibition at 6 µM
NIH 10867 (continued)
MOUSE VAS DEFERENS PREPARATION
Condition
EC50 (µM)
Maximum Response (%)
Control
1.5 ± 0.15
47.4 ± 8.8
Naltrexone (100 nM)
2.48 ± 0.58
43.6 ± 1.2
Shift (x-fold)
n
3
1.7
3
SOL: 3 mM in methanol
SUMMARY
NIH 10867, in concentrations of 30 nM to 10 µM, decreased the magnitude of the twitch of the electrically stimulated
mouse vas deferens preparation - a response not blocked by naltrexone. NIH 10867,30 µM, was devoid of significant
antagonist activity at µ-, - and -opioid receptors. In the monkey cortex binding assay, it failed to displace any of the
ligands.
* * *
NIH 10869
(-)2-Cyanomethyl-5,9
-dimethyl-2’-hydroxy-6,7-benzomorphan.HCl
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
166
574
68.5
MOUSE VAS DEFERENS PREPARATION
Condition
EC50 (µM)
Maximum Response (%)
Control
1.72 ± 0.13
83.0 ± 2.3
Naltrexone (100 nM)
5.41 ± 0.49
42.8 ± 1.4
3.1
3
ICI-174864(100 nM)
3.03 ± 0.12
80.4 ± 3.7
1.8
3
3.03 ± 0.77
76.0 ± 5.0
1.8
3
Nor-BNI ( 10 nM)
SOL: 3 mM in H2O
Shift (x-fold)
n
9
SUMMARY
NIH 10869, in concentrations of 300 nM to 30 µM, decreased the magnitude of the twitch of the electrically stimulated
mouse vas deferens preparation. Naltrexone (100 nM) shifted the concentration-effect curve to the right. Neither
421
NIH 10869 (continued)
ICI-174864 (100 nM) nor nor-binaltorphimine (10 nM) shifted the NM 10869 concentration-effect curve significantly.
In the presence of NIH 10869,30 µM, there was a 4.6-fold shift to the right in the sufentanil concentration-effect curve,
a 10.7-fold shift to the right in the DSLET concentration effect curve, and a 3.8-fold shift to the right in the U50,488
concentration-effect curve. Thus, NIH 10869 was a weak, mixed agonist-antagonist with some selectivity as an
antagonist at delta opioid receptors. In the monkey cortex binding assay, the compound had moderate affinity for each
binding site, with highest affinity for kappa sites. These data suggest that NIH 10869 is likely to be an opioid agonistantagonist of moderate potency; it’s agonist effect may be exerted through different receptor types.
*
NIH 10870
*
*
(+)-2-Cyanomethyl-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan.HCl
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
4490
13.7% inhibition at 6 µM
1310
MOUSE VAS DEFERENS PREPARATlON
Condition
EC50 (µM)
Maximum Response
(%)
Control
7.93 ± 1.11
35.4 ± 3.7
Naltrexone (100 nM)
12.56 ± 0.93
25.9 ± 5.2
Shift (x-fold)
n
3
1.6
3
SOL: 3 mM in H2O
SUMMARY:
NIH 10870, in concentrations of 1 nM to 30 µM, slightly decreased the magnitude of the twitch of the electrically
stimulated mouse vas deferens preparation - a response not blocked by naltrexone. NIH 10870,30 µM, was devoid
of significant antagonist activity at µ-, - and -opioid receptors. In the monkey cortex binding assay, although IC50‘s
were obtained for mu- and kappa-binding sites, they are unlikely to be predictive of in vivo narcotic activity, except
perhaps at very high doses.
422
NIH 10874
7-Benzoyl-2-piperidineomethyl-1,4-benzodioxane.HCl
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
0% inhibition at 6 µM
3% inhibition at 6 µM
4% inhibltion at 6 µM
MOUSE VAS DEFERENS PREPARATION
Condition
EC 5 0 (nM)
Maximum Response (%)
Control
20.6 ± 2.2
100
Naltrexone (100 nM)
45.5 ± 6.1
100
2.2
3
ICI-174864 (100 nM)
27.2 ± 4.0
100
1.3
3
27.9 ± 4.2
100
1.4
3
Nor-BNI (10 nM)
SOL: 3 mM in H2O
Shift (x-fold)
n
9
SUMMARY
NIH 10874, in concentrations of 10 nM to 1 µM. decreased the magnitude of the twitch of the electrically
stimulated mouse vas deferens preparation. Naltrexone (100 nM), ICI-174864 (100 nM), and norbinaltorphimine (10 nM) failed to shift the NIH 10874 concentration-effect curve significantly. Thus, NIH 10574
was a potent agonist dcvoid of opioid activity on the isolated mouse vas deferens preparation. In the monkey
cortex binding assay, the compound had no significant activity.
*
NIH 10875
*
Pseudocodeine.HCl
MONKEY CORTEX BINDING (nM)
(a)
(b)
(c)
µ-receptor:
-receptor:
-receptor:
427
27.3% inhibition at 6 µM
20.5% inhibition at 6 µM
423
*
NIH 10875 (continued)
MOUSE VAS DEFERENS PREPARATION
Condition
EC50 (µM)
Maximum Response (%)
Control
14.8 ± 4.5
62.9 ± 7.4
Naltrexone (100 nM)
3.9 ± 0.5
17.2 ± 1.9
0.3
4
ICI-174864 (100 nM)
25.8 ± 17.5
76.1 ± 6.5
1.7
3
17.2 ± 75
51.9 ± 6.7
1.2
3
Nor-BNI (10 nM)
Shift (x-fold)
n
10
SOL: 3 mM in H2O
SUMMARY
NIH 10875 is a complex drug with low affinity for mu-binding sites. In concentrations of 1 µM to 100 µM, it
decreased the magnitude of the twitch of the electrically stimulated mouse vas deferens preparation. The
maximum response was a 62.9% inhibition of the twitch. Because of limitations in solubility, higher
concentrations could not be evaluated. Naltrexone (100 nM) decreased markedly the maximum response to NIH
10875 but did not shift the concentration-effect curve to the right or left. Naltrexonc, 100 nM, also reversed the
inhibition produced by NIH 10875. Neither ICI 174864 (100 nM) nor nor-binaltorphimine (10 nM) shifted the
NIH 10875 concentration-effect curve significantly. Thus, in the mouse vas deferens preparation, NIH 10875
was a very weak agonist with unusual activity at mu opioid receptors.
*
*
*
(-)-2-(3-Cyanopropyl)-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan
NIH 10884
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
6.52
21.6
0.34
MOUSE VAS DEFERENS PREPARATION
Condition
Control
Naltrexone ( 100 nM)
EC50 (nM)
Maximum Response (%)
42.7 ± 4.0
Shift (x-fold)
100
631.5 ± 229.8
100 ± 6.3
n
9
14.8
3
ICI-174864 (100 nM)
67.8 ± 10.0
100
1.6
3
Nor-BNI (10 nM)
335.4 ± 56.9
100
7.9
3
424
NIH 10884 (continued)
SUMMARY
NIH 10884 in concentrations of 10 nM to 1 µM decreased the magnitude of the twitch of the electrically
stimulated mouse vas deferens preparation. Naltrexone (a mu opioid receptor antagonist) shifted the NIH 10884
concentration effect curve to the right. Nor-binaltorphimine (a kappa opioid receptor antagonist) also shifted the
NM 10884 concentration-effect curve to the right. ICI-174864 (a delta-opioid receptor antagonists) did not shift
teh NIH 10884 concentration-effect curve significantly. None of the antagonists decreased maximum responses
to NIH 10884. Thus, NIH 10884 has characteristics typical of a kappa-opioid receptor agonist. In the monkey
cortex binding assay, NIH 10884 was highly potent and selective for kappa binding sites, as well.
* * *
NIH 10886
(±)-Isonicotine oxalate
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
-receptor:
15.8% inhibition at 6 µM
0.0% inhibition at 6 µM
9.6% inhibition at 6 µM
MOUSE VAS DEFERENS PREPARATION
NIH 10886 was devoid of significant agonist activity on the isolated, electrically stimulated mouse vas deferens
preparation when tested in concentrations from 100 nM to 30 µM. At a concentration of 30 µM, NIH 10886
caused a 5.07-fold shift to the right in the sufentanil concentration-effect curve, a 2.17-fold shift to the right in
the DSLET concentration-effect curve, and a 1.51-fold shift to the right in the U50,488 concentration-effect
curve. Higher concentrations could not be studied due to an insufficient supply of the drug. NIH 10886 did not
alter the maximum response obtained with any of the agonists. Thus, NIH 10886 appears to be a very weak
antagonist at mu, and possibly delta-opiold receptors.
SUMMARY
NIH 10886 had no significant activity in the binding assay: and there was weak evidence of antagonist
activity in the mouse vas deferens preparation. NIH 10886 probably had no significant opioid activity
in these assays.
* * *
NIH 10887
-Conotoxin MVIIA (reduced, cyclic (1-16), (8-20), (15-25))
H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-CysCys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2
cyclic (1-16), (8-20), (15-25)-tris(disulfide)
MONKEY CORTEX BINDING (nM)
µ-receptor: 1% inhibition at 6 µM
-receptor: 1190
425
-receptor: 0.3% inhibition at 6 µM
NIH 10887 (continued)
MOUSE VAS DEFERENS PREPARATION
Condition
Control
Naltrexone ( 100 nM)
EC50 (nM)
Maximum Response (%)
4.78 ± 0.58
Shift (x-fold)
100
100 ± 6.3
5.02 ± 0.47
n
3
1.0
3
REINFORCING EFFECTS IN RHESUS MONKEYS
NIH 10867 was evaluated across a wide range of doses. Four doses could be evaluated in a single session, and
in different sessions, the concentration of drug was adjusted so that the dose range was altered as well. Doses
of from 0.000001 to 0.01 mg/kg/inj were tested. We did not go to higher doses because of concerns about
hypotensive effects of the drug. (As many as 20 injections can be taken at each dose). The reason such small
doses were tested was because slightly higher rates seemed to be maintained by the smaller doses of each dose
series that was tested. Therefore, the possibility that low rates were maintained because the drug was especially
potent was evaluated. As can be observed in the accompanying figure, although alfentanil maintained a doserelated increase in rates of responding that were greater than 2.0 responses/sec at peak, NIH 10887 did not
maintain rates of responding that indicated a reinforcing effect of this drug. Observation of the animals after selfadministration sections did not indicate that the drug had any effects at the doses taken. Therefore, across the
range of doses tested, there was no indication that this drug had any effects that were different from saline. In
other studies ongoing in the laboratory, an intravenous dose of 0.1 mg/kg was observed to produce a distinctly
pale appearance in a monkey, indicating a hypotensive effect.
426
NIH 10887 (continued)
SUMMARY
NIH 10887, in concentrations of 1 nM to 30 µM, decreased the magnitude of the twitch of the electrically
stimulated mouse vas deferens preparation. Naltrexone (100 nM) did not shift the NIH 10887 concentration
effect curve. Thus, NIH 10887 is a potent, highly efficacious agonist on the mouse vas deferens preparation.
Opioid agonist properties were not detectable. In the monkey cortex binding assay, it failed to produce
significant displacement of any of the tritiated ligands. It also did not act as a reinforcer in the rhesus monkey
over a very wide range of doses up to 0.01 mg/kg/inj
* * *
NIH 10899
2-Methyl-5-(3-pyridyl)morphan.2 oxalate
MONKEY CORTEX BINDING (nM)
µ-receptor:
-receptor:
28.8 ± 5.2% inhibition at 10 µM
-receptor:
29.1 ± 3.0% inhibition at 10 µM
SUMMARY
NIH 10899 had weak affinity for the µ-opioid receptor, approximately 1500 times less than the standard µpeptide DAMGO. In contrast, it does appear to have some degree of selectivity for µ- over - and -receptors.
*
*
*
REFERENCES
Bertalmio, A.J.; Herling, S.; Hampton, R.Y.; Winger, G.; and Woods, J.H. A procedure for rapid evaluation of
the discriminative stimulus effects of drugs. J Pharmacol Meth 7:289-299, 1982.
Carter, B.D. and Medzihradsky, F. Opioid signal transduction in intact and fragmented SH-SY5Y neural cells.
J Neurochem 58:1611-1619, 1992.
Clark, M.J.; Carter, B.D.; and Medzihradsky, F. Selectivity of ligand binding to opioid receptors in brain
membranes from the rat, monkey and guinea pig. Eur J Pharmacol 148:343-351, 1988.
Clark, M.J. and Medzihradsky, F. Coupling of multiple opioid receptors to GTPase following selective receptor
alkylation in brain membranes. Neuropharmacol 26:1763-1770, 1987.
Dykstra, L.A. and Woods, J.H. A tail withdrawal procedure for assessing analgesic activity in rhesus monkeys.
J Pharmacol Meth 15:263-269, 1986.
Emmerson, P.J.; Liu, M.-R.; Woods, J.H.; and Medzihradsky, F. Binding affinity and selectivity of opioids at
mu, delta and kappa receptors in monkey brain membranes. J. Pharmacol Exp. Ther. 271:1630-1637, 1994.
France, C.P. and Woods, J.H. Discriminative stimulus effects of naltrexone in morphine-treated rhesus monkeys.
J Pharmacol Exp Ther 250:937-943, 1989.
France, C.P.; de Costa, B.R.; Jacobson, A.E.; Rice, K.C.; and Woods, J.H. Apparent affinity of opioid
427
antagonists in morphine-treated rhesus monkeys discriminating between saline and naltrexone. J Pharmacol Exp
Ther 252:600-604, 1990.
France, C.P. and Woods, J.H. Respiratory effects of receptor-selective opioids in rhesus monkeys. In: Quirion,
R., Jhamandas, K. and Gianoulakis, C. (Eds.), Progress in Clinical and Biological Research: The International
Narcotics Research Conference (INRC) ‘89, Vol. 328. Alan R. Liss, Inc.: New York, pp. 295-298, 1990.
Howell, L.L.; Bergman, J.; and Morse, W.H. Effects of levorphanol and several -selective opioids on respiration and behavior in rhesus monkeys. J Pharmacol Exp Ther 245:364-372, 1988.
Medzihradsky, F. Novel biochemical determinants in the preclinical evaluation of opiates. NIDA Res Monogr
76:349-355, 1987.
Medzihradsky, F.; Emmerson, P.J; and Mousigian, C.A. Lipophilicity of opioids determined by a novel
micromethod. J Pharmacol Meth 27:61-69, 1992.
Medzihradsky, F.; Dahlstrom, P.J.; Woods, J.H.; Fischel, S.V.; and Mitsos, S.E. Resolution in the receptor
binding of putative µ and opiates. Life Sci 34:2129-2138, 1984.
Perrine, T.D.; Atwell, L.; Tice, I.B.; Jacobson, A.E.; and May, E.L. Analgesic activity as determined by the
Nilsen method, J Pharm Sci 61:86-88, 1972.
Solomon, R.E.; Herling, S.; Domino, E.F.; and Woods, J.H. Discriminative stimulus effects of N-substituted analogs of phencyclidine in rhesus monkeys. Neuropharmacol 21:1329-1336, 1982.
Smith, C.B. New approaches to the evaluation of opioid agonists and antagonists upon the mouse vas deferens
preparation. NIDA Res Monogr 76:288-294, 1986.
Smith, C.B.; Medzihradsky, F.; Hollingsworth, P.J.; DeCosta, B.; Rice, K.C.; and Woods, J.H. Norbinaltorphimine is a reversible, noncompetitive opioid antagonist in the mouse vas deferens with high affinity
for receptors in monkey brain membranes. In: Quirion, R.; Jhamandas, K.; and Gianoulakis, C. eds., The
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functions. Drug and Alc Depend 24:135-142, 1989.
Woods, J.H.; Smith, C.B; Medzihradsky, F.; and Swain, H.H. Preclinical testing of new analgesic drugs. In:
Beers, F.R., Jr. and Basset, E.G. eds. Mechanisms of Pain and Analgesic Compounds. New York: Raven Press,
pp. 429-445, 1979.
428
PROGRESS REPORT FROM THE TESTING PROGRAM FOR STIMULANT AND DEPRESSANT
DRUGS (1996)
C.P. France; L.R. Gerak; J.K. Rowlett; W.L. Woolverton; G. Winger and J.H. Woods
Louisiana State University Medical Center, New Orleans, LA; University of Mississippi Medical Center, Jackson,
MS; University of Michigan, Ann Arbor, Ml
INTRODUCTION
The research group involved in the evaluation of stimulant and depressant compounds has been in existence for
approximately 13 years. The group now includes laboratories at Louisiana State University Medical Center
(France, Gerak), University of Mississippi Medical Center (Woolverton, Rowlett), and the University of
Michigan (Winger, Woods) and is part of the Drug Evaluation Committee (Dr. T. Cicero, Chair) of the College
on Problems of Drug Dependence (CPDD) which is supported by both CPDD and the National Institute on Drug
Abuse (NIDA). One of the purposes of the group is to evaluate new compounds, generally classified as either
stimulants or depressants, for their abuse liability and physical dependence potential. Compounds are received,
coded and distributed by Dr. A. Jacobson at the National institute of Diabetes, Digestive and Kidney Diseases
(NIDDK). National Institutes of Health (NIH), for blind testing in the various laboratories. They are evaluated
for discriminative stimulus effects in pentobarbital-trained monkeys (UMMC), amphetamine-trained monkeys
(UMMC), triazolam-trained monkeys (LSUMC), flumazenil-trained monkeys that receive diazepam daily
(LSUMC) and also for reinforcing effects in monkeys that previously self-administered methohexital (UM). This
report includes the results of evaluation of the following compounds: CPDD-0007, CPDD-0032, CPDD-0042
and CPDD-0044.
METHODS
Reinforcing Effects in Rhesus Monkeys (UM)
Subjects
Subjects were rhesus monkeys (Macaca mulatta) experienced with self-administration of sodium methohexital
and saline. Animals were surgically prepared with indwelling silicone rubber catheters using 10 mg/kg i.m.
ketamine and 2.0 mg/kg i.m. xylazine as anesthetics. Catheters were implanted in jugular (internal or external),
femoral or brachial veins as necessary. Catheters passed subcutaneously (s.c.) to the mid-scapular region, exited
the body and continued, through a hollow restraining arm, to the outside rear of the cage.
Apparatus
The restraint and catheter protection devices are described in detail by Deneau et al. (1969). Each monkey wore
a tubular stainless steel harness that protected the exit site of the catheter and allowed relatively unrestricted
movements within the cage. A Teflon cloth jacket (Alice King Chatham Medical Arts, Los Angeles, CA)
provided further protection for animals who tended to locate and pull their catheters. The harness was connected
to a flexible spring arm that carried the catheter to the back of the cage where it joined tubing passing through
a roller infusion pump (Watson and Marlow Co., Model MHRK 55, Falmouth, UK).
Monkeys were individually housed in stainless steel cages, measuring 83.3 X 76.2 X 91.4 cm deep. A 15.4 cm
square stimulus panel was located on the side of each cage, approximately 10 cm from the front and 19 cm from
the bottom of the cage. Across the top of the stimulus panel, 1.5 cm apart, were three circles, 2.5 cm in diameter.
covered with translucent plastic and capable of being illuminated from behind by 5 W colored bulbs. The two
side lights could be illuminated red and the center light green. Below each of the two red stimulus lights was a
response lever (Model 121-07; BRS-LVE, Beltsville, MD) capable of being operated by a force of 0.010 to 0.0 15
429
N. Experimental control was provided by an IBM PS/2 computer programmed with Med-PC (Med-Associates,
Fairheld, VT) software and located in an adjoining room.
Procedure
Reinforcing effects of CPDD-0044 were evaluated in a substitution self-administration procedure with
methohexital serving as the baseline drug. Test sessions and baseline sessions had the same general structure.
At the start of each session, a red light was illuminated over one of two levers. When a monkey completed the
fixed-ratio requirement of 10 presses on that lever (fixed-ratio [FR] 10), a 5-second, 1.0 ml injection of saline
solution, sodium methohexital (0.1 mg/kg), or a test compound was delivered. The red light was extinguished
and a center green light illuminated for the duration of the infusion. Each injection was followed by a 10-second
timeout during which all stimulus lights were extinguished and responding had no programmed consequence
Twice daily experimental sessions lasted 130 mm each. On approximately half of the baseline sessions, the
monkeys could respond for saline. All animals showed clear and consistent differential responses to saline and
methohexital before test compounds were substituted.
In test sessions a dose of the test compound was made available for one session. Other conditions were similar
to those of the baseline sessions.
Drugs
Both drugs were given in an injection volume of 1.0 ml. The methohexital training dose was 0.1 mg/kg/injection.
Four doses of CPDD-0044 were evaluated (0.00 1.0.01, 0.1 and 1.0 mg/kg/injection); not all monkeys received
all doses, but each of the three monkeys were evaluated at the two largest doses (0.1 and 1.0 mg/kg/injection).
In most cases, two observations were made at the tested doses in each monkey.
Discriminative Stimulus Effects of CPDD-4044 in Rhesus Monkeys (pentobarbital and amphetamine
discriminations, UMMC)
Subjects
The subjects were seven adult rhesus monkeys (Macaca mulatta) weighing between 6.4 and 12.2 kg. Monkeys
were housed individually in stainless steel cages in which water was available continuously. They were fed 150
to 200 g of Teklad monkey chow after each session and were given a chewable vitamin tablet 3 days/week.
The monkeys had been trained previously to discriminate d-amphetamine (Ou3, 7739, 8515 and 8405) or
pentobarbital (AQ63, 8814 and 8902) from saline in a two-lever, discrete-trial shock avoidance procedure. All
monkeys had received other test drugs prior to testing with CPDD-0044.
Apparatus
During experimental sessions animals were seated in primate restraint chairs and placed inside sound-attenuating
cubicles. All chains were fitted with shoes containing brass plates in the soles that permitted delivery of electric
shock produced by a shock generator (SG 903 BRS/LVE, Laurel, MD). Chambers were equipped with two
response levers (PRL-001, BRS/LVE, Laurel, MD) mounted on one wall. There were four white lights above
each lever. Chambers were illuminated with ceiling-mounted 40w incandescent house lights. Experimental
events were programmed and recorded with an Apple Macintosh II computer in a room adjacent to the one in
which animals were tested.
Procedure
The training and test procedures have been reported in detail elsewhere (Woolverton et al., 1994). A monkey
was placed in the restraint chair and either saline (1-2 ml) or the training drug was administered intragastrically
430
(i.g.) via a nasogastric tube, followed by a 1.5 ml saline flush Fifty-five minutes after infusion, the monkey was
placed into the experimental chamber.
The session began with a S-minute time-out which was followed by 30 trials. On each trial the house tight and
lever lights were illuminated and responding on the correct lever postponed scheduled shock and extinguished
the lights. Incorrect responses reset the response requirement on the correct lever. The correct lever was
determined by the pre-session infusion (drug or saline). If the response requirement (FR 1, 2 or FR 5) was not
satisfied on the correct lever within 5 seconds (1 0 seconds for FR 5) of the onset of the lights, shock (250 msec
duration, 3 or 7 mA intensity) was delivered. If the response requirement was not satisfied within 2 additional
seconds (4 seconds for FR 5) of this shock, a second shock was delivered and the trial automatically ended. The
session was terminated when 2 shocks were delivered during 2 consecutive trials. Trials were separated by 30see timeouts.
Training sessions were conducted five days a week according to the following schedule: SDDSS, DSSDD, where
S denotes sessions preceded by saline and D denotes sessions preceded by drug. Discrimination training
continued until at least 90% of the responses in the first trial were on the correct lever and subjects avoided shock
on at least 90% of the trials (27/30) for seven out of eight consecutive sessions. When subjects failed to satisfy
criteria, the training sequence was conducted until the criteria were once again satisfied.
Test sessions were identical to training sessions except that test drugs were administered and completing the
response requirement on either lever avoided shock.
Drugs
A stock solution of d-amphetamine sulfate (National Institute on Drug Abuse, Rockville, MD) was dissolved in
saline in a concentration of 5.0 mg/ml. The training dose of amphetamine was either 0.56 or 1.0 mg/kg i.g.
Pentobarbital was mixed daily by diluting Nembutal (Abbott Laboratories, N. Chicago, IL). The training dose
was 10 mg/kg for all pentobarbital-trained monkeys. CPDD-0044 was dissolved in 0.9% saline immediate before
administrations doses of 1.0, 3.0, 10.0 and 30.0 mg/kg were evaluated at an infusion volume of 0.25 mg/kg.
Discriminative Stimulus Eflects in Rhesus Monkeys (triazolam and flumazenil discriminations, LSUMC)
Subjects
The subjects were five adult and three juvenile rhesus monkeys (Macaca mulatta) weighing between 3.0 and 9.0
kg. Two juvenile monkeys participated in the flumazenil discrimination study and four adults participated in the
triazolam discrimination study. Monkeys were housed individually in stainless steel cages in which water was
continuously available (except for monkey LU who was water restricted to facilitate drinking punch that
contained drug). Monkeys received primate chow (Harlan Teklad, Madison, WI) daily as well as fresh fruit and
peanuts several days per week. All studies were conducted in accordance with the guidelines of the Institutional
Animal Care and Use Committee. Louisiana State University Medical Center. New Orleans. and the Guide for
the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health.
Apparatus
Monkeys were seated in chairs that provided restraint at the neck. Chairs were equipped with shoes containing
brass electrodes, to which brief (250 msec) electric shock could be delivered an an a.c. shock generator located
adjacent to the chambers. During experimental sessions, chairs were located in sound-attenuating, ventilated
chambers that were equipped with several response levers, a food cup and an array of stimulus lights.
Procedure
Flumazenil Discrimination. Monkeys consumed 5.6 mg/kg of diazepam in 45-50 ml of fruit punch 3 hrs prior
to daily sessions in which they discriminated between s.c. injections of 0.32 mg/kg of flumazenil and vehicle
431
while responding under a FR 5 schedule of stimulus-shock termination. Daily training sessions consisted of
several discrete, 15-minute cycles. Each cycle comprised a 10-minute pretreatment period, during which the
chamber was dark and lever presses had no programmed consequence, followed by a response period, during
which the chamber was illuminated red and monkeys could postpone scheduled shock for 30 seconds by
responding five times on the appropriate lever as determined by the s.c. injection administered during the first
minute of the 10-minute timeout (e.g., left lever after vehicle, right lever after flumazenil). Failure to satisfy the
response requirement within 10-seconds resulted in the delivery of a brief shock. The response period ended after
5 minutes or the delivery of 4 shocks, whichever occurred first. Responses on the injection-inappropriate lever
reset the response requirement on the correct lever.
Test sessions were identical to training sessions except that various doses of flumazenil or the test compound
were administered during the first minute of each timeout and five consecutive responses on either lever
postponed scheduled shock.
Triazolam Discrimination. Monkeys discriminated between s.c. injections of 0.032 (subject MA) or 0.1 mg/kg
of triazolam and vehicle while responding under a FR 5 schedule of stimulus-shock termination. Daily sessions
comprised a single cycle that included a 15-minute pretreatment period, during which the chamber was dark and
lever presses had no programmed consequence, followed by a response period, during which the chamber was
illuminated red and monkeys could postpone scheduled shock for 30 seconds by responding five times on the
appropriate lever, as determined by the s.c. injection administered 45 minutes prior to the beginning of the
session, 60 minutes prior to the beginning of the response period (e.g., left lever after vehicle, right lever after
triazolam). Failure to satisfy the response requirement within 10 seconds resulted in the delivery of a brief shock.
The response period ended after 5 minutes or the delivery of 4 shocks, whichever occurred first. Responses on
the injection-inappropriate lever reset the response requirement on the correct lever.
Test sessions were identical to training sessions except that various doses of triazolam or the teat compound were
administered 45 minute3 prior to the session and five consecutive responses on either lever postponed scheduled
shock.
Drugs
Diazepam (Zenith Laboratories, Northvale, NJ) was suspended in 45-50 ml (depending on body weight) of fruit
punch or apple juice containing suspending Agent K to yield a dose of 5.6 mg/kg/daily drinking episode.
Fhunazenil (F. Hoffman LaRoche, LTD, Basel, Switzerland) was dissolved in a vehicle of 10% ethanol, 40%
propylene glycol and 50% saline; triazolam (Upjohn, Kalamazoo, MI), CPDD-0007, and CPDD-0032 were
dissolved in a vehicle of 10% ethanol, 20% emulphor and 70% water. CPDD-0007 was studied up to a dose of
32.0 mg/kg s.c.; limited solubility precluded studies of larger doses. CPDD-0032 was studied up to a dose of
either 0.32 (triazolam study) or 3.2 (flumazenil study) mg/kg s.c.; limited solubility precluded studies on larger
doses in the flumazenil study. CPDD-0042 and CPDD-0044 were dissolved in sterile water. CPDD-0042 was
studied up to a dose of 5.6 mg/kg s.c.; larger doses of this compound were not studied and were reported to
produce convulsions in other studies (1). CPDD-0044 was studied up to a dose of 32.0 mg/kg s.c.
RESULTS
CPDD-0007
Methaqualone
(2-methyl-3-o-tolyl-4(3H)-quinazolinone)
432
Discriminative Stimulus Effects In Rhesus Monkeys (triazolam and flumazenil discriminations)
Up to a dose of 32.0 mg/kg, CPDD-0007 failed to substitute (i.e.. did not produce at least 80% drug-lever
responding) for the flumazenil discriminative stimulus (Table 1). Moreover, rates of responding were greater
than 70% of control rates with all doses of CPDD-0007 (data not shown).
Up to a dose of 32.0 mg/kg, CPDD-0007 failed to occasion triazolam-lever responding (Table 2). Moreover,
rates of responding were not altered by any dose of CPDD-0007 (data not shown).
TABLE 1. Discriminative stimulus effects of flumazenil and CPDD-0007 in diazepam-treated monkeys
discriminating between flumazeail and vehicle.
Flumazenil (mg/kg)
CPDD-0007 (mg/kg)
Subject Vehicle
0.0032 0.1
0.32
1.0
1.0
3.2
10.0
32.0
DU
0
8.2
11.1
75.0
87.5
0
0
0
0
LU
0
3.5
0
37.7
84.0
10.0
0
0
0
TABLE 2. Discriminative stimulus effects of triazolam and CPDD-0007 in monkeys discriminating
between triazolam and vehicle.
Triazolam (mg/kg)
CPDD-0007 (mg/kg)
Subject Vehicle
0.0032 0.01
0.032
0.1
1.0
3.2
10.0
32.0
SA
0
0
11.1
54.4
95.0
n.s.
0
0
20.0
RO
0
0
0
0
100
n.s.
0
0
0
n.s. = not studied
CPDD-0032
Flunitrazepam
Discriminative Stimulus Effects in Rhesus Monkeys (triazolam and flumazenil discriminations)
Up to a dose of 3.2 mg/kg, CPDD-0032 failed to occasion flumazenil-lever responding (Table 3). Moreover,
rates of responding were above 80% of control rates with all doses of CPDD-0032 (data not shown).
CPDD-0032 substituted (i.e., produced at least 80% drug-lever responding) for triazolam in a dose-related manner
in both monkeys with doses of CPDD-0032 larger than 0.032 mg/kg occasioning greater than 80% triazolamlever responding (Table 4). Average rates of responding were decreased to less than 50% of control after s.c.
injection of 0.1 mg/kg of CPDD-0032 (data not shown).
433
TABLE 3. Discriminative stimulus effects of flumazenil and CPDD-0032 in diazepam-treated monkeys
discriminating between flumazenil and vehicle.
CPDD-0032 (mg/kg)
Flumazenil (mg/kg)
Subject Vehicle
0.032
0.1
0.32
1.0
0.1
0.32
1.0
3.2
DU
0
8.2
11.1
75.0
87.5
0
0
0
0
LU
0
3.5
0
37.7
84.0
0
0
4.0
0
TABLE 4. Discriminative stimulus effects of triazolam and CPDD-0032 monkeys discriminating between
triazolam and vehicle.
Triazolam (mg/kg)
CPDD-0032 (mg/kg)
Subject Vehicle 0.0032 0.01
0.032
0.1
0.0032 0.01
0.032
0.1
0.32
MA
0
0
100
97.8
95.2
0
50.0
40.0
97.6
*
CA
0
0
0
0
100
0
9.3
45.4
90.0
91.8
* = no responding
CPDD-0042
Zipeprol [4-(2-methoxy-2-phenylethyl)-
-mehoxyphenylmethyl)-1-piperezineethanol.2HCl]
Discriminative Stimulus Effects ln Rhesus Monkeys (triazolam and flumazenil discriminations)
Up to a dose of 5.6 mg/kg, CPDD-0042 failed to substitute for the flumazenil discriminative stimulus (Table 5).
Rates of responding were increased modestly by CPDD-0042 (to 141% and 123% of control in monkeys DU
and LU, respectively, at a cumulative dose of 1.0 mg/kg, data not shown).
Up to a dose of 5.6 mg/kg, CPDD-0042 tailed to occasion triazolam-lever responding (Table 6). Moreover,
CPDD 0042 did not alter rates of responding in one monkey (MA) and increased rates modestly (to 128% of
control at a cumulative dose of 5.6 mg/kg) in another (RO; data not shown).
434
TABLE 5. Discriminative stimulus effects of flumazenil and CPDD-0042 in diazepam-treated monkeys
discriminating between flumazenil and vehicle
Flumazenil (mg/kg)
CPDD-0042 (mg/kg)
Subject Vehicle
0.032
0.1
0.32
1.0
0.32
1.0
3.2
5.6
DU
4.3
8.2
11.1
75.0
87.5
2.0
0
0
0
LU
0
3.5
0
37.7
84.0
0
0
0
0
TABLE 6. Discriminative stimulus effects of triazolam and CPDD-0042 in monkeys discriminating
between triazolam and vehicle.
Triazolam (mg/kg)
Subject
Vehicle
CPDD-0042 (mg/kg)
0.0032 0.01
0.032
0.1
1.0
3.2
5.6
MARG
0
0
11.8
90.0
100
0
0
0
RO
0
0
0
0
100
0
0
0
CPDD-0044
-Hydroxybutyric acid, sodium salt
Reinforcing Effects in Rhesus Monkeys
Four doses of CPDD-0044 (0.001, 0.01, 0.1 and 1.0 mg/kg/injection) were evaluated in three monkeys. CPDD0044 maintained very little self administration behavior; the number of injections taken of CPDD-0044 was not
greater than the number of injections of saline and was considerably less than the number of injections taken of
methohexital.
Discriminative Stimulus Effects in Rhesus Monkeys (pentobarbital and amphetamine discriminations)
CPDD-0044 engendered a maximum of 50% drug-appropriate responding in amphetamine-trained monkeys
(Table 7) and no drug-appropriate responding in pentobarbital-trained monkeys (Table 8). The amphetamineappropriate responding that was engendered by CPDD-0044 was not dose related and response rates were not
systematically altered by CPDD-0044 in either group of monkeys (data not shown).
435
TABLE 7. Discriminative stimulus effects of amphetamine and CPDD-0044 in monkeys discriminating
between amphetamine and vehicle.
CPDD-0044 (mg/kg)
Subject
Vehicle
Amphetamine
1.0
3.0
10.0
30.0
Ou3
0
100
0
47
50
0
7739
0
100
n.s.
0
0
0
8515
0
100
n.s.
0
48
0
8405
0
92
n.s.
22
18
50
n.s. = not studied
Discriminative Stimulus Effects in Rhesus Monkeys (triazolam and flumazenil discriminations)
Up to a dose of 32.0 mg/kg, CPDD-0044 failed to substitute for the flumazenil discriminative stimulus (Table
9). Rates of responding were increased modestly by CPDD-0044 (to an average of 142% of control at a dose
of 32.0 mg/kg; data not shown).
In two monkeys (RO and CA), CPDD-0044 failed to occasion any triazolam-lever responding up to a dose of
32.0 mg/kg s.c. Moreover, CPDD-0044 did not alter rates of responding in these two monkeys. In a third
monkey (MARG), CPDD-0044 produced 81 and 40% triazolam-lever responding at doses of 3.2 and 10.0 mg/kg,
respectively. A retest with 10.0 mg/kg in monkey MARG confirmed the initial finding with this dose occasioning
6 1% triazolam-lever responding. Rate of responding was decreased to 76% of control in monkey MARG at a
dose of 32.0 mg/kg of CPDD-0044.
TABLE 8. Discriminative stimulus effects of pentobarbitnl and CPDD-0044 in monkeys discriminating
between pentobarbital and vehicle.
CPDD-0044 (mg/kg)
Subject
Vehicle
Pentobarbital
1.0
3.0
10.0
30.0
AQ63
0
100
0
0
0
0
8814
0
100
n.s.
0
0
0
8902
0
100
n.s.
0
0
0
n.s. = not studied
436
TABLE 9. Discriminative stimulus effects of flumazenil and CPDD-0044 in diazepam-treated monkeys
discriminating between flumazenil and vehicle
CPDD-0044 (mg/kg)
Flumazenil (mg/kg)
Subject Vehicle 0.01
0.032
0.1
0.32
1.0
1.0
3.2
10.0
32.0
DU
4.3
n.s.
8.2
11.1
75.0
87.5
2.2
0
0
8.2
IG
0
0
74.5
57.7
100
n.s.
11.1
0
0
0
n.s. = not studied
TABLE 10. Discriminative stimulus effects of triazolam and CPDD-0044 in monkeys discriminating
between triazolam and vehicle
Triazolam (mg/kg)
CPDD-0044 (mg/kg)
Subject Vehicle
0.0032 0.01
0.032
0.1
1.0
3.2
10.0
32.0
MARG 10
0
11.8
90.0
100
3.9
81.5
40.0
0
RO
0
0
0
0
100
0
0
0
0
CA
0
0
32.3
81.8
93.8
0
0
0
0
CONCLUSIONS
CPDD-0007
CPDD-0007 (methaqualone) failed to substitute for for flumazenil in diazepam-treated monkeys and also failed to
substitute for triazolam in otherwise untreated monkeys. While it is possible that doses larger than 32.0 mg/kg
of CPDD 0007 might have discriminative stimulus effects under the conditions described above or under
conditions different from those used in the current study, it is clear that for doses up to and including 32.0 mg/kg.
CPDD-0007 fails to exert either benzodiazepine antagonist or benzodiazepine agonist actions in rhesus monkeys
(also see 3, 4, 8 for results from other procedures).
CPDD-0032
CPDD-0032 (flunitrazepam) failed to substitute for flumazenil in diazepam-treated monkeys discriminating
between flumazenil and vehicle; however, CPDD-0032 substituted completely for triazolam in monkeys
discriminating between triazolam and vehicle. Up to a dose of 3.2 mg/kg. CPDD-0032 failed to alter rates of
lever pressing in monkeys treated daily with 5.6 mg/kg (p.o.) of diazepam. In contrast, in otherwise untreated
monkeys (i.e., those discriminating triazolam), CPDD-0032 dose-dependently decreased response rates with a
potency that was not different from triazolam. Collectively these results demonstrate that CPDD-0032 shares
discriminative stimulus and rate-decreasing effects with and has a potency similar to triazolam. That CPDD-0032
437
was less effective in decreasing rates of responding in diazepam-treated monkeys could indicate that daily
treatment with diazepam generated cross-tolerance to the rate-decreasing effects of CPDD-0032. In summary,
CPDD-0032 appears to be a benzodiazepine-like agonist with a potency similar to triazolam (also see 5 for results
from other procedures).
CPDD-0042
CPDD-0042 (zipeprol) failed to substitute for flumazenil in diazepam-treated monkeys and also failed to
substitute for triazolam in otherwise untreated monkeys. While it is possible that CPDD-0042 might have
discriminative stimulus effects under conditions different from those used in the current study, it is clear that, for
doses up to and including 5.6 mg/kg, CPDD-0042 fails to exert either benzodiazepine antagonist or
bcnsodiazepine agonist actions in rhesus monkeys (also see 2,6 for results from other procedures).
CPDD-0044
CPDD-0044 ( -hydroxybutyric acid) did not maintain self-administration responding in any of the three monkeys
tested. In drug discrimination studies, CPDD-0044 had, at most, partial amphetamine-like discriminative stimulus
effects and no pentobarbital-like discriminative stimulus effects. CPDDW failed to substitute for flumazenil
in diazepam-treated monkeys and also failed to substitute for triazolam in two of three untreated monkeys. One
dose of CPDD-0044 substituted for triazolam in one monkey, although the effects of CPDD-0044 in this monkey,
over a 32-fold dose range, were not dose related. While it is possible that CPDD-0044 might have discriminative
stimulus effects under conditions different from those used in the current study, for doses up to and including 32.0
mg/kg, CPDD-0044 fails to reliably exert either amphetamine-like, pentobarbital-like, triazolam-like or
benzodiazepine antagonist actions in rhesus monkeys (also see 7).
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ACKNOWLEDGEMENTS
This research was supported, in part, by the College on Problems of Drug Dependence.
439
STANDARD BINDING AND FUNCTIONAL ASSAYS RELATED TO MEDICATIONS
DEVELOPMENT DIVISION TESTING FOR POTENTIAL COCAINE AND OPIATE
NARCOTIC TREATMENT MEDICATIONS
L. Toll, I. P. Berzetei-Gurske, W. E. Polgar, S. R. Brandt, I. D. Adapa, L. Rodriguez, R.
W. Schwartz, D. Haggart A. O’Brien, A. While, J. M. Kennedy, K. Craymer, L. Farrington,
and J. S. Auh
SRI International, Menlo Park, CA
INTRODUCTION
One of the key missions of the National institute on Drug Abuse is the development of drugs for the treatment of
drug abuse. Although there are presently three drugs approved for treatment of opiate narcotic addiction (methadone,
naltrexone, and LAAM), second and third generation compounds are desired. Because of the absence of any
clinically used medications, of particular importance is the identification and development of treatment compounds
for the psychostimulant cocaine.
The Medications Development Division at NIDA has established an Opiate Treatment Discovery Program (OTDP).
and a Cocaine Treatment Discovery Program (CTDP) with the purpose of using simple preclinical tests for the
identification and evaluation of compounds that may be of use in the treatment of opiate narcotic and cocaine abuse.
Tests in these programs include in vitro binding and biochemical assays, and in vivo pharmacological studies,
designed to inexpensively select the most promising compounds for further evaluation and possible development as
treatment medications. The strategy chosen was to test a large number of unknown compounds at molecular targets
(receptors or transporters) that may be involved in the addiction process for opiates and cocaine.
The potential sites for treatment of opiate addiction have been reasonably well defined over the past several years.
The approved medications act as either very long-lasting µ opiate agonists (methadone and LAAM), or a µ opiate
antagonist (naltrexone). In addition, µ partial agonists, such as buprenorphine, have had indications of some
usefulness in preclinical studies, and clinical trials (Kosten et al., 1992). Accordingly, for the OTDP, the binding
affinity and activity of a large number of opiate compounds have been tested at µ-, -, and -opiate receptors.
Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried
out in CHO cells transfected with human receptors. Activity has been determined using the in vitro bioassays
guinea pig ileum (GPI) and mouse vas deferens (MVD). Additional studies have been carried out by measuring
stimulation of [35S]GTP S binding in transfected ceils.
The sites of action for potential cocaine treatment medications are significantly less well defined. Cocaine is a local
anesthetic that has pharmacological actions throughout the body. However, the CNS stimulant actions of cocaine
are known to be mediated by its ability to block the reuptake of the biogenic amines dopamine, norepinephrine, and
serotonin (5-hydroxytryptamine, 5-HT) (Ritz et al. 1990; Reith, 1988). The addictive property of cocaine appears to
be related to its ability to block dopamine reuptake (Kuhar et al., 1988). Accordingly, cocaine mediates its effects
by increasing synaptic levels of dopamine and the other biogenic amines. Based upon the success of opiate
addiction medications, potential cocaine treatment medications could include long-lasting cocaine analogs, longlasting dopamine receptor agonists, dopamine receptor antagonists, dopamine receptor partial agonists.
Unfortunately, unlike opiates, for which we know the it receptor mediates the rewarding actions, we don’t know
which of the five dopamine receptors mediate the rewarding aspects of cocaine administration.
The objective of one CIDP contract was to evaluate a large number of compounds that interact with biogenic amine
receptors for potential cocaine treatment medications. We characterized compounds at dopamine (D1, D2, and D3),
5-HT (5-HT 1A, 5-HT2A, 5-HT2C, 5-HT3), phencyclidine (PCP), and sigma ( ) binding sites. The characterization
included both determination of binding affinities and, where possible, an evaluation of the agonist or antagonist
potencies of compounds at the dopamine and 5-HT receptors. Activity at D1 receptors has been determined by
measuring stimulation of cAMP accumulation. Activity at D2 and D3 was determined by measuring stimulation of
mitogenic activity. Activity at 5-HT2A receptors was measured in the rat aorta spiral, in vitro. and activity at the 5HT 3 receptor was measured in the GPI.
440
Prior to the study of unknowns at each site discussed above, our binding and functional assays were validated by the
characterization of a large number of known standard compounds. In this manuscript. we will list binding affinities
and activities of standard compounds derived for both OTDP and CTDP programs.
METHODS
Receptor Binding
Serotonin Receptors
Human 5-HT1A receptors on HA7 cells were donated by Dr. Marc Caron. NIH-3T3-GF6 cells containing rat 5HT2A
receptors and NIH-3T3-P cells containing rat 5-HT2C receptors were obtained from Dr. David Julius. Each cell line
is grown in Dulbecco’s minimum essential medium (DMEM) containing 10% fetal calf serum, 0.05% penstreptomycin, and 400 µg/ml G418. The cells are scraped from the 100 x 20 mm plates and centrifuged at 500 x g
for 5 min. The pellet is homogenized in 50 mM Tris-HCl, pH 7.7, with a polytron, centrifuged at 27.000 x g, and
resuspended in the same buffer, washed once and resuspended in 25 mM Tris-HCl containing 100 µM ascorbic acid
and 10 µM nialamide at pH 7.4 for 5-HT1A receptors, 25 mM Tris-HCl, pH 7.7 for 5-HT2A receptors, and 50 mM
Tris-HCl, pH 7.7, 4 mM CaCl2, 10 µM pargyline, and 0.1% ascorbic acid for 5-HT2C receptors. The binding
assays contain [3H]8-0H-DPAT (0.5 nM final concentration), and 30 µg protein/tube, [3H]kctanserin (0.40 nM
final concentration) with 30 µg protein/tube, or [3Hlmesulergine (0.4 nM final concentration), and 8 µg
protein/tube, in a volume of 1.0 ml for 5-HT1A, 5-HT2A, and 5-HT2C receptors respectively. The tubes are
incubated at 25°C for 60 min before filtration.
5-HT3 receptors are found in the neuroblastoma x glioma hybrid cells NG108-15, which are grown in DMEM with
HAT supplement and 10% fetal calf serum. The cell membranes are prepared as described above and resuspended in
25 mM Tris-HCl, pH 7.7 with 1 mM EDTA. The assay is performed in 0.5 ml with [3H]GR65630 (1.6 nM final
concentration), and 0.13 mg protein to each tube. The tubes are then incubated at 25°C for 45 min. Nonspecific
binding is defined by 1 µM of zacopride. Filters are soaked in 0.1% polyethyleneimine (PEI) before filtering.
Dopamine Receptors
Human D1 receptors in L cells, obtained from, Dr. David Grandy, are grown and prepared as described for the HA7
cells. The final pellet is resuspended in 50 mM Tris-HCl containing 120 mM NaCI, 5 mM KCl, 2 mM CaCl2,
and 1 mM MgCl2, pH 7.7. Binding is conducted as described above using [3H]SCH 23,390 (0.18 nM final
concentration) and 70 µg protein/ tube. Human D2- and D3-receptor-containing CHOp- cells were obtained from Dr.
Robert MacKenzie, and are grown in a minimum essential medium ( MEM) containing 10% fetal calf serum.
0.05% penicillin-streptomycin, and 600 µg/ml G418. Membranes are prepared as described above. The final pellet
is resuspended in 50 mM Tris containing 120 mM NaCl, 5 mM of KCl, 1.5 mM CaCl2, 4 mM of MgCl2, and 1
mM EDTA, pH 7.4. The binding incubation is in 2.0 ml and contains 30 µg protein/tube, and [3H]YM-09151-2
(0.2 nM final concentration). Filters are soaked in 0.1% PEI before filtering.
µ, , and
Opioid Receptors
Receptor binding studies were initially conducted on Hartley guinea pig brain membranes. Guinea pigs were
decapitated and the brains quickly removed and weighed, then homogenized in 50 mM Tris HCl, pH 7.5, using a
Polytron homogenizer. The homogenate was centrifuged at 40,000 x g for 15 min, rehomogenized, and centrifuged
once more. The final pellet was resuspended in Tris HCl, pH 7.5. at a final concentration of 6.67 mg original wet
weight of tissue per milliliter.
Routine binding assays are conducted using [3H]DAMGO, [3H]Cl-DPDPE, [3H]U69,593 for binding to µ, ,
receptors, respectively. Binding is conducted in a total volume of 2.0 ml. usually for 1 h at 25°C. Samples are
filtered and counted as described above.
Binding was also conducted on cloned receptors. Human -opioid receptor-containing CHO cells were obtained
from Dr. Lee-Yuan Liu-Chen, and are grown in DMEM with 10% fetal calf serum, 0.4 mg/ml G418, and 0.1%
penicillin/streptomycin. Human µ-opioid receptor-containing CHO cells were obtained from Dr. George Uhl, and
are grown in F12 medium containing 10% fetal calf serum and 0.4 mg/ml G418. Human -opioid receptor-
441
containing CHO cells were obtained from Dr. Hank Yamamura, and are grown in F12 medium containing 10% fetal
calf serum and 0.5 mg/ml hygromycin B. Cell membranes are prepared as described above. For binding, 30 mg
protein is incubated in 50 mM Tris buffer pH 7.7, with approximately 0.5 nM of the radioligand. Incubation
volume is 1.0 ml. Samples were filtered and counted as described above.
Functional Biochemical Assays
cAMP Production
C6 cells containing monkey D1 receptor were obtained from Dr. Kim Neve, and were grown on 96-well plates in
DMEM containing 10% FBS and 2 µg/ml of puromycin. D1 receptors stimulate adenylyl cyclase, so for these
receptors an increase in cAMP accumulation in intact cells is measured. When the cells in each well have learned
confluence, the medium is removed and each well is rinsed with 0.1 ml of Krebs-HEPES buffer (130 mM of NaCl,
4.8 mM of KCl, 1.2 mM of KH2PO4, 1.3 mM of CaCl2, 1.2 mM of MgSO4, 25 mM of HEPES, and 10 mM of
glucose, pH 7.3). The test drug is diluted in Krebs-HEPES buffer containing 0.1% ascorbic acid, 10 µM of
pargyline, and 50 µM of 3-isobutyl-1-methylxantine (IBMX) and 0.1 ml is added to each well. The plates am
preincubated for 20 mm at 37°C with or without antagonist, then incubated for an additional 10 min with the test
compound. After incubation, the medium is removed and 0.1 ml of 0.5 M formic acid is added, then the supernatant
is removed and 1yophilized. cAMP is quantitated using the protein kinase binding assay of Gilman (1970).
Stimulation of Mitogenesis
To measure D2 and D3 stimulation of mitogenesis (Chio et al., 1994). CHOp- cells are used in a 96-well mate
containing approximately 5.000 cells/well. The cells are incubated at 37°C in a MEM with 10% FBS, 0.05
penicillin-streptomycin, and 200 µg/ml Geneticin (G418 sulfate). After 48 h, the wells are rinsed twice with 100µl aliquots of serum-free a MEM and incubated for 24 h at 37°C in serum-free MEM. The medium is then
removed and replaced with 90 µl of serum-free a MEM and 10 µl of drug in sterile water. After another 24 h of
incubation at 37°C, 0.25 µCi of [3H]thymidine is added to each well. The cells are incubated for 2 h at 37°C.
Then, 10 µl/well of 10x trypsin is added to remove the cells, and the plate is filtered using a Tomtec cell harvester,
and counted in a Betaplate Reader (Wallac).
[ 3 5 S]GTP S Binding
[ 3 5 S]GTP S binding is used to measure activity of µ, , and opioid receptors. Binding is conducted basically as
described by Traynor and Nahorski (1995). Cells are prepared as described above, and suspended in Buffer A,
containing 20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, pH 7.4. For the binding assay, membranes (15 mg
protein) are incubated with [35S]GTP S (50 µM). GDP (usually 10 µM), and the desired compound, in a total
volume of 1 ml, for 60 mm at 25°C. Samples are filtered over glass fiber filters and counted as described for the
binding assays above. Dose-response curves with the full agonists DAMGO, DPDPE, and U69,593 are determined
in each experiment to identify full and partial agonist compounds at µ-, -, and -opioid receptors, respectively.
In Vitro Functional Smooth Muscle Bioassays
5-HT 2 A Receptor
Rat Aorta Spiral (RAS) Tissue Preparation
Male albino Wistar rats (200-300 g body weight) are sacrificed and their aortas quickly removed, cleaned, and cut
into a spiral. The spiral is mounted in an 8-ml water-jacketed tissue bath containing Krebs-bicarbonate solution
(118 mM NaCl, 2.5 mM CaCl2, 4.7 mM KCl, 25 mM NaHCO3, 1.2 mM KH2PO4, 1.2 mM MgSO4, and 11.5
mM glucose). The spiral is first incubated with oxygenated (5% CO2 in oxygen) Krebs solution at 37°C under 2.0
g tension for 30 min, then an additional 30 min in the presence of 500 µM of pargyline, a monoamine oxidase
inhibitor, and 10 µM of benextramine tetrahydrochloride, an a1-adrenoceptor inhibitor (Marin et al., 1981). Excess
unreacted pargyline and benextramine are then removed from the bath by flushing the system several times with the
Krebs solution.
Serotonin (5-HT) Standard Curve
For standardization purposes, the spiral is cumulatively contracted with increasing concentrations of 5-HT in the
presence of 10-4 M ascorbic acid. The 5-HT-induced contractions are recorded using an isometric transducer
(Metrigram) coupled to a Gould multichannel polygraph.
442
Agonist Determinations
A concentration-response curve is generated for the test compound, and an ED50 (agonist concentration that produces
half of the maximum contraction attainable by the agonist) value determined. To verify the test compound’s
agonist activity at 5-HT2A receptors, assays are conducted in the presence of 100 nM ketanserin.
Antagonist Determinations
Test compounds that do not produce a contraction of the spiral on their own are tested for 5-HT2A antagonist
activity. The test compound is incubated with the spiral for 30 mm, and then the 5-HT standard curve is repeated in
the presence of the drug. Antagonist activities are calculated for each single tissue from full concentration-response
curves before and after addition of a single antagonist concentration. At least three different concentrations are used,
and only one antagonist concentration is tested on each tissue. pA2 values are determined from Schild plots (Schild,
1949) using a statistical analysis program developed by B. Eynon (SRI International).
5-HT3 Receptor
Longitudinal Muscle Strip of Guinea Pig Ileum (GPI) Preparation
Male Hartley guinea pigs weighing 350-40 g are decapitated and the small intestine removed. The longitudinal
muscle, with the myenteric plexus attached, is gently separated from the underlying circular muscle by the method
of Paton and Vizi (1969). The muscle strips are mounted in an 8-ml, water-jacketed organ bath containing Krebsbicarbonate solution. The tissues are kept at 37°C and bubbled with 5% CO2 in oxygen, An initial tension of
1.0 g is applied to the strips. The tissues are equilibrated for 60 min before the start of the experiments. The
contractions are recorded as described above.
Agonist and Antagonist Determinations
Concentration-response curves are constructed with the selective 5-HT3 agonist 2-methyl-5-HT at concentrations
from 1 to 100 µM. hrdividual doses are given 20 min apart. Then the test compound is injected into the tissue
bath. If the compound contracts the GPI preparation, a concentration-response curve is constructed and the ED50,
value is determined both in the absence and presence of 100 nM ICS 205-930, a selective 5-HT3 antagonist.
Antagonist determinations using the Schild method are conducted as described above for the 5-HT2A receptor, using
the selective 5-HT3 agonist 2-methyl-5-HT.
Opioid Receptors
Longitudinal Muscle Strip of Guinea Pig Ileum (GPI)
The tissue is prepared as described above for the 5-HT3 receptor except that the muscle strip is stimulated for 60 mm
before the start of each experiment Field electrical stimulation is delivered through platinum wire electrodes
positioned at the top and bottom of the organ bath and kept a ftxed distance apart (3.5 cm). The upper electrode is a
ring 4 mm in diameter. The parameters of rectangular stimulation are supramaximal voltage, 1-ms impulse
duration at 0.1 Hz. A Grass S-88 electrostimulator is used for stimulation.
Electrically Stimulated Mouse Vas Deferens (MVD)
Swiss-Webster mice weighing 30-35 g are used The vasa deferentia are prepared according to the method of Hughes
et al. (1975), bathed at 31°C in Mg2+ -free Krebs solution, and bubbled with a mixture of oxygen and CO2 (95:5).
An initial tension of 200-350 mg is used. The parameters of field stimulation have been modified slightly from the
original description (Ronai et al., 1977); paired shocks of 100-ms delay between supramaximal rectangular pulses of
1-ms duration are delivered at a rate of 0.1 Hz.
Kinetics
The agonist potencies of lest compounds are determined from concentration-response curves and characterized by
their IC50 values. IC50 is defined as the concentration of the agonist that causes 50% inhibition of the electrically
induced contractions.
Compounds with antagonist activity are characterized by the equilibrium dissociation constant (Ke) calculated from
the following equation:
443
Ke=a/(DR- 1)
where “a” is the nanomolar concentration of antagonist and DR is the virtual shift of the agonist concentrationresponse curve to the right in the presence of a given concentration of antagonist. In the case of mixed agonistantagonist compounds, the dose ratios are determined by the “single-dose method” introduced by Kosterlitz and Watt
(1968).
A standard ratio with respect to a reference compound is also determined. The reference compound for µ- agonists is
DAMGO. that for - agonists is U69,593 and that for - agonists is DPDPE. Their Ke values with the
respective/selective antagonists are taken as 1.0.
RESULTS AND DISCUSSION
Cocaine Treatment Discovery Program
Binding affinities derived at serotonin and dopamine receptors are shown in Table 1. Affinities are given as K0.5
values ± Standard Deviation of, in general, two experiments. Also shown are Hill coefticients derived in those two
experiments. K0.5 values are derived from the Cheng-Prusoff equation: Ki = IC50/( 1 + [L]/Kd). This equation is
only strictly valid for inhibition curves with Hill coefficients of 1.0. Because binding experiments have generally
used [3H]antagonists that bind to high and low affinity conformations, Hill coefficients of unlabeled agonists are
often less than 1.0, necessitating the designation K0.5.
Activity at D1 receptors was determined by measuring agonist-stimulated increase in cAMP accumulation. One
problem encountered with this assay was that compounds known to he partial agonists exhibited full agonist
activity when measured in the D1 receptor-containing cells first obtained. Subsequently, we obtained C6 cells
containing either high or low copy number of the monkey D1 receptor. As seen in Table 2, both cell lines could be
successfully used to measure an agonist-stimulated increase in cAMP accumulation. However, in the high
expressing cells both full agonists dopamine and SKF-81297, and partial agonists SKF-38393 and SKF-77434 acted
as full agonists. In the low expressing cells, both partial agonists clearly produced significantly less cAMP than
the full agonists tested. In addition, as would be predicted for low expressing cells with no receptor reserve, each of
the agonists was fess potent, as demonstrated by a higher value for the EC50. To identify partial agonist
compounds, all further experiments were conducted on the low expressing cells.
Activity at D2 and D3 receptors was determined by measuring stimulation of mitogenic activity (Table 3). All
experiments were done in comparison to stimulation of mitogenesis by the D2/D3 full agonist quinpirole, conducted
on the same day. In this way percent maximal stimulation could he accurately determined. This method has been
useful for the identification of full and partial agonists at D2 and D3 receptors.
Functional activity at 5-HT2A and 5-HT3 receptors have been determined using smooth muscle bioassays (Table 4),
as described in Methods. Most of the standards tested have been antagonists at one or both of the 5-HT receptors.
For each antagonist, Ke values were determined by full Schild analysis.
Opiate Treatment Discovery Program
Table 5 shows values derived from binding to the µ-, -, and -opioid receptors. At the beginning of the contract,
all opioid binding studies were conducted on guinea pig brain membranes. With the cloning of the opioid receptors,
and the subsequent availability of human receptors, recent experiments were conducted on human opioid receptor
containing CHO cells. A comparison of guinea pig brain and human receptor binding indicates a very close
correlation between the two species. These affinities are listed as Ki values and were also derived from the ChengPrusoff equation. Because [3H]agonists were used in all of these binding experiments, Hill coefficients were
uniformly close to 1.0, and the designation Ki is appropriate.
Historically, smooth muscle bioassays have been used extensively for the characterization of opioid compounds.
The guinea pig ileum can be used for characterization of compounds at µ and
receptors. The mouse vas deferens
has µ, , and receptors. However, it is apparently highest in receptors, and has often been used to characterize
compounds at the opioid receptor. The activities of standard compounds at µ and receptors in the GPI, and at
receptors in the MVD are shown in Table 6. The values shown are: IC50, concentration at which the compounds
444
inhibits 50% of the magnitude of the electrically-induced contractions; the dose ratio (DR), the shift in IC50 in the
presence of 200 nM CTAP, 1 nM Nor-BNI, or 1 nM naltrindole; the Ke of the antagonist and the ratio with respect
to the prototypical agonist. Together, these values show the activity of each compound, as well as the selectivity
of each compound.
Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of
[ 3 5 S]GTP S binding in membranes from cells transfected with human µ, , or receptors. As with the
mitogenesis assay, a standard prototypical agonist (DAMGO, DPDPE, and U69,693 for µ, , and receptors) is
tested in every experiment so that percent maximal stimulation, with respect to the standard agonist, can be
determined for each compound. In general, values determined in the GTP S assays correspond quite well with the
data derived from the smooth muscle bioassays. Compounds that are listed as flat at any particular site either are
antagonists, or have low affinity for that particular site. Ke values of antagonists have not yet been determined in
this assay. The advantages of this assay are that one measures activity in tissue containing a single receptor type,
so that the use of selective antagonists is not necessary to clearly identify the site of action. In addition, GTP S
binding seems to clearly identify the efficacy of compounds. For instance, compounds such as buprenorphine and
pentazocine can easily be identified as partial agonists.
The values listed in each of these tables have also been incorporated into NIDA’s Medications Development
Database. NIDA’s OTDP and CTDP programs are still active, and we encourage the delivery of compounds into
these programs for the continued identification of potential addiction medications.
REFERENCES
Chio, C.L., Lajiness, M.E., and Huff, R.M. Activation of heterologously expressed D3 dopamine receptors:
Comparison with D2 dopamine receptors. Mol Pharmacol 45: 51-60, 1994.
Gilman, A. G. A protein binding assay for adenosine 3’-5'-cyclic monophosphate. Proc Natl Acad Sci USA 67:
305-312, 1970.
Hughes, J., Kosterlitz, H. W. and Leslie, F.M. Effect of morphine on adrenergic transmission in the mouse vas
deferens: Assessment of agonist and antagonist potencies of narcotic analgesics. Brit J Pharmac 53:371-381, 1975.
Kosten, T.R., Morgan, C., and Kleber, H.D. Phase II clinical trials of buprenorphine: Detoxification and induction
onto naltrexone. In: Buprenorphine: An alternative treatment for opioid dependence, J. Blaine (Ed) NIDA Res.
Monogr. 121, U.S. Dept. HHS, Rockville, MD, 1992, pp. 101-119.
Kosterlitz, H. W., and Watt, A.J. Kinetic parameters of narcotic agonists and antagonists, with particular reference
to N-allylnoroxymorphone (naloxone). Br J Pharmacol Chemother 33: 266-276, 1968.
Kuhar, M. J., Ritz, M.C. and Sharkey, J. Cocaine receptors on dopamine transporters mediate cocaine-reinforced
behavior. In: Mechanisms of Cocaine Abuse and Toxicity, D. Clouet, K. Asghar, and R. Brown (Eds.). NIDA
Res. Monogr. 88, U.S. Dept. HHS, Rockville, MD, 1988, pp. 14-22.
Marin, J., Salaices, M., Gomez, B., and Lluch, S. Noradrenergic component in the vasoconstriction induced by 5hydroxytryptamine in goat cerebral arteries. J Pharm Pharmac 33:715-719, 1981.
Paton, W. D. M., and Vizi, E.S. The inhibitory action of noradrenaline and adrenaline on acetylcholine output on
guinea-pig longitudinal muscle strip. Br J Pharmacol 35: 10-29, 1969.
Reith, M.E.A. Cocaine receptors on monoamine transporters and sodium channels. In: Mechanisms of Cocaine
Abuse and Toxicity, D. Clouet, K. Asghar, and R. Brown (Eds.). NIDA Res. Monogr. 88, U.S. Dept. HHS,
Rockville, MD, 1988, pp. 2341.
Ritz, M.C., E. J. Cone, E.J. and Kubar, M.J. Cocaine inhibition of ligand binding at dopamine, norepinephrine
and serotonln transporters: A structure-activity study. Life Sci 46: 635-645, 1990.
Ronai, A. Z., Graf, L., Szekely, J.I., Dunai-Kovacs, Zs., and Bajusz, S. Differential behaviour of LPH-(61-69)peptide in different model systems: Comparison of the opioid activities of LPH-(61-91)-peptide and its fragments.
FEBS Lett 74: 182-184, 1977.
Schild, H. O. pAx and competitive drug antagonism. Br J Pharmacol Chemother 4: 277-297, 1949.
ACKNOWLEDGMENTS: This work was supported by NIDA contracts N01DA-3-8302 and N01DA-4-8307.
445
Table 1
AFFINITIES OF STANDARD COMPOUNDS AT DOPAMINE AND SEROTONIN RECEPTORS
Table 1 (continued)
AFFINITIES OF STANDARD COMPOUNDS AT DOPAMINE AND SEROTONIN RECEPTORS
Table 1 (continued)
AFFINITIES OF STANDARD COMPOUNDS AT DOPAMINE AND SEROTONIN RECEPTORS
Table 1 (continued)
AFFlNITlES OF STANDARD COMPOUNDS AT DOPAMINE AND SEROTONIN RECEPTORS
Table 2
AGONIST POTENCIES FOR STIMULATION OF cAMP ACCUMULATION IN C6D1L
(Low Expressor) AND C6D1H (High Expressor) CELLS
C6D1L
Compound
EC50 (nM)
C6D1H
% Max Stim.
EC50 (nM)
% Max. Stim.
180
92
Dopamine
52
100
2.3
100
SKF-38393
44
34
6.4
95
SKF-77434
22
10
5.6
89
0.14
94
Apomorphine
SKF-81297
3.4
113
SKF-82958
5.2
88
450
Table 3
AGONIST POTENCIES FOR STIMULATION OF MITOGENESIS IN CHOp-D2 and D3 CELLS
% Max
Stim
D3
EC50 (nM)
% Max
Stim
11.00 ± 3.75
66
8.3 ± 2
100
(+)Bromocriptine
0.34 ± 0.2
81
23.0 ± 12
119
Dihydroergocristine
0.82 ± 0.015
99
22.0 ± 2
Dihydroergotamine
1.20 ± 0.48
59
3.1 ± 0.7
100
90
6.1 ± 0.4
100
76
1.4 ± 0.4
90
8.4 ± 5.74
100
Compound
Apomorphine
Dopamine
N-0437
D2
EC50 (nM)
65.00 ± 15
0.45 ± 0.28
98
Quinpirole
19.00 ± 16
100
S(-)-3-PPP
64.00 ± 7
90
SKF-82958
158.00 ± 56.5
52
7-OH-DPAT
2.80 ± 0.55
102
1.0 ± 0.24
86
Terguride
0.28 ± 0.13
96
0.72 ± 0.06
88
451
Table 4
BIOASSAY RESULTS AT 5-HT 2 A AND 5-HT 3 RECEPTORS
a
No agonist activity was found from 10-9 to 10-5M.
There was a maximum depression at each concentrations, studied.
b
Table 4 (continued)
BIOASSAY RESULTS AT 5-HT2A AND 5-HT 3 RECEPTORS
a
c
No agonist activity was found.
There was a maximum depression at 2.5 x 10-6 M concentration, studied.
Table 4 (concluded)
BIOASSAY RESULTS AT 5-HT2A AND 5-HT3 RECEPTORS
GUINEA PIG ILEUM
5-HT 3
RAT AORTA SPIRAL
5-HT 2 A
COMPOUND
Serotonin
ED50 [µM]
Agonist
0.447 ± 0.26
(11)
DR with
Ketanserin
Ke [nM] Antagonist
YM-09151-2
b
0.38 ± 0.11e
(6)
17.87 ± 5.57
(8)
There was a maximum depression at each concentrations, studied.
Determined in the presence of 100 nM ketanserin.
e
EDTA was used in the experiment instead of ascorbic acid.
d
DR with
ICS 205-930
Ke [nM] Antagonist
0.64 ± 0.25d
(6)
2.95 ± 1.29
(15)
2-Me-Serotonin
Spiperone
ED50 [µM]
Agonist
254.79 ± 58.61b
(4)
Table 5
AFFINITIES OF STANDARD COMPOUNDS AT
-OPIOID RECEPTORS OF GUINEA-PIG BRAIN MEMBRANES AND HUMAN
RECEPTORS ON CHO CELLS
Table 5 (continued)
AFFINITIES OF STANDARD COMPOUNDS AT
-OPIOID RECEPTORS OF GUINEA-PIG BRAIN MEMBRANES AND HUMAN
RECEPTORS ON CHO CELLS
Table 5 (continued)
AFFINITIES OF STANDARD COMPOUNDS AT
-OPIOID RECEPTORS OF GUINEA-PIG BRAIN MEMBRANES AND HUMAN
RECEPTORS ON CHO CELLS
Table 6
RESULTS OF STANDARD COMPOUNDS IN THE OPIATE BIOASSAYS
Table 6 (continued)
RESULTS OF STANDARD COMPOUNDS IN THE OPIATE BIOASSAYS
a
Nalorphine is a -opioid receptor agonist and a µ/ receptor antagonist. In the GPI the µ antagonist activity was determined in the presence of 20
nM Nor-BNI. Its pA2 value at µ is 7.49/-0.87, and at is 6.79/-1.05.
b
NalBzoH is an antagonist at all three opioid receptors. The pA2 value at µ is 8.81/-1.02, at is 7.76/-0.96, and at is 7.76/-1.19.
c
Nalmefene is an antagonist at all three opioid receptors. The pA2 value at µ is 9.38/-1.05, at is 7.82/-1.15, and at is 8.48/-1.01.
d
Naloxone is an antagonist at all three opioid receptors. The pA2 value at µ is 8.51/-1.07, at
is 7.30/-1.05, and at is 7.73/-0.99.
e
Naltrexone is an antagonist at all three opioid receptors. The pA2 value at µ is 9.19/-1.08, at is 8.08/-1.09, and at is 8.11/-1.03.
f
CTAP is a very selective µ receptor antagonist. Its pA2 value is 7.65 and the slope is -1.02.
g
The agonist activity could not be reversed neither with CTAP nor with nor-BNI. In -FNA treated GPI the compound is a antagonist. The pA2
value at the is 9.16/-1.28.
Table 6 (continued)
RESULTS OF STANDARD COMPOUNDS IN THE OPIATE BIOASSAYS
*Experiments with dynorphins, Met- and Leu-enkephalins were done in the presence of enzyme inhibitors.
Naltrindole is an antagonist at all three opioid receptors. The pA2 value at µ is 7.53/-1.13, at is 10.92/-0.83, and at is 7.61/-0.85.
i
NTB is an antagonist at all three opioid receptors. The pA2 value at µ is 7.95/-0.94, at is 10.55/-1.03, and at is 7.22/-1.02.
h
Table 6 (continued)
RESULTS OF STANDARD COMPOUNDS IN THE OPIATE BlOASSAYS
j
BNTX is an antagonist at all three opioid receptors. The pA2 value at in is 8.56/-0.93, at is 8.90/-1.01, and at
k
l
TIPP
is a very selective, competitive -opioid receptor antagonist. The pA2 value at is 9.17/-0.99.
IC50 could not be determined. Very shallow dose-response curve.
is 7.43/-0.78.
Table 6 (continued)
RESULTS OF STANDARD COMPOUNDS IN THE OPIATE BIOASSAYS
m
Nor-BNI is a selective 1 antagonist. Its pA2 value at the
receptor is 7.87/-1.04.
1
receptor is 10.02 and the slope is -1.14. The pA2 value at µ receptor is 7.26/-1.19, and at
Table 6 (concluded)
RESULTS OF STANDARD COMPOUNDS IN THE OPIATE BIOASSAYS
In
In the GPI the µ antagonist activity was determined in the presence of 20 nM Nor-BNI.The pA2 value in the GPI is 7.69/-1.22. In the MVD from
10-9 to 10-6 M slight inhibition; from 5 x 10-6 to 5 x 10-5 M enhancement.The pA2 value in the MVD at the µ receptor is 8.20/-1.20, and at the is
7.55/-0.99.
o
IC50 could not be determined.
p
IC50 could not be determined from 10-9 to 5 x 10-5 M (maximum inhibition = 17%).The pA2 value in the MVD at the µ receptor is 9.02/-1.01, and at
the is 8.23/-0.95. The experiments were done in the presence of 5 nM nor-BNI to block any agonist effect on the tissue.
Table 7
35
STIMULATION OF [ S]GTP S BINDING TO µ, , AND
% Stimulation compared to DAMGO, DPDPE or U69,593, respectively.
RECEPTORS
Table 7 (continued)
RESULTS ON HUMAN
-CHO CELL MEMBRANES USING GTP S BINDING
% Stimulation compared to DAMGO, DPDPE or U69,593, respectively.
Table 7 (continued)
RESULTS ON HUMAN
-CHO CELL MEMBRANES USING GTP S BINDING
% stimulation compared to DAMGO, DPDPE or U69,593, respectively.
AUTHOR INDEX
Adapa I.D., 440
Abdallah, A.B., 184
Abraham, P., 273
Abram, F.Y., 189
Abramson, D., 96
Abumrad, N.N., 35
Aceto, M.D., 363, 309
Acri, J.B., 276
Adamson, L.K., 64
Adinoff, B., 151
Adler, M.W., 11, 166, 200, 224
Aerts, N., 118
Agoston, G.E., 78
Ahmed, S., 213
Ainslie, G., 30
Alexander, D., 151
Ali, J.A., 242
Ali, S.F., 236, 237
Aling. K., 215
Allen, R.M., 224, 226
Allran, K., 198
Alper, K.R., 105, 135
Allerman. A.I., 91, 99, 158, 183, 245, 344
Amass, L., 99
Ambrosio, E., 171
Amendola, C.A., 84
Ananthan, S., 113
Andem, M.I., 100, 340
Anderson, A., 77
Andia, J., 186
Andrade, X., 185, 335
Angeli-Gade, S., 243
Angelopoulos, I., 123
Anglin, M.D., 102, 182, 193, 262, 323
Annon, J.J., 262
Anthony, J.C., 68, 122, 248
Apfelbaum, J.L., 229
Appanaitis, H.A., 224
Apparsundaram, S., 34
Archer, S., 81, 85
Arendt, R., 123
Armstrong, D.L., 242
Astemborski, J., 181
Atillasoy, A., 185, 335
Ator, N.A., 14, 174, 270
Ator, R., 270
Aub, J.S., 440
Audbya, A., 274
Avants, S.K., 197, 320
Ayestas, M.A., 296
Babor, T., 240
Badger, G.J., 147
Baggott, M.J., 292
Bahl, S.M., 125
Bailey, U.J.O., 248
Baker, D.A., 139, 289
Baldessarini, R.J., 77
Baldwin, R.M., 152
Ball, S.A., 259, 316, 322
Balster, R.L., 110, 232, 233, 234
Bandarage, U. K., 156,235, 236
Banstra, E.S., 179
Baragatti, G., 291
Bard, K.A., 124
Baron, S., 176
Barrett-Larimore, R.L., 283
Barron, B., 96, 151,207
Bartok, R.E., 88
Bartrokis, G., 209
Batki, S.L., 92, 142
Baumann, M.H., 236, 296
Bayer, B.M., 115
Beal, J.M., 180, 250
Beals, J., 249
Beardsley, M., 104
Beardsley, P.M., 95, 110
Beauverie, P., 311
Beckwith, L., 135
Belding, M.A., 318
Belle, L.R., 121
Bencheriff, B., 107, 328
Bendahhou, E., 268
Benkelfat, C., 31
Berg, G., 165
Berger, S.P., 142, 143, 303
Berglund, B., 93, 162
Bergman, A., 132
Bergman, J., 73, 282
Bernardy, N.C., 240
Berrettini, W., 287
Bertha, C.M., 79, 235, 236
Berzetei-Gurske, I.P., 440
Bespalov, A.Y., 110
Bessard, G., 291
Besse, S., 207
Best, S., 151
Bickel, W.K. 46, 65, 69, 161, 172, 183, 311
Bidlack, J.M., 2, 85, 112,113, 114, 128, 129,
181, 225
Biederman, J., 129
467
Bigelow, G.E., 45, 89, 139, 218, 308, 314,
327
Birmingham, A., 284
Blakely, R.D., 33, 34
Bliss, R.L., 138
Blitz, C., 252
Bloom, A.S., 66, 203
Bloomer, C., 154
Blundell, P., 78
Boardman, C., 206
Bodner, G., 105,116
Boja, J.W., 273, 278
Boles, SM., 190
Bonate, P.L., 295
Booth, R.E., 180, 186, 194
Bordnick P.S., 98, 143, 144, 145, 146, 151
Borenstein, M., 221
Borg, L., 111, 167
Bostrom, A.G., 158, 266
Bouchez, J., 311
Bowen, S.E., 234
Bowen, W.D., 79, 235, 236, 272
Bowman, E.R., 309, 363
Bayer, J.S., 222
Bradley, M. 92
Brady, K.T., 137
Brady, T.M., 187
Brakke, K.E., 170
Brandt, M.R., 109
Brandt, S.R., 440
Bremner, K., 75
Breslau, N., 48
Brethen, P., 298, 299
Brewerton, T., 257
Brewster, J.T., 264
Bridge, P., 209, 306
Brine, G.A., 163
Bristow, L., 279
Broadbear, J.H., 212
Brockington, A., 302
Brodkin, E., 293
Brook, D.W., 103
Brook, J.S., 103
Broome, K.M., 187, 323
Brooner, R.K., 32, 112, 113, 129, 130, 254,
263, 321, 327, 341
Brown, L.S. Jr., 319, 344
Brunswick, A.F., 178
Bryant, T.A., 296
Buchhalter, A.R., 314
Budney, A.J., 69
Buhringer, G., 332
Bullock, M., 260
Burleson, J.A., 252
Busdiecker, O., 123
Busto, U.E., 75, 220
Butelman, E.R., 85, 227
Byers, B., 184
Byrnes, K., 177
Cabrera, C., 345
Cacciola, J.S., 91, 99, 183, 245
Cadet, J.-L., 272, 289
Caine, S.B., 279
Calarco, J.S., 206
Calhoun, S.R., 175
Callahan, P.M., 216, 301
Calsyn, D.A., 97, 326
Camf, J., 75, 290
Campbell, J., 149, 343
Campbell, U.C., 230
Cannon, D.G., 86
Canty, M., 201
Carey, G., 282
Guise, D., 331
Carlson, G., 260
Carmona, G.N., 217, 220
Caron, M.G., 34
Carpenter, L.L., 152
Carpenter, M., 316
Carriero, N.J., 260
Carroll, F.I., 33, 157, 163, 272, 273, 278
Carroll, M.E., 210, 230
Casadonte, P.P., 90
Castle, M., 241
Casalman, S., 165
Cashman, J.R., 77
Catapano, D., 141
Caunt, L., 160
CDATOSC, 188
Cecero, J.J., 322
Chabot, R., 135
Chairasini, D., 207
Chait, B.T., 225, 227
Chakrabarti, A., 237, 238
Chambers, L.K., 64, 77
Ghan, M. 324
Chang, L., 197
Chang, S.L., 114, 117
Charuvastra, V.C., 228, 312
Chawarski, M.C., 89, 310, 316, 338
Chen, K., 69
Chen, R., 96, 143, 144, 151, 207
Chen, X.H., 224
Chen, Z., 78
Cherek, D.R., 333, 339
Cheskin, L.J., 204
468
Chiamulera, C., 157
Chiang, C.N., 306
Chilcoat, H.D., 48
Childers, S.R., 127
Childress, A.R., 59, 67, 106, 146
Chitwood, D.D., 179, 330
Chivers, T., 325
Cho, J.-K., 66, 203
Chu, M., 319, 320
Churchill, S.S., 179
Chutuape, M.A., 316, 317, 325
Cicero, T.J., 212
CIDUS, 184
Clark, D.C., 190
Clark, H.W., 150, 256
Clark, L.L., 97
Clincke, G., 118
Co, C., 277
Coalson, D.W., 111, 228, 229
Cochrane, C., 257
Coffey, G.P., 139
Coffman, L.M., 252
Cohen, B.M., 106, 154, 219
Cohen, D.J., 81
Cohen, J., 342
Cole, O.J., 134
Coles, CD., 124, 125, 342
Collin, M., 123, 279
Collins, E.D., 172, 221
Collins, S.L., 84, 279
Colón, H., 186
Comer, S.D., 70, 172, 221, 239
Comerford, D., 330
Comfort, M., 337, 340
Compton, D.R., 94
Compton, P., 228
Compton, W.M., III, 184, 189, 194, 320, 321
Cone, E.J., 218, 220, 223
Conley, K.M., 111
Conrod, P., 31
Contreras, P.C., 295
Cook, C.D., 168, 169, 269
Cook, J.M., 72
Cook, T.G., 344
Cooke, R.H., 100, 340
Coombs, R.H., 249, 336
Cooney, N., 320
Coop, A., 79, 80
Copeland, A., 39
Copersino, M.L., 132
Coppel, A., 313
Cornelius, M.D., 136
Corrigall, W.A., 64
Cottler, L.B., 103, 184, 189, 194, 320, 321
Couceyro, P.R., 83, 269, 270
Covey, W.C., 227
Covi, L., 145
Cowan, A., 88, 221
Coyle, S.L., 39
Craddock, S.G., 323
Craft, R.M., 88, 222
Craymer, K., 440
Crespo, J.A., 171
Criado, J.R., 164, 165
Crouch, D.J., 71, 119
Crowley, T. J., 130, 194, 251, 264
Cruz, S.L., 233
Cunningham, K.A., 216, 301
Cunningham-Williams, R.M., 194
Curtis, A.E., 300
Dacpano, G., 132
Dallery, J., 267
Damaj, M.I., 65
Danek, K., 33
Daniels, S.L., 138, 258, 332
Danila, B., 262
Dannals, R.F., 107, 328
Dansereau, D.F., 189
DATOS, 188
Daunais, J.B., 127
Davenny, K., 181
Davies, H., 284
Davis, S.L., 126
Dawe, S., 120
Dawson, D., 193
Day, N.L., 136
Day, S., 145, 146
Dayer, C.A., 177
de Costa, B.R., 235
De Haes, P., 118
de la Torre, R., 75,290
De Souza, E.B., 270
de Wit, H., 30, 31, 242, 292
Deichler, P., 194
De Jesus, A., 131, 179
Delucchi, K., 142, 143, 192, 203, 266
Delva, J., 248
Dematteis, M., 291
DeMatteo, D.S., 324
Demsky, S., 319
Deren, S., 104, 186, 195
Dersch, C.M., 79, 80, 161
Des Jarlais, D.C., 185, 205, 335
Desmond, D., 103, 194
Cornish, J., 306
Deutsch, C.R., 315
469
Deutsch, H.M., 76
Devous, M.D., 151
Dewey, S.L., 280
Dewey, W.L., 9
Dhopesh, V., 306
Dhother, S., 96, 207
Di Marino, M.E., 139
Diamant, K., 155
Diamond, H.F., 213, 214
DiClemente, R., 191
DiGregorio, J., 263
Dilley, J.W., 192
Dimen, K.R., 96
Ding, Y.S., 157
Dinsmoor, M., 133
Dixon, H., 97
Donovan, D.M., 268
Dorfman, D., 198
Douglas, S.D., 26
Dow, S., 101
Downey, K.K., 66
Doyle, S.R., 266
Droll, K.P., 222
Droungas, A., 67
Dudish-Poulsen, S.A., 144
Duncan, R.C., 179
Dunn, K.L., 115
Duran, R., 254
Duwe, A., 332
Dworkin, S.I., 33, 244, 277, 278
Dykstra, L.A., 201, 224, 226
Easterling, K.W., 110
Easton, C., 240
Eaves, D., 192
Eckhardt, E., 264
Eckman, T.A., 256
Eder, H., 155, 343
Edgar, D.M., 295
Edwards, C.H., 91, 134
Edwards, M.A., 279
Ehlers, K.M., 251
Ehrenkaufer, R., 154
Ehrman, R.N., 67, 97
Eichmiller, P.R., 309
Eisenberg, R., 58
Einstein, T.K., 23, 200
Eissenberg, T., 89, 314
Elk, R., 125, 330
Elliot, E.E., 174
Elliott K.J., 87
Ellis, W., 292
Elmer, G., 171, 302
Engber, T.M., 295
Ennis, E., 99
Enriquez, P., 198
Ensminger, M., 261
Erney, E.L., 67
Ernst, T., 197
Erös-Sarnyai, M., 138
Espinosa, M., 135
Etheridge, R.M., 188
Etzersdorfer, P., 343
Evans, SM., 132, 334, 335
Fahnbulleh III, F.W., 264
Falk, J.L., 219, 284
Fang, B., 96, 151, 207
Fant, R.V., 71, 308
Farabee, D., 103
Faraone, S.V., 129
Farkas, K., 123
Farré, M., 75, 290
Farrington, L., 440
Fein, G., 154
Felch, L.J., 139
Fernando, S.R., 238
Ferrado, R., 171
Festinger, D.S., 247, 259, 324
Fiala, M., 117
Fidler-Sheppard, R., 108
Filing, J.I., 100, 340
Finlinson, A., 186
Finnell, R.H., 27
Fiorentine, R., 323
Firely, M., 247
Fischer, G., 155, 343
Fischman, M.W., 34, 41, 70, 172, 221, 239,
335
Flaherty, J.A., 187
Flannery, B.A., 146
Fleckenstein, A.E., 288, 344
Fleming, D.N., 93, 94
Fleming, P.R., 93
Flippen-Anderson, J.L., 162
Flory, M., 178
Flynn, P.M., 323
Folkman, S., 192
Follis, A., 247
Foltin, R.W., 35, 70, 239, 334, 335
Fontaine, K.R., 204
Foote, I., 329
Fowler, J.S., 35
Fox, B.S., 84
Fox, L.M., 303
France, C.P., 73, 109, 168, 429
Franki, N., 114, 202
Emurian, C.S., 175
410
Frederick, S.L., 159
Freedland, C., 237
Freedland, R.L., 124
French, E.D., 233
French, M.T., 330
Friedman, S.R., 185, 205
Friedmann, P., 205, 335
Froimowitz, M., 281
Frosch, D.L., 67, 191
Frost, J.J., 107, 328
Fuchs, K., 306
Fuchs, R.A., 139, 140, 289
Fudala, P.J., 206, 306
Fuller, S.A., 66
Funada, M., 268
Fuqiang, Z., 163
Fureman, I., 206
Fursy, T., 162
Gabriele, F., 134, 313
Gabrielli, W., 149
Gabryszuk, M., 285, 290
Gage, H., 154
Gainetdinov, R., 34
Galinkin, J.L., III, 228, 229
Gallagher, T., 184
Galloway, G.P., 175
Gan, T., 72
Gan, X., 117
Garcia de Soria, V., 171, 205
García-Lecumberri, C., 171
Gardner, E.L., 124, 281
Gardner, J.M., 124
Gariti, P., 158
Garnand, D., 312
Garrett, B.E., 285
Garvey, K., 247
Gatch, M., 86
Gauthier, C.A., 168
Gaveriaux-Ruff, C., 112
Geller, E.B., 166, 200, 224
Gendelman, H.E., 52
George, F., 58
George, M.S., 151
Gerak, L.R., 73, 429
Geyen, D.J., 180, 250
Ghosh, S., 108
Giacchino, J.L., 165
Gibb, J.W., 288, 344
Gibbons, N., 114
Gil-Rivas, V., 323
Gilliam, A.F., 94, 345
Giordano, A., 281
Glassman, S.D., 257
Glennon, R.A., 285, 290
Glick, S.D., 156
Glowa, J.R., 141, 211, 214
Godboldte, C., 338
Goeders, N.E., 212
Goehl, D., 146, 206
Goehl, L., 206
Gogüs, A, 240
Gold, L.H., 198, 299
Goldberg. S.R., 140, 208, 216, 217, 220
Goldman, M., 209
Goldstein, M.F., 104, 195, 264
Goldstein, R.B., 247
Gombas, W., 343
Gomez, O.W., 179
Gomez-Flores, R., 199
Gonzalez, J., 287
Gonzalez, M.D., 78
Gorelick, D.A., 107, 159, 204, 208, 209, 220,
260, 305, 309, 328
Gorman, A.L., 87
Gosnell, F., 59
Gossop, M., 91
Gottheil, E., 195, 257
Goutopoulos, A., 94, 95
Grabowski, J., 76, 125, 266, 330
Graf, J.A., 114
Graham, S., 125
Grannum, J., 338
Grant, K.A., 243, 284
Grasing, K., 108
Graves, M.C., 117
Greberman, S.B., 261
Grech, D.M., 74
Green, R.J., 158
Greenfield, L., 337
Greenfield, S.F., 121, 253
Greenough, A., 125
Greenwald, M.K., 32, 112
Greig, N.H., 217, 220
Grella, C.E., 102, 188, 193
Griffin, P., 165
Griffiths, R.R., 74, 285, 286
Grocki, S., 64
Groff, R.S., 140
Groves, M., 192
Guidry, H.M., 180
Guillemet, I., 130
Gulati, V., 298, 299
Gunduz, M., 105, 167
Guodong, Y., 163
Gupman, A.E., 246
Gursoy, B., 240
471
Guydish, J., 324
Haberny, K.A., 139
Haggart, D., 440
Haile, C.N., 293
Hall, D., 115
Hall, G.W., 260
Hall, S.M., 68, 90, 143, 159, 203, 326
Hailer, D.L., 193
Hamid, R., 186
Hammer, M.A., 144
Handelsman, L., 198, 329
Haney, M., 70, 239, 335
Hanson, G.R., 288, 344
Harada, N., 152
Harald, E., 134, 313
Harden, P., 31
Hardin, J.S., 231
Harris, D.S., 142
Harris, L.S., 363
Harris, P., 160
Harsch, H.H., 66, 203
Hart, C., 143
Hartz, D., 326
Hasson, A.L., 298, 299
Hatsukami, D.K., 138, 144
Hauf, M.A., 92
Haug, N.A., 339, 341
Havassy, B.E., 90, 190
Hawkins, W., 96
Hays, L.R., 175
He, X., 72
Heagy, W., 201
Heather, N., 120
Heatherington, A.C. 176
Heinrichs, S.C., 213
Heishman, S.J., 71, 119, 250
Helmers, K., 31
Hemby, L.W., 146
Hen, R., 270
Henningfield, J.E., 159
Henriksen, S.J., 164, 165
Henry, S., 204
Herbst, K., 332
Herbst, MD., 297
Herman, B.H., 306
Hernández, C., 75
Heyliger, S.O., 127
Heyman, G., 30
Heyser, C.J., 119, 299
Higgins S.T., 69, 147, 161
Hill, B.H., 309
Hill, K.P., 81, 85, 128
Hillard, C.J., 93
Hiller, J.M., 128
Ho, A., 83, 105, 111, 116, 122, 153, 166,
167, 232, 271, 300
Ho, L.B., 303
Ho, W.-Z., 26
Hoffer, B.J., 52
Hoffman, J.A., 82, 102, 103, 190
Hoffman, J.M., 82
Hoffman, V., 102
Hogan, I., 240
Hole, A.V., 146
Hollander, J.R., 263
Holloway, H., 220
Holmberg, S., 184
Holmes, I., 180
Holmquist, C., 273
Holtzman, S.G., 76, 110, 170, 288, 294, 304
Hong, J.-S., 199
Hopfer, C., 130
Hopper, J.A., 66, 296
Horton, I., 321
Horton-MacNeill Jr, A., 267
Houtsmuller, E.J., 314
How, T., 23
Howard, J., 135
Howell, L.L., 33, 82, 278
Howlett, A.C., 93, 162
Hser, Y.-I., 102, 193
Hsieh, S., 188
Hsu, Jr. K., 303
Hua, L., 232
Huang, Q., 72
Hubbard, C., 284
Huber, A., 101, 399, 297, 298, 299
Huestis, M.A., 223
Huff, R.A., 164
Hughes, J.R., 160
Humeniuk, R.E., 120, 243
Humfleet, G., 68
Hunter, R., 278
Hurt, H., 27
Husbands, S.M., 272
Hutchinson, I., 85
Ignatowski, T.A., 113
Iguchi, M.Y., 108, 247, 318
Ikeda, H., 217
Ildefonso, G., 185, 335
Ilgin, N., 107, 328
Inciardi, J.A., 103, 185
Ingersoll, K.S., 193
Innis, R.B., 152
Inturrisi, C.E., 87
Issari, P., 249, 336
472
Izenwasser, S., 78, 171, 272, 273, 275
Jackson, T.R., 97
Jacob, III, P., 291
Jacobs, E.A., 311
Jacobson, A.E., 346
Jacoby, M.H., 192
Jagsch, R., 343
James, H., 134
Janetka, J., 161
Janiszewski, D.J., 229
Janowsky, A., 77
Jansson, L.M., 133, 342
Järbe, T.U.C., 94, 95, 108
Jarvis, M.E., 67, 133
Jasinski, D.R., 133
Jauffret, M., 313
Jean, C., 338
Jefferson, L., 204
Jeohn, G.-H., 199
Jewell, J.L., 305
Ji, Z., 309
Joe, G.W., 98, 187
Johanson, C.-E., 32, 41, 45, 112
John, D., 180, 194
John. E.R., 105
Johnson, A.A., 134
Johnson, B.A., 96, 143, 144, 151, 207
Johnson, B.D., 196
Johnson, D.E., 131
Johnson, E., 121
Johnson, E.O., 40, 131, 245, 246
Johnson, K.M., 230
Johnson, M., 155
Johnson, P.I., 165
Johnson, R.E., 89, 133, 314
Johnson, V., 250
Jones, H.E., 232, 234
Jones, M.S., 312
Jones, R.T., 291, 292, 310
Jones, S., 33, 34, 134
Jones, T., 92
Jose-Melchor, R., 197
Joseph, D.B., 79
Joy, L.I., 338
Jufer, R., 218, 220
Juon, H.-S., 261
Justice, A., 292
Justice, Jr, J.B., 33, 288
Kable, J. 33
Kadden, R.M., 252
Kahler, L., 260
Kakiuchi, T., 152, 153
Kalivas, P.W., 84
Kaltenbach, K., 337, 340
Kamien, J.B., 45, 46, 99
Kaminer, Y., 252
Kampman. K.M., 97, 206, 306
Kandel, D.B., 69
Kantak, K.M., 84, 279
Kanthasamy, A.G., 303
Kapasi, A., 114, 201
Kaplan, H.L., 220
Kaplan, S., 192
Karmel, B.Z., 124
Kasper, S., 155
Kathiramalainathan, K., 220
Kathrin, S.-M., 134
Kato, H., 171
Katovic, N., 343
Katz, J.L., 272, 283, 303
Kaufman, M.J., 106, 154, 210, 219
Kautz, M.A., 243
Kavadia, V., 125
Kearn, C.S., 93
Keating, J., 125
Keeney, M. M., 259
Keese, L., 134
Kehner, G.B., 88
Kellam, S., 43
Kelly, J.F., 121
Kelly, T.H., 175
Kennedy, J.M., 440
Kenny, P., 207
Kesee, L., 134
Keverline-Frantz, K.K., 273
Khroyan, T.V., 289
Kidorf, M.S., 129, 254, 263, 321, 327
Kieffer, B.L., 112
Kilic, C., 240
Kilts, J.D., 274
Kim, S.A., 86
Kimmel, H.L., 170
Kincaid, J., 198
King, A., 111
King, V.L., 129, 254, 263, 321, 327
Kintaudi, P., 315
Kirby, K.C., 76, 247, 259, 324
Kishioka, S., 167
Kissin, W., 133, 342
Kisson, W.B., 133
Klaassen, A., 213
Klafta J.M., 111, 228, 229
Kleber, H.D., 132, 331
Klein, H., 190
Kline, R.H., 273, 283
Klock, P.A., 111, 228, 229
473
Knight, E.M., 134, 227
Knight, K., 75
Knight, P.R., 227
Knisley, J, 133
Ko, M.-C., 85
Kokoshka, J.M., 288
Kollins, S.H., 47, 294
Kong, L.-Y., 199
Konstanturos, A., 119
Koob, G.F., 119, 198, 213
Kometsky, C., 280
Kosten, T.A., 160, 293, 316
Kosten, T.R., 36, 48, 131, 137, 152, 197,
308, 316, 320, 328
Kouri, E.M., 70
Kowalik, S., 105, 135
Kowalis, K.
Koylu, E.O., 269, 270
Kramer, H.K., 128
Kreek, M.J., 36, 83, 105, 111, 116, 122, 128,
152, 153, 166, 167, 225,227, 232, 271,
300
Kreuter, J., 153, 271
Kruzich, P.J., 222
Kuczenski. R., 82
Kuehne, M.E., 156, 235, 236
Kufner, H., 332
Kuhar, M.J., 33, 83, 157, 269, 270, 273, 278
Kuhn, C.M., 126, 301
Kukes, T.J., 106, 154, 210
Kula, N.S., 77
Kulagowski, J., 279
Kumaraswamy, G., 337
Kun, K., 307
Kunko, P.M., 214, 272
Kushner, S.A., 280
Kwiatkowski, C.F., 180, 194
LaBounty, L.P., 210
Lachman, H., 268
Ladenheim, B.N., 272, 289
LaForge, K.S., 83, 166
Lai, J.-P., 26
Lamb, R.J., 94, 95, 108, 247
Lambert, P.D., 269, 270
Lamki, L., 96, 151, 207
Lancaster, J.S., 267
Landrum, A.M., 82
Landry, D.W., 345
Lane, S.D., 333, 339
Lange, N., 106
Langleben, D., 155
Laya, H., 134
Latour, C., 207
Lau, C.E., 176, 219, 284
Laudet, A., 126
Law, F., 306, 307
Lawler, C.P., 274
Lawrence, G.L., 170
Lee, R.-S., 164, 165
Leech, S.I., 136
Lefebvre, M., 255
Legan, S.J., 175
Lehmann, P., 91
Leiderman, D., 209
Leikin, J.B., 223
Lemarquand, D., 31
Leon, S.L., 252
Leonido-Ye, E.M., 197
Lepore, M., 281
LeSage, M.G., 141, 211
Leshner, A.I., 3
Leukefeld, C.G., 103
Levant, B., 77
Levin, F.R., 132, 152, 255, 334
Levitt, J.M., 106, 154
Lewis, D.E., 223, 226
Lewis, J.W., 226
Lewis, S.N., 170
Li, S.H., 301, 320
Liang, A.Y., 78
Liang, F., 78, 157
Liberto, J.G., 78, 309
Lichtman, A.H., 96
Lidz, V., 263
Liebson, I.A., 308
Liguori, A., 244
Lin, E., 310
Lin, S., 94, 95
Lindholm, J., 209
Ling, D.A., 312
Ling, N.C., 270
Ling, W., 67, 101, 191, 209, 228, 298, 299,
312, 315, 322
Linner, K., 201
Lipton, D.S., 264
Liskow, B., 149
Little, P.J., 126
Liu, H.F., 268
Liu, X., 281
Llosa, T., 258
Logan, J., 35
London, J., 192
Longshore, D., 182, 188
Lu, X.-C., 234
Lu, Y.F., 163
Lucas, K., 242
414
Luck, G.J., 100, 340
Lugo, W., 205
Lukas, P., 313
Lukas, S.E., 70, 72 106, 138, 154, 258, 332,
334
Lundahl, L.H., 258, 332, 334
Lundy, A., 195, 257
Lynch, M.E., 124, 342
Lynch, W.J., 210
Lysle, D.T., 23, 201
Ma, F., 219
Maas, L.C., 154
MacArthur, R.B., 221
Macenski, M.J., 211, 333, 345
Macfadden, W., 306
Mach, R.H., 154, 280
Mackler, S., 27
Madden, G.J., 23, 65
Madras, B.K., 78, 274
Mager, D., 240
Maggos, C.E., 153, 166, 232
Magura, S., 101, 126, 319, 329
Maillet, M., 207
Mailman, R.B., 274
Maisonneuve, I.M., 156
Makriyannis, A., 94, 95
Malcolm, R., 137, 257
Malison, R.T., 152
Malkemeker, U., 317
Mallaret, M., 29, 291
Malow, R.M., 148
Maniar, S., 167
Mann, G.L., 156
Mansbach, R.S., 64, 237
Mantsch, J.R., 212
Marczyk, G.R., 324
Margolin, A., 197, 320
Markman, I., 100, 340
Marlowe, D.B., 247, 253, 259, 324
Marques, P.R., 336
Marsch, L.A., 183
Marsden, J., 91
Marshall, J.E., 325
Martin, B.R., 65, 94, 95, 96, 239, 345
Martin, C.A., 175
Martín, S., 171
Martin, T.J., 86
Mas, A., 290
Mas, M., 75
Mascia, J., 123
Mascovich, A., 192
Masson, C.L., 92, 192
Matecka, D., 162, 271
Mathews, W.B., 107, 328
Matsumto, R.R., 235, 303
Matsuzawa, S., 241
Matthes, H.W.D., 112
Mattick, R.P., 104, 120
Maude-Griffin, P., 326
Maugans, W., 151
May, E.L., 363
McAvay, G., 247
McBride, D.C., 185, 330
McCafferty, M.R., 166
McCance, E., 137, 152
McCann, M., 322
McCord, J., 261
McCormick, C.M., 133, 342
McCreary, A.C., 301
McCullough, K., 79, 80, 161
McDavit, S., 254
McDermott, P.A., 344
McDermott, R., 203
McDonald. J.C., 210
McDonald, J.S., 299
McDowell, D.M., 255
McElgin, W., 106
McGill, T., 100
McGinnis, D., 97
McGirr, K., 83, 278
McIntosh, E.M., 115
McKay, J.R., 91, 99, 183
Mcketin, R., 104
McLaughlin, J.P., 225
McLellan, A. T., 245, 318, 331
McMahon, R.C., 148
McMillan, D.E., 325
McNamara, C., 100, 148, 149
Medzihradsky, F., 408
Meert, T.F., 118
Meil, W.M., 278
Meisch, R.A., 96, 109, 151, 207, 211, 333
Meissler, Jr, J.J., 200
Melichar, J., 306, 307
Mello, N.K., 55, 86, 219, 275, 277, 279
Meltzer, P.C., 78
Mendelson, J., 291, 292, 310
Mendelson, J.H., 106, 154, 210, 219, 275
Mengis, M., 326
Menoyo, E., 75
Metsch, L.R., 330
Meager, D., 183, 206, 344
Metzger, R.R., 288, 344
Meza, E., 240
Michael, M., 100, 148, 191
Mick, E., 129
475
Mickalian, J.D., 142, 143
Mignot, E., 295
Mikulich, S.K., 99, 130, 251, 252
Milby, J.B., 100, 148, 149, 191
Miller, M., 185, 335
Miner, L.L., 268
Minnes, S., 123
Mintzer, M.Z., 74
Miotto, K., 322
Mirshashi, T., 233
Musky, A.F., 129
Misawa, M., 171, 173, 217, 241
Mishra, P.K., 115
Mo, Q., 214
Mody, S., 92, 130
Moeller, F.G., 339
Molnar-Southon, D., 315
Monahan, G., 262
Monterroso, E., 184
Montgomery, A., 306
Montoya, I.D., 208, 260, 342
Moon, J., 92
Moore, C.M., 223
Moore, J., 137
Morgan, D., 169, 269
Morral, A.R., 108, 318
Morrow, C.E., 179
Morton, T., 154
Mosher, K., 108
Mozley, P.D., 106
Muenz, L.R., 121
Muhammad, S., 315
Mulvaney, F.D., 245, 262
Muñoz, R., 68
Munzar, P., 140
Musachio, J.L., 107, 328
Muse, K.M., 175
Myers, J., 153
Myles, J., 306, 307
Nader, M.A., 127, 154, 280, 284
Nader, S., 284
Nagase, H., 171, 241
Nahas, G., 207
Nahom, D., 191
Nair, M., 25
Najavits, L.M., 253
Nakayama, D.K., 23
Napier, T.C., 165
Narula, G., 134
Narvaez, R., 92
Nath, R.P., 291
Navaline, H., 206
Navarro, H., 157
Neaigus, A., 185, 335
Needle, R.H., 39
Negus, S.S., 55, 86, 275, 277, 279
Neisewander, J.L., 139, 140, 289
Nelson, C.B., 244
Nelson, R.A., 107, 209, 305, 328
Nemazany, A., 162
Neumark, Y.D., 68, 122, 248
Neumeyer, J.L., 77
Neviaser, S., 96
Newman. A.H., 78, 234, 272, 273, 283, 303
Newman, L.C., 87
Newton, T.F., 117, 209
Ni, Q., 127, 162
Nichols, D.E., 274
Nicholson, K.L., 232
Nickel, E.J., 149
Nishimura, M., 217
Nishiyama, S., 152, 153
Norbeck, J., 309
Novins, D.K., 249
Novy, P.L., 160
Nunes, E.V., 247, 255
Nutt, D., 306, 307
Nwakeze, P.C., 319
O’Brien, A., 440
O’Brien, C.P., 67, 97, 99, 100, 106, 146,
241, 306, 340
O’Brien, S.J., 52
O’Connor, P.G., 89, 204, 310
O’Dell, L.E., 139
O’Donnell, E., 90
O’Kane, J.B., 186
O’Malley, K.L., 274
O’Malley, S.O., 141
O’Sullivan, M.J., 179
Oderinde, V., 96, 143
Oglesby, M.W., 281
Ohuoha, D.C., 302
Ojeda, L., 205
Ojo, B., 76
Okin, R.L., 192
Oliver, D., 186
Oliveto, A., 137, 316
Onaivi, E.S., 237, 238
Orozco, S., 72
Ouaou, R.W., 150
Overton, D., 151, 207
Owens, S.M., 231
Oyemade, U.J., 134
Ozgen, G., 240
Pakes, J., 89, 92, 130, 310, 338
Palij, M., 329
416
Pitts, R.C., 226
Platt, A.K., 263
Plait, J.J., 253, 359, 324
Platzman, K.A., 124
Plessinger, M.A., 81
Plöchl, W., 155
Plunkett, M., 249
Poddig, B., 317
Podus, D., 265
Polgar, W.E., 440
Polis, I., 198, 299
Ponath, C., 324
Pope Jr, H.G., 70
Porges, S., 208
Porrino, L.J., 127
Porter, M., 167
Portnoff, M., 191
Portoghese, P., 201
Poudevida, S., 290
Powell, K.R., 294
Prendergast, M.L., 265
Preston, K.L., 45, 131, 139, 145, 179, 196,
223, 260, 327
Price, L.H., 152
Price, R.K., 48
Prichep, L.S., 105, 135
Proksch, J.W., 231
Quiñones-Jenab, V., 122
Radonovich, K.J., 69
Radzius, A., 159
Ragsdale, T., 315
Raisch, D.W., 312
Rajogopal, D., 340
Ralston, P., 92
Ramamoorthy, S., 34
Rao, S.M., 66, 316
Raskind-Hood, C.L., 342
Ratkos, L.M., 207
Raven, H.T., 107, 328
Rawls, J.E., 319
Rawson, R.A., 67, 101, 191, 298, 299, 315,
322
Raynovich, J., 92
Rea, W.P., 276
Reback, C.J., 102
Reber, E., 331
Reddi, K., 114
Reddy, K., 202
Reed, B., 33
Reed, S., 208
Rees, V., 120
Reggio, P.H., 238
Reid, M.S., 142
Pandina, R.J., 250
Pani, A.K., 276
Paninopoulas, M.A., 324
Pankiewicz, J., 66, 203
Panlilio, L.V., 215
Paone, D., 205
Paredes, W., 281
Parker, J., 329
Paronis, C.A., 73
Parsons, L.H., 299
Partilla, J.S., 79, 162, 163
Patel, J.A., 114
Patel, S., 279
Patrick, G.S., 65
Patterson, A.B., 304
Payne, J.K., 151
Pazzaglia, P.J., 242
Pearson, F., 186
Pechulis, A.D., 81
Pellegrino, T.C., 115
Peltier, R.L., 281
Peluso, J., 112
Penick, E., 149
Penn, P., 254, 329
Pentel, P.R., 138, 144
Perkins, K.A., 45, 46, 205
Perkins, M.P., 205
Perkins, P., 205
Perlman, DC., 205
Perret, G., 271
Pertwee, R.G., 94, 238, 345
Peters, T.J., 125
Peterson, J., 31
Petra, E., 134
Petrakis, I., 137
Petro, C., 331
Petry, N.M., 172, 311
Pettinati, H.M., 100, 340
Pezawas, L., 155
Pham, K., 83
Phibbs, C.S., 192
Phillips, A., 59
Phillips, M., 230
Pickens, R.W., 40, 42, 121, 131, 179, 245,
246
Picker, M.J., 168, 169, 269
Pickworth, W.B., 71
Pierce, R.C., 84
Pierre, P.J., 293
Pihl, R.O., 31
Pinto, F., 79, 194
Pitre, U., 189
Pitt, L., 319
477
Reilly, P.M., 150, 256
Reinhold, J., 134, 313
Reiss, J., 253
Reivich, M., 106
Renshaw, P.F., 106, 154, 210, 219
Reus, V.I., 68, 159
Revay, R.S., 268
Rhoades, H.M., 266, 330
Rice, K.C., 79, 80, 86, 93, 161, 162, 271
Rich, J.D., 181
Richards, J.B., 31, 148
Richter, T., 209
Riegel, AC., 233
Riggs, P.D., 251, 252
Riggs, R.L., 160
Riley, A.L., 115, 213, 214
Riley, M.E., 113
Rinaldi, P., 198
Roache, J.D., 76
Robbins, T.W., 198
Roberts, A.C., 198
Robens, A.J., 299
Roberts, D.C.S., 59
Roberts, L.J., 256
Robillard, H., 203
Robinson, J., 244
Robinson, S.E., 214
Robles, E., 327
Robles, R., 186
Rocha, B.A., 270
Roche, M.J., 238
Rodriguez E., 101
Rodriguez, L., 440
Rodriguez, L.A., 268
Rodriquez-Crane, S., 190
Rogers, T.J., 200
Rogers, V., 138
Roll, J.M., 286
Romach, M.K., 220
Rose, D., 198
Rose, S.L., 106, 154
Rosen, M.I., 308
Rosenberg, M., 208
Rosenblum, A., 101, 329
Rosenthal, M.S., 105, 132
Roset, P.N., 75, 290
Ross, B., 305
Ross, D., 191
Ross, M.H., 106
Ross, W.P., 157
Rothman, R.B., 79, 80, 127, 140, 161, 162,
163, 236, 271, 295, 301, 308
Rotrosen, J.P., 90
Rounsaville, B.J., 252, 322
Rounsaville, R.
Rovetti, C.C., 64
Rowan-Szal, G.A., 98
Rowe, L.A., 302
Rowlett, J.K., 55, 283, 429
Ruckel, S., 145
Rukstalis, M, 97
Rush. CR., 45, 47, 242, 294
Rutherford, M.J., 91, 99, 183, 262, 344
Rutigliano, P., 341
Sachs, D.P.L., 158
Sacktor, N., 52
Sagaduyu, A., 240
Sage, R., 319
Solomon, N., 205
San, L., 290
Sanwal, V., 114
Saxe, L., 331
Saxon, A.J., 326
Scalzo, F.M., 229
Scanley, B.E., 328
Schad, C.A., 288
Schechter, M.D., 278
Schindler, C.W., 140, 208, 215, 216, 217,
220
Schissel, M., 92
Schluger, J.H., 105, 167, 111, 271
Schlussman, S.D., 122, 152, 153, 232, 300
Schmeidler, J., 198
Schmidl-Mohl, K., 343
Schmirler, J., 186
Schmitz, J.M., 76, 98, 143, 144, 145, 146,
330
Schnoll, S., 133, 134
Schoenbaum, E., 181
Schottenfeld, R.S., 61, 89, 92, 130, 310, 320
Schottenfeld, S.D., 320
Schroeder, S., 34
Schuh, K.J., 314
Schuh, L.M., 66, 297
Schulger, J.H., 105, 111
Schulteis, G., 213
Schumacher, J.E., 100, 148, 149, 191
Schuman, P., 181
Schumann, I., 332
Schuster, C.R., 32, 66, 112, 297
Schwartz, R.W., 440
Schwartz, S.A., 25
Schwebel, A.K., 98
Schweri, M.M., 76
Scott, J.L., 328
Scotti, R., 206
478
Sees, K.L., 68, 203, 256
Segar, G., 91
Seibyl, J.P., 152
Sekar, P., 191
Sellers, E.M., 43, 75, 220, 222
Seltzman, H.H., 94, 238, 345
Selwyn, P., 204
Sequin, J., 31
Seracini, A.M., 247, 255
Serot, R., 195
Serota, R., 257
Serper, M.R., 132
Shafer, A., 143
Shaham, Y., 64, 107
Shandler, I., 338
Shaner, A., 256
Sharma, P., 114
Sharpe, L., 268
Shaw, V.N., 182
Shea, C., 35
Shedlin, M., 186
Shelton, K.L., 333, 345
Sheppard, R., 95
Sherwood, R.A., 125
Sheth, S., 146
Shi, J., 204
Shillington, A.M., 156
Shimoyama, M., 87
Shimoyama, N., 87
Shipley Jr, T.E., 338
Shippenberg, T.S., 55, 275, 276
Shirt, S., 313
Shoaib, M., 140, 217
Sholar, J.W., 219
Sholar, M.B., 210, 219
Shopshire, M.S., 150, 256
Shoptaw, S., 67, 101, 191
Siegel, A.J., 210
Sigmon, S.C., 147
Silveri, M., 343
Silverman, K., 223, 325, 339, 327
Silverman, P.B., 295
Sim, L.J., 127
Simms, D., 96, 143, 144, 151, 207
Simon, E.J., 36, 128
Simon, S.L., 298
Simons, L., 338
Simpson, D.D., 98, 187, 198
Sindelar, J., 320
Singer, E., 197
Singer, L., 123
Singha, A.K., 137
Singhal, P.C., 114, 202
Singleton, E.G., 145, 250
Sinha, R., 141, 240
Sitharthan, T., 120
Sizemore, G.M., 86, 277
Small, C., 337
Smith, B.J., 45, 46
Smith, C.B., 408
Smith. D.E., 175
Smith, D.K., 181
Smith, J.A., 214
Smith, J.E., 86, 277
Smith, M.A., 169
Snyder, K., 343
Soderberg, L.S.F., 116
Sofuoglu, M., 138
Solomon, L.J., 160
Sora, I., 268
Sorensen, J.L., 39, 192
Soriano, J., 131
Soto, J., 253
Spangler, R., 122, 166, 232
Spaulding, L., 146
Spealman, R.D., 55, 283
Spear, L.P., 343
Specio, S.E., 140
Specker, S., 26, 260
Spector, J., 281
Spencer, T., 129
Spengler, R.N., 227
Sperry, L.L., 66, 203
Spickard, A., 61
Spitznagel, E.L., 184
Stafford, D., 141, 211
Stahl, J.M., 170
Stahler, G.J., 338
Stange, D., 100, 148
Stauffer, R., 107, 305, 328
Steele, B.W., 179
Steffensen, S.C., 164, 165
Stein, E.A., 66, 203
Steketee, J.D., 302
Sterling, G.H., 166
Sterling, R.C., 195, 257
Stevens, C.W., 87
Stewart A.L., 91, 109, 318
Stewart D., 91
Stewart, J., 107
Stewart R.B., 109, 110
Stimmel, B., 198, 329
Stine, S.M., 137, 320, 328
Stitzer, M.L., 145, 314, 316, 317, 327, 325,
341,339
Sloller, K.B., 254, 321, 327
479
Stotts, A.L., 98, 145, 146
Strain, E.C., 89, 286, 308
Stratmann, J.A., 88
Stromberg, M.F., 241
Stuven, K., 195
Su, T.-P., 289
Subrahmanyam, R.V., 280
Suess, P., 208
Suo, J.-L., 115, 200
Surratt, H.L., 185
Suzuki, T., 171, 173, 217, 241
Svikis, D.S., 131, 133, 39, 341, 342
Taffe, M.A., 82, 198
Tajima, B., 324
Takahashi, N., 268
Takushi, R.Y., 260
Taliano,V., 337
Tallarida, R.J., 200
Tamagnan, G., 77
Tampakeras, M., 255
Tancer, M.E., 66
Tanners, L., 198
Taylor, R.C., 71, 119
Tella, S.R., 208
Telles, P.R., 185
Tennant, F., 202
Terbas, O., 240
TerBrugge, K., 75
Tessari, M., 157
Thomas, B.F., 94, 238, 345
Thomas, H.M., 149
Thomas, N., 196
Thompson, A.C., 275, 276
Thompson, L.L., 251
Thompson, S.S., 230
Thorndike, E.B., 216, 217
Thrower, C., 146
Thurnher, M., 155
Ti, A.S., 336
Tidey, J.W., 161
Tippetts, A.S., 336
Todd, RD., 274
Toll, L., 440
Tolliver, B.K., 303
Tomkins, D.M., 255
Tortella, F.C., 234
Tortu, S., 104, 186
Tourian, K., 183
Touzeau, D., 311, 313
Trager, R.S, 100, 340
Tran-Nguyen, L.T.I., 139, 140
Trauth, J., 126
Traynor, J.R., 408
Tremblay, R., 31
Triesman, G., 328
Triffleman, E., 48
Trudeau, K.J., 131, 160
True, W.R., 48
Tsao, L.-I., 289
Tsuda, M., 173
Tsukada, H., 152, 153
Tucker, M.J., 196
Tyler, R., 135
Tyndale, R.F., 220, 222
Tzanis, E.L., 311
Tzeng, T.-B., 221
Uhl, G.R., 36, 164, 268
Ulug, B., 240
Ulusphin, A., 240
Umbricht-Schneiter, A., 145, 179, 196
Underiner, G., 77
Unterwald, E.M., 153, 271
Upton, R., 310
Usdan, S.L., 148, 149
Vagge, L.M., 121
Valdivia, J., 317
Valerio, E., 157
van Bemmel, B., 226
van den Bree, M.B.M., 40, 121, 131, 245
Van Etten, M.L., 68, 122
Van Maanen, R., 196
Vandenbergh, D.J., 268
Vaughan, R.A., 78, 164
Vaught, J.L., 295
Velez, M., 342
Velten, E., 329
Vezina, P., 293
Villemagne, V., 271
Villier, C., 291
Vilner, B.J., 235, 272
Visker, K.E., 156
Vitkun, S., 35
Vivian, J.A., 226
Vlahov, D., 181
Vocci, F.J., 59, 306
Vogelson, L., 151
Volkow, N., 33, 35, 157
Volpicelli, J.R., 100, 241
Volpicelli, L., 241, 340
Von Bargen, J., 184
Vorhees, C.V., 27
Votaw, J.R., 82
Wager, C. 193
Wagner, L., 151,207
Walker, D.J., 228
Walker, E.A., 224, 226
480
Walker, Q.D., 301
Wallace, D., 100, 148, 149
Wallace, M.J., 214
Wallis, C.J., 281
Walot,. I., 197
Walsh, R., 55, 306
Walsh, S.L., 55, 89, 139, 218, 314
Wang. C., 80, 230
Wang. G.-J., 35
Wang, J.B., 163, 164
Wang, L., 80
Wang, N.S., 108
Wang, Y., 66, 219
Wang, Z., 173
Wang, Y.G., 66, 219
Ward, A.S., 70, 239
Wasserman, D.A., 90, 318
Weber, R.J., 24, 113, 115, 199, 200
Wechsberg, W.M., 103, 194
Weed, M.R., 198
Weerts, E.M., 74
Weinrieb, R., 206
Weinstein, M.G., 318
Weinstein, S.P., 195, 257
Weiss, E., 338
Weiss, R.D., 121, 253
Weiss, S.J., 215
Weissman, G., 180
Weissman, M.M., 247
Wells, E.A., 97
Wells, L.T., 96, 207
Welm, S., 291, 292, 310
Wenger, G.R., 176, 177, 178
Wenhua, Z., 163
Wertz, J.S., 254, 321, 327
Wessinger, W.D., 231
Wesson, D.R., 175
West, J.P., 201
West, W.L., 134
Westney, L., 134
Westney, O., 134
White, A., 440
White, H.R., 246
White, J.M., 120, 174, 243
Whitmore, E.A., 251
Whitney, S., 126
Widman, M., 253, 263
Wilens, T.E., 129
Wiley, C.A., 52
Wiley, J.L., 234, 239
Wilkins, D.G., 288, 344
Wilkins, J., 256
Williams, A.J., 234
Williams, K., 198
Williams, K.L., 118
Williams, S.E., 125
Williams, W., 236
Wills, T.A., 247
Wilson, A., 91
Wilson, S., 307
Wines, J.D., 138, 258
Winger, G.D., 212, 345, 408, 429
Winick, C., 61, 331
Winningham, L., 329
Wittchen, H.U., 244
Wolfgang, G., 134, 313
Wong, C.J., 147, 223
Wong, D.F., 271
Wong, M.M., 181
Wood, R.W., 81
Woods, J.H., 85, 118, 167, 212, 226, 227,
345, 408, 429
Woodward, J.J., 233
Woody, G., 206
Woolfolk, D.R., 304
Woolverton, W.L., 215, 283, 429
Wright, D.W., 176, 178
Wright, J., 66
Wu, J., 184
Wu, K.-M., 281
Wyatt, S.A., 160
Wyner, D., 253
Xin, L., 166
Xu, H., 79, 80, 161, 162, 163
Xu, J.Y., 128
Xu, L., 77
Xue, Y., 221
Yahai, Z., 163
Yamashita, T., 123
Yang, G., 173, 307
Ye, X, 76
Yokoi, F., 271
Young, C.J., 111, 228, 229
Young, J.E., 259
Young, R., 285, 290
Young, S., 31
Yu, E., 306
Yu, J., 225, 227
Yu, L., 36
Yu, Q.-S., 217
Yu, Y., 164
Yuferov, V.P., 83, 232
Zacny, J.P., 111, 228, 229
Zanis, D.A., 262, 318
Zernig, G., 218
Zhang, F., 173
481
Zhang, L., 117
Zhang, M., 85
Zhang, X., 80
Zhang, Y., 79, 86
Zhaolin, W.
Zheng, Q.X., 163
Zhou, W., 173, 307
Zhou, Y., 83,86, 166, 232, 300
Ziedonis, D.M., 131, 160
Ziegelstein, R.C., 209
Zogg, J., 322
Yokoi, F., 271
Zule, W., 194
Zuo, Y., 136
482
SUBJECT INDEX
ACCU DROP
an aid for smoking cessation, 158
Acculturation
substance use and Mexican-American youth, 249
ACEA-1021
NMDA/glycine antagonists block cocaine sensitization and toxicity, 303
ACEA-1328
NMDA/glycine antagonists block cocaine sensitization and toxicity, 303
l- -Acetylmethadol
See LAAM
ACTH
cocaine self-administration in rhesus monkeys, 212
pharmacokinetics with cocaine in men, 219
Addiction
picoeconomic approach, 30
research progress and future prospects, 3-8
Addiction Severity Index
comparison of self-administered and standard interview, 245
development of new scales, 344
Adolescents
ADHD and depression in substance using delinquents, relationship to nicotine, 251
adult drug arrests indicate juvenile drug arrests, 261
bupropion for ADHD with conduct disorder and substance use disorder, 252
drug arrests and HIV risk behaviors in detainees in juvenile justice system, 262
effects of temperament on substance use in adolescent children of drug abusers, 247
group psychotherapies for substance abusers, 252
longitudinal trajectories of drug use and deviant behavior, 250
outcome of girls referred for conduct disorder and substance abuse/dependence, 251
stages of use among American-Indian adolescents, 249
treatment model for court assigned, adjudicated adolescent drug abusers. 253
treatment needs among juvenile arrestees, 130
Aggression
laboratory measures in female parolees, 339
AHN649
cortical EEG and behavioral studies in the rat, neurotoxicity profile, 234
AIDs
drug and sexual risk behaviors, 101
drug dependence and psychiatric illnesses, 193
drug treatment staff, response to deaths in programs, 192
node-link maps, risk levels and residential drug abuse treatment, 189
preventing HIV/AIDS among middle-aged and elderly intravenous drug users, 181
risk behaviors, cocaine use, and treatment outcomes, 190
two-way relational model between drug use and HIV/AIDS, 182
See also HIV
Alcohol
See Ethanol
Alprazolam
interaction with caffeine under chronic dose regimens on DRL performance, 284
pharmacokinetic/pharmacodynamic model for stimulatory and sedative effects, 176
Amineptine
discriminative stimulus effects in rats, 291
483
1-Aminocyclopropane carboxylic acid (ACPC), (NIH 10840)
analgesia in mice, 378
analgesia in rhesus monkeys, 378
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 378, 419
inhibition of electrically stimulated mouse vas deferens, 419
physical dependence evaluation in rhesus monkeys, 378
Amlodipine
treatment of cocaine dependence, 137
Amphetamine
anorectic agents differentially affect monomania transmission, 296
comparison of preclinical pharmacology with modafinil, 295
drug discrimination in humans, 294
effect on conditioned responding before and after daily THC dosing, 94
effects on extracellular dopamine, 288
effects on extracellular dopamine in the macaque, 82
effects on follicular and luteal phases of the menstrual cycle, 292
effects on prior exposure to and priming with amphetamine on self-administration, 293
effects on symbolic delayed matching performance in rats, 178
effects on temporal discrimination in rats, 176
euphoria in males, 334
fluoxetine treatment of smokable amphetamine dependence, 297
7-hydroxy-DPAT effects on stereotypies and conditioned place preference, 289
impact of illicit use on neuropsychological functioning, 104
morphine effects enhanced in rats discriminating cocaine but not amphetamine, 304
novelty-seeking behavior related to drug-induced locomotor activity, 293
opioid modification of the discriminative stimulus effects, 294
relationship between discriminative-stimulus and subject-rated effects, 47
relationship of ADHD to abuse and dependence, 130
Anabolic steroids
evaluation of abusers across one or two cycles of use, 206
Anandamide
synthesis and biological evaluation of analogs, 93, 94
Anger management treatment
comparisons and follow-up, 150
therapist adherence measure, 150
Antisocial Personality Disorder
effects on aggressive responding, 1121
effects on risk-taking behavior, 32
factors share by alcohol dependence and antisocial personality, 121
Apomorphine
sensitization and conditioning, 295
Archer, Sydney
In memoriam, 1
Asparate
enhanced response to cocaine in behaviorally sensitized rats, 214
Attention Deficit/Hyperactivity Disorder
depression in substance-using delinquents, relationship to nicotine, 251
impact on development of drug and alcohol abuse and dependence, 129
parent reports and stimulant treatment, 130
psychiatric comorbidity and substance abuse treatment outcome in, 129
Ayahuasca
behavioral profile of constituents, 237
484
Azidothymidine
synergism with met-enkephalin in retarding murine retrovirus infection, 26
Benzodiazepine
computerized tomography in chronic benzodiazepine users, 75
conformational topography of receptor subtypes, 72
expectancies in dependence, 76
incentive program in methadone maintenance for sustaining post-detox abstinence, 325
7-Benzoyl-2-piperidineomethyl-1,4-benzodioxane HCl, (NIH 10874)
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 423
inhibition of electrically stimulated mouse vas deferens, 423
N-[(R,S)-2-Benzyl-3[(S)(2-amino-4-methylthio)butyldithiol-1-oxopropyl]-L-phenylalanine
benzyl ester methyl sulfite), (NIH 10833)
analgesia in mice, 374
analgesia in rhesus monkeys, 374
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 374, 417
inhibition of electrically stimulated mouse vas deferens, 4 17
physical dependence evaluation in rhesus monkeys, 375
self-administration by monkeys, 375
Benzyhdenenaltrexone
differential opioid effects on the immune system, 24-25
Benztropine
effects of pretreatment on cocaine’s effects in male volunteers, 138
intravenous self-administration of analogs by monkeys, 283
nor-Binaltorphimine
effects on ethanol-reinforced responding in rhesus monkeys, 118
pharmacological effects against selective opioid agonists in frogs, 87
Bremazocine
discrimination between bremazocine and butorphanol in pigeons, 169
selectivity in pigeons discriminating fentanyl, bremazocine and water, 168
Buprenorphine
behavioral and physiological effects in non-drug-abusing volunteers, 111
behavioral economic analyses of self-administration, 172
comparison with methadone maintenance in opioid addicts, 313
craving despite high doses in opioid dependence, 311
differential opioid effects on the immune system, 24-25
maintenance in pregnant opioid addicts, 134
naloxone interactions in dependent patients stabilized on buprenorphine, 310
open-label study in the treatment of opioid dependence, 309
pilot study of three dose schedules, 89
plasma levels and effectiveness of thrice-weekly administration, 310
quality of life assessment in treatment for opioid dependence, 312
auantitation in rat plasma by GC/MS, 221
subjective withdrawal with-sextuple the daily dose, 311
urine toxicology with buprenorphine/naloxone combination treatment, 312
n o r -Buprenorphine
quantitation in rat plasma by GC/MS, 221
Bupropion
effects of cocaine prior to and during bupropion maintenance of cocaine abusers, 137
relationship between discriminative-stimulus and subject-rated effects, 47
treatment for ADHD with conduct disorder and substance-use disorder, 252
485
Butorphanol
clocinnamox effects on butorphanol behavioral effects, 226
discrimination between bremazocine and butorphanol in pigeons, 169
effects in opioid-withdrawn volunteers, 308
effects on cue-elicited cocaine craving, 143
pA2 analysis of opioid antinociceptive effects in rats, 224
Caffeine
alternative reinforcer and caffeine effects on human cocaine self-administration, 286
characteristics of patients with chronic use of OTC analgesics containing caffeine, 286
comparison with intravenous nicotine in cocaine abusers, 285
interaction with alprazolam under chronic-dose regimens on DRL performance, 284
potentiation of ephedrine’s amphetamine-like stimulus effects, 285
Cannabinoids
evidence for CB2 receptors on rat microglial cells, 93
synthesis and evaluation of arachidonylphosphonates, 238
See also Marijuana and Tetrahydrocannabinol
Cannabis
See Marijuana, Cannabinoids, and Tetrahydrocannabinol
Carfentanil
differential responses in chronic cocaine users, depressed patient and controls, 328
CART
genetic variations in expression in Lewis and Fisher rats, 83
novel pentides with psychostimulant-like behavioral profile, 270
peptide immunohistochemistry in the rat, 269
CDTP-30,640
effects on brain-reward mechanisms, 281
4-Chlorobenztropine
behavioral and neurochemical effects in the rat, 303
(-)-6-(Chlorohexyl)-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan HCl, (NIH 10897)
analgesia in mice, 396
analgesia in rhesus monkeys, 397
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 396
physical dependence evaluation in rhesus monkeys, 397
(2S,5S,9S-(+)-2-(6-Chlorohexyl)-5-9
dimethyl-2’-hydroxy-benzomorphan
HCl,
(NIH 10898)
analgesia in mice, 398
analgesia in rhesus monkeys, 398
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 398
physical dependence evaluation in rhesus monkeys, 398
Cigarettes
See Tobacco
See also Nicotine
Cimetidine
LAAM adjunctive therapy for opioid dependence, 316
1 4 -Cinnamoylamino
codeinone
pharmacological properties of stereoisomer derivatives, 81
C1ocinnamox
effects of a clocinnamox-etorphine combination on a primate titration procedure, 116
effects on butorphanol behavioral effects, 226
effects on ethanol-reinforced responding in rhesus monkeys, 118
486
Clonidine
effects on respiration during precipitated opioid withdrawal in monkeys, 167
Cocaine
abnormal cortical subcortical interaction in withdrawal, 105
abnormal metyrapone test during abstinence, 105
abstinence contingency impact on homeless addicts’ non-drug activities, 149
ACTH and cortisol in self-administration in rhesus monkeys, 212
actions and interactions with ibogaine in rhesus monkeys, 309
addiction outpatient treatment for dependent mothers, 100
affinity of analogs for transporters, 77
AIDS risk behaviors, cocaine use, and treatment outcomes, 190
alterations in preproenkephalin mRNA levels in guinea pig brain, 83
alternative reinforcer and caffeine effects on human cocaine self-administration, 286
amlodipine treatment of dependence, 137
anger management treatment, comparisons and follow-up, 150
antagonists from combinatorial chemistry, 77
anti-cocaine antibody effects on self-administration, 84
anti-cocaine antibody eliminates reinforcing effects, 345
antisocial personality disorder in risk behaviors among cocaine users, 184
arousal and modulation as a function of gestation and prenatal drug exposure, 124
attention and memory impairment in abusing schizophrenic patients, 132
aversive events in dependent outpatients, 147
Bayley Scales in normal, cocaine-exposed and CNS-injured infants, 124
benztropine pretreatment on cocaine’s effects in male volunteers, 138
brain imaging during cue-induced craving, 106
butorphanol effects on cue-elicited cocaine craving, 143
butyrylcholinesterase on plasma cocaine concentration, 220
cardiac conduction in humans, 209
cardiovascular changes in humans, 209
cardiovascular effects, 207
carfentanil responses in chronic cocaine users, depressed patient and controls, 328
cerebral blood flow following procaine in cocaine addiction, 151
cerebral blood volume reduction in females, 154
cerebral vasospasm in humans, 106
characteristics of stimulant abusers and their response to treatment, 298
cigarette smoking during early cocaine abstinence, 159
cocaine effects prior to and during bupropion maintenance of abusers, 137
cognitive-behavioral therapy for cocaine-using methadone patients, 329
comparison of basal motor activity, cocaine-stimulation and brain cocaine levels, 299
comparison of intravenous nicotine and caffeine in cocaine abusers, 285
comparison of two aftercare treatments, 99
conditioned suppression of operant responding, 216
consequences of dopamine transporter gene mutation, 36
corticotropin-releasing factor receptor blockade attenuates rewarding properties, 213
craving assessments in cocaine treatment, 145
craving and dopamine outflow in the amygdala during withdrawal, 139
craving and withdrawal symptoms during detoxification, 145
cue reactivity paradigm, 143
cymserine potentiation of discriminative stimulus properties, 217
daytime and nighttime sleep patterns during abstinence, 305
dietary practices in cocaine-dependent pregnant women, 125
discriminative effects of cocaine/opioid combinations, 55
discriminative stimulus associated with cocaine or food, 215
487
dopamine agonists on reinstatement of cocaine-seeking behavior in relapse, 283
dopamine receptor blockade, effects on self-administration, 279
dopamine receptor down-regulation following cocaine self-administration, 154
dopamine transporter availability in mazindol-treated cocaine addicts, 152
dopamine transporter for medication development, 33
DPDPE and DADLE potentiate cocaine motor effects, 304
drug discrimination and physiological effects, 291
EEG abnormalities in children exposed in utero, 135
effectiveness of intensive services for women with cocaine-exposed infants, 126
effects of abstinence on human motor activity, 305
effects of “binge” pattern administration of cocaine on dopamine receptors, 153
effects of “binge” pattern administration of cocaine on serotonin receptors, 152
effects of “binge” pattern administration of cocaine on the dopamine transporter, 152
effects of “binge” pattern cocaine on locomotor activity and stereotypy in mice, 300
effects of chronic dopamine antagonist exposure on cocaine self-administration, 281
effects of kappa agonists on self-administration by rhesus monkeys, 277
effects of long-term withdrawal from cocaine on dopamine receptors, 153
effects of stage of change and HIV risk-reduction counseling on users, 189
effects on brain blood flow, 15 1
effects on cerebral blood flow in rhesus monkeys, 82
effects on extracellular dopamine in the macaque, 82
effects on motor coordination and balance, 119
effects on preprodynorphin mRNA levels and nest building in pregnant rats, 122
effects on symbolic delayed matching performance in rats, 178
effects on temporal discrimination in rats, 176
enhanced aspartate response to cocaine in behaviorally sensitized rats, 214
erythrocythemia due to splenic contractions, 210
ethanol influence in abuse treatment, 326
fee rebates to reinforce abstinence and counseling attendance in abusers, 99
female participation in abstinence studies, 334
fetal exposures and neurobehavioral birth outcomes, 123
fluoxetine effects on cue-reactivity/cue-induced craving in cocaine dependence, 142
GBR12906 suppression of self-administration, 271
genetic analysis of place preference in SMXA RI inbred strains of mice, 217
gender differences and psychiatric symptoms in abuse/dependence, 131
gender differences in crack use and HIV risk among non-injecting heroin users, 185
gender differences in responsivity in rats, 301
gestation exposure on long-term consequences of early experience, 343
GR125487D effects on cocaine-induced motor activity, 302
GR127935 effects on cocaine locomotor and discriminative stimulus effects, 301
hair analysis, 336
hepatitis B infection in cocaine users, 203
HIV risk behaviors in cocaine-using methadone patients, 101
HIV risk reduction among homeless users completing treatment and aftercare, 191
ibogaine reversal of cocaine withdrawal effects, 237
increases inulin and HIV-1 permeability across the blood-brain barrier, 117
influence on brain volume, 155
interaction with dopamine agonists in rhesus monkeys, 280
intervention effectiveness among cocaine snorters at risk for HIV, 185
isradipine reversal of cocaine-induced changes in brain blood flow, 96
lamotrigine for cocaine abuse in HIV-seropositive patients, 197
legalization, 264
luteinizing hormone, 275
488
mecamylamine reduces conditioned cocaine craving in cocaine-dependent subjects, 142
medications development, 56
memantine influence on “hinge” cocaine-induced elevation of dynorphin mRNA, 232
methadone dose response in opioid/cocaine dependent patients, 328
methylphenidate analogs for treatment, 76
microdialysis of the ventral pallidum during self-administration, 277
morphine effects enhanced in rats discriminating cocaine but not amphetamine, 304
morphological and molecular correlates of effects on the heart, 207
motivational enhancement in treatment, 97, 98
mu opioid receptor binding during early and prolonged cocaine abstinence, 107
neurobiology of abuse, 55
neurochemical changes in users with HIV-1, 197
7-nitroindazole effects on cocaine discrimination in rats, 279
NMDA/glycine antagonists block cocaine sensitization and toxicity, 303
noradrenergic involvement in the discriminative stimulus effects, 216
olanzapine attenuation of cocaine’s discriminative stimulus and reinforcing effects, 278
pathological gambling in dependent outpatients, 260
personality disorders and criminal activity among abusers, 259
pharmacokinetic effects, 218
pharmacokinetics and pharmacodynamics, 219
pharmacokinetics with adrenocorticotropic hormone in men, 219
pharmacotherapy of abuse with RTI-113, 278
phentermine and fenfluramine effects of reacquisition of cocaine self-administration, 140
phentermine in monkeys under progressive-ratio schedules of cocaine delivery, 141
phenytoin effects on cocaine self-administration in humans, 138
polysubstance abuse greater among cocaine users, 332
predictive validity of the extinction/reinstatement model of drug craving, 140
preexposure fails to sensitize taste aversion learning, 213
prenatal exposure on CNS development, 27-29
prenatal exposure on immune function, 114
pretreatment substance abuse, treatment dropout and relapse in abusers, 148
psychiatric comorbidity in abusers, 132, 258
psychosurgery in dependence, 258
rate of rise in brain concentrations and reinforcing strength, 218
real-time naturalistic evaluation of cocaine craving, 146
regulation of cocaine and antidepressant-sensitive transporters, 34
reinforced and extinguished behavior using progressive-ratio schedules, 211
reinforcement in serotonin receptor knockout mice, 270
reinforcer modulation of cocaine-seeking behavior following cocaine exposure, 144
reinforcing effects of cocaine/ethanol combinations, 333
reinstatement of self-administration by stressors, 212
relationship between dopamine transporter occupancy and cocaine subjective effects, 35
relationship between resistance to learning serostatus and disclosing cocaine use, 195
relationship of ADHD to abuse and dependence, 130
respiratory sinus arrhythmia and heart rate reactivity to posture change, 208
role of calcium/ca1modufin-dependent protein kinase II in sensitization, 84
schedule responding maintained by cocaine or food, 215
SCH 23390 injection into ventral tegmental area, effects on cocaine sensitization, 302
screening potential medication for treatment of dependence, 97
self-administration in rhesus monkeys, 211, 282
sensory motor development in exposed infants, 123
sex differences in response to smoked cocaine in humans, 335
sigma ligands on cocaine-induced convulsions, 235
489
situational confidence questionnaire scores as predictors of treatment outcome, 147
stress response and stress-induced craving in abusers, 141
subjective rating scale sensitive to acute effects, 139
sweat patch monitoring of use during treatment, 223
titration of drug dose in rats reinforced by intravenous cocaine or heroin, 210
tolerance to cardiovascular effects to self-administered cocaine in rats, 208
tolerance to locomotor effects in C57BL/6J mice with “binge” pattern cocaine, 300
treatment for homeless abusers, 100
treatment non-compliance in dependent mothers, 340
use and treatment retention in a national treatment sample, 98
use patterns among homeless persons, 148
venlafaxine treatment of major depression and cocaine dependence, 255
-vinyl GABA attenuates cocaine self-administration in rats, 280
voucher-based reinforcement of brief cocaine abstinence in methadone patients, 327
weight control as a motivation for abuse, 257
Codeine
cytochrome P450 2D6 inhibition influences metabolism and abuse liability, 220
subjective, psychomotor, and analgesic effects in healthy volunteers, 228
-Conotoxin MVIIA (reduced, cyclic (1-16), (8-20), (15-25), (NIH 10887)
analgesia in mice, 393
analgesia in rhesus monkeys, 394
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 393, 425
inhibition of electrically stimulated mouse vas deferens, 426
physical dependence evaluation in rhesus monkeys, 393
reinforcing effects in rhesus monkeys, 426
self-administration by monkeys, 394, 426
Corticosterone
novelty seeking behavior related to drug-induced locomotor activity, 293
Corticotropin-releasing factor
receptor blockade attenuates rewarding properties of cocaine in rats, 213
role in relapse to heroin-seeking, 107
Cortisol
cocaine self-administration in rhesus monkeys, 212
effects of endogenous levels on natural killer cell activity, 116
CPDD 0007, (Methaqualone)
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 433
drug discrimination in rhesus monkeys, 432-433
CPDD 0032, (Flunitrazepam)
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 433-434
drug discrimination in rhesus monkeys, 433-434
CPDD 0042, (Zipeprol [4-(2-methoxy-2-phenylethyl)- -(methoxyphenylmethyl)-1piperazineethanol 2 HCl)
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 435
drug discrimination in rhesus monkeys, 434 - 435
C P D D 0 0 4 4 , -Hydroxybutyric acid, sodium salt
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 435-437
drug discrimination in rhesus monkeys, 437
490
reinforcing effects in rhesus monkeys, 435
self-administration by monkeys, 438
d -CPPene
effect on tolerance to morphine’s discriminative stimulus effects, 110
Crack
See Cocaine
Craving
assessments in cocaine treatment, 145
predictive validity of the extinction/reinstatement model of drug craving, 140
real-time naturalistic evaluation of cocaine craving, 146
retrospective assessment of drug and non-drug craving states, 146
Crime
adult drug arrests indicate juvenile drug arrests, 261
common and distinct etiologies with drugs, 261
recidivism among substance-dependent inmates, 262
CTOP
injections into the ventral pallidum block development of morphine sensitization, 165
Cue reactivity
sensitivity of a laboratory paradigm, 143
specificity, 144
(-)-2-Cyanomethyl-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan
HCl,
(NIH
10869)
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 421
inhibition of electrically stimulated mouse vas deferens, 421
(+)-2-Cyanomethyl-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan HCl, (NIH 10870)
analgesia in mice, 388
analgesia in rhesus monkeys, 389
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 388, 422
inhibition of electrically stimulated mouse vas deferens, 422
physical dependence evaluation in rhesus monkeys, 388
(-)-Cyanopentyl-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan
HCl,
(NIH
10871)
analgesia in mice, 389
analgesia in rhesus monkeys, 390
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 389
physical dependence evaluation in rhesus monkeys, 390
(-)-2-(3-Cyanopropyl)-5,9 -dimethyl-2’hydroxy-6,7-benzomorphan,
(NIH
10884)
analgesia in mice, 390
analgesia in rhesus monkeys, 391
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 390, 424
inhibition of electrically stimulated mouse vas deferens, 424
physical dependence evaluation in rhesus monkeys, 391
(+)-2-(3-Cyanopropyl)-5,9
-dimethyl-2’hydroxy-6,7-benzomorphan,
(NIH
10885)
analgesia in mice, 391
analgesia in rhesus monkeys, 392
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 391,
physical dependence evaluation in rhesus monkeys, 392
Cyclazocine
pharmacological characterization, 225
491
Cycloserine
effect on naloxone-precipitated opioid withdrawal, 308
Cymserine
potentiation of cocaine’s discriminative stimulus properties, 217
Cytochrome P450 2D6
deficient metabolism protects against oral opioid dependence, 222
inhibition modifies codeine metabolism and abuse liability, 220
DADLE
attenuation of methamphetamine neurotoxicity, 289
potentiates cocaine motor effects, 304
DAMGO
developmental comparison of G-protein coupling to mu opioid receptors, 126
Data analyses
effects of symmetry violations and missing data, 266
longitudinal data from clinical trials, 266
DATOS
drug addiction and treatment careers among clients, 193
Delta opioids
behavioral effects of SNC80 in rhesus monkeys, 86
modulate apoptosis in cultured lymphocytes, 201
role in naloxone-induced place aversion in dependent mice, 171
role in reinforcing effects of heroin using 5’-NTII, 86
SNC 80 analogs, search for selective delta antagonists, 161
synthesis of receptor affinity analogs, 80
Dextromethorphan
cortical EEG and behavioral studies in the rat, neurotoxicity profile, 234
Diazepam
comparison of the acute effects of diazepam, lorazepam and zolpidem, 174
discriminative stimulant effects of abused inhalants in mice, 234
effects of SR 141716A on diazepam substitution in THC discrimination in rats, 239
effects on symbolic delayed matching performance in rats, 178
effects on temporal discrimination in rats, 176
influence of chronic treatment on discriminative stimulus of flumazenil, 73
influence of gender and menstrual cycle phase on behavioral effects, 175
matching-to-sample performance of pigeons, 177
NMDA receptors in the expression of withdrawal signs, 173
See also Benzodiazepines
Dihydroetorphine HCl, (NIH 10846)
analgesia in mice, 382
analgesia in rhesus monkeys, 384
biological evaluation of physical dependence potential and abuse liability, 352
displacement of radiolabeled opioid binding, 382, 420
inhibition of electrically stimulated mouse vas deferens, 420
physical dependence evaluation in rhesus monkeys, 384
self-administration by monkeys, 384
7,8-Dihydromorphinans,
antinociceptive properties of 3-chloroacrylamido derivatives, 85
Diltiazem
effects on respiration during precipitated opioid withdrawal in monkeys, 167
(-)-5,9 -Dimethyl-2-heptyl-2’-propionoxy-6,7-benzomorphan
HCl,
(NIH
10860)
analgesia in mice, 385
analgesia in rhesus monkeys, 386
biological evaluation of physical dependence potential and abuse liability, 354
492
displacement of radiolabeled opioid binding, 385
physical dependence evaluation in rhesus monkeys, 386
(-)-5,9 -Dimethyl-2’-hydroxy-2-(2-hydroxyethyl)-6,7-benzomorphan oxalate, (NIH 10864)
analgesia in mice, 386
analgesia in rhesus monkeys, 387
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 386
physical dependence evaluation in rhesus monkeys, 387
(3,5-Dimethyltricyclo[3.3.1.1 3,7 ]decan-1-amine (Memantine), (NIH 10839)
analgesia in mice, 377
analgesia in rhesus monkeys, 377
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 377, 418
inhibition of electrically stimulated mouse vas deferens, 418
physical dependence evaluation in rhesus monkeys, 377
3 -(Diphenylmethoxy)tropane
photoaffinity label for the dopamine transporter, 78
synthesis and molecular modeling of novel aromatic substituted analogs, 273
Dizocilpine (MK-801)
developmental PCP exposure produces attenuated responses to PCP and MK-801, 229
effect on tolerance to morphine’s discriminative stimulus effects, 110
effects on respiration during precipitated opioid withdrawal in monkeys, 167
neurobiological effects compared to ibogaine, 236
Deprenyl
prevents long-term behavioral and neurochemical changes after opioid withdrawal, 108
Dezocine
discriminative stimulus properties, 169
Dopamine receptors
functional selectivity, 274
Dopamine transporter
affinity of cocaine and phenyltropane analogs for, 77
availability in mazindol-treated cocaine addicts, 152
characterization of substrate transport, 33
cocaine medication development, 33
consequences of gene mutation, 36
differential effects of psychostimulants, 344
3 -(diphenylmethoxy)tropane based photoaffinity label, 78
dissociation of [ 3 H]cocaine binding from transporters, 274
dopamine effects in mice lacking the dopamine transporter, 34
effects of “binge” pattern administration of cocaine on the dopamine transporter, 152
food, sex, and drug incentives, implications for anti-craving medications, 59-60
GBR12909 analogs as uptake inhibitors, 79
gene marker frequencies in polysubstance abusers, 268
irreversible ligands based upon rimcazole, 272
knockout transgenic mice, 268
oxatropane inhibitors, 78
phosphorylation of the receptor, 164
relationship between occupancy and cocaine-induced subjective effects, 35
repeated U69,593 administration decreases dopamine transporter number, 275
reversible and rapid effects of methamphetamine, 288
DPDPE
potentiate cocaine motor effects, 304
493
Drug abuse
acculturation, substance use and Mexican-American youth, 249
adult drug arrests indicate juvenile drug arrests, 261
bupropion for ADHD with conduct disorder and substance use disorder, 252
common and distinct etiologies with crime, 261
community interventions, 61-63
deaf persons, 264
distinguishing motivational and motor effects of drugs, 267
drug arrests and HIV risk behaviors in detainees in juvenile justice system, 262
drug use patterns for assessing the course of drug use, 332
effects of antisocial personality disorder on risk-taking behavior, 32
effects of temperament on substance use in adolescent children of drug abusers, 247
effects on a laboratory model of impulsivity, 31
effects on the family, 247
electronic tracking of national trends in treatment, 331
evaluation of community interventions, 331
genetic and environmental influences, 40
genome, 36-38
group psychotherapies for adolescent substance abusers, 252
health care need and utilization of intravenous drug uses and others, 330
impact of prevention program on parental self-esteem, coping, childrearing skills, 248
impulsivity and risk-taking, 30-32
impulsivity trait and state characteristics, 31
independent versus substance-induced major depression, 254
intercollegiate women athletes, 336
intergenerational transmission of use patterns and norms, 246
longitudinal trajectories of drug use and deviant behavior, 250
meta-analysis of treatment effectiveness, 265
neurobiology of, 50
neuropsychological assessment, 267
novel applications of human drug discrimination, 45
nutritional status and hepatic function during drug use and abstinence, 204
outcome of adolescent girls referred for conduct disorder and substance abuse, 251
picoeconomic approach, 30
polysubstance abuse greater among cocaine users, 332
process evaluation methods for treatment programs, 329
psychiatric comorbidity and familial influence, 131
recidivism among substance-dependent inmates, 262
re-engagement of drop outs from a drug treatment program, 195
refined phenotype, 40
relapse prevention group therapy, patients with substance abuse/bipolar disorders, 253
research progress and future prospects, 3-8
risk factors: a birth cohort of preadolescents, 136
risk factors common with post-traumatic stress disorder, 50
skills management for substance abusing schizophrenic patients, 256
stages of use among American-Indian adolescents, 249
temperament among drug abusers in treatment, 149
treatment for substance use, PTSD, and anger management, 256
treatment model for court assigned, adjudicated adolescent drug abusers, 253
treatment needs among adult arrestees, 92
treatment needs among juvenile arrestees, 130
treatments for dual diagnosis, 254
494
Drug abuse treatment
See Drug abuse and Drug dependence
See also specific treatment
Drug dependence
activity scale as process marker of treatment efficacy, 338
aftercare for women using the African-American church community, 338
behavioral adaptation to changes in reinforcement contingencies, 333
coercion, motivation and change in treatment, 324
concurrent validity of subtyping according to level of sociopathy, 322
continuity of drug use patterns among high risk women, 342
effectiveness of intensive case management with women, 337
ethnicity differences in reliability of DSM-IV diagnosis, 321
genetic and environmental influences, 40
increasing employment of opioid dependent outpatients, 263
influence of centralized intake on treatment outcome, 324
influence of sexual and physical abuse on treatment outcomes, 323
multiple treatment outcomes for women enrolled as outpatients, 337
parenting skills questionnaire revised, lest-retest reliability, 342
predictive validity of diagnoses, 321
psychiatric symptomatology in drug dependent pregnant women, 341
psychological impairment, treatment selection, and access, 323
relationship between dependence and risk of dying, 122
reliability of diagnostic instruments for dependence, 320
risk factors common with post-traumatic stress disorder, 50
treatment outcome and program duration, 322
type A and type B clusters in substance-dependent treatment-seeking women, 341
voucher incentives on residential length of stay and outpatient treatment attendance, 339
Drug discrimination
cocaine/opioid combinations, 55
ethanol, 46
functional versus competitive antagonism in humans, 46
nicotine, 46
novel aspects in humans, 45
opioids, 45
Drug self-administration
method for testing the specificity of manipulations, 108
Drug testing
intercollegiate women athletes, 336
Dynorphin
memantine influence on “binge” cocaine-induced elevation of dynorphin mRNA, 232
modulation of LPS-induced neurotoxicity in cortical neuron/glia cultures, 199
release from preoptic anterior hypothalamus during interleukin-1 fever, 166
Dynorphin A(1-13)
elevation of serum prolactin levels, 167
subjective responses in normal controls and methadone-maintenance patients, 111
Dynorphin A(2-17)
biotransformation and duration of action in rhesus monkeys, 227
effects on dopamine levels and cocaine-induced sensitization, 276
Eliprodil
effect on tolerance to morphine’s discriminative stimulus effects, 110
Enadoline
antipruritic activity, 88
405
Epherdine
potentiation of caffeine’s amphetamine-like stimulus effects, 285
Epibatidine
synthesis of analogs as potential PET and SPECT ligands, 157
Erythrocythemia
cocaine-induced splenic contractions, 210
(-)-Eseroline (L)-ascorbate, (NIH 10820, NIH 10398)
analgesia in mice, 370
analgesia in rhesus monkeys, 371
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 370, 415
inhibition of electrically stimulated mouse vas deferens, 415
physical dependence evaluation in rhesus monkeys, 371
Ethanol
age at onset of alcoholism, influence of genes, environment and sibling competition, 245
arousal and modulation as a function of gestation and prenatal drug exposure, 124
characterization of withdrawal signs during acute and protracted phases, 120
discriminative effects of self-administered ethanol, 345
DSM-IV alcohol disorders among 14-17 year olds in Munich, Germany, 244
effect of depression on return to drinking, 121
effect on cognition, heart rate and subjective mood when combined with marijuana, 72
effect on mood, equilibrium, and simulated driving, 244
effect on success in quitting smoking, 68
effect on motor coordination and balance, 119
effects of opioid antagonists on reinforced responding in rhesus monkeys, 118
factors share by alcohol dependence and antisocial personality, 121
fetal outcomes when mothers used early in pregnancy, 125
gender differences on schedule-induced consumption in monkeys, 243
group therapy on readiness to change scores in substance abusers, 240
human drug discrimination, 46
ibogaine effects on intake and motivated responding in rats, 255
influence in cocaine abuse treatment, 326
methamphetamine reversal of ethanol-induced body sway in standing humans, 292
mood during acute and protracted withdrawal, 243
naltrexone, naltrindole and -funaltrexamine on consumption in the rat, 241
opioid system in ethanol-induced place preference under conditioned fear, 241
pimozide effects on subjective responses to ethanol in humans. 242
rat models of drug-seeking relapse, 157
recovering alcoholic versus non-alcoholic smokers, 160
reinforcing effects of drug/ethanol combinations, 333
relationship between alcohol dependence and risk of dying, 122
self-administration in rats, 119
serotonergic agents in drug discrimination, 118
sibling risk for substance use and dependence, 246
use of cue exposure to control drinking, 120
use patterns among homeless persons, 148
Ethics
laboratory research with humans, 41-44
Ethylketocyclazocine
effects on cocaine self-administration by rhesus monkeys, 277
Eticlopride
effects of chronic exposure on cocaine self-administration, 281
496
Etorphine HCl, (NIH 8068)
analgesia in mice, 369
biological evaluation of physical dependence potential and abuse liability, 352
displacement of radiolabeled opioid binding, 369
effects of a clocinnamox-etorphine combination on a primate titration procedure, 116
physical dependence evaluation in rhesus monkeys, 370
responsiveness to serotonergic drugs after high-dose fenfluramine treatment, 296
self-administration by monkeys, 370
Fenfluramine
detection in hair and nails, 223
effects of reacquisition of cocaine self-administration, 140
Fentanyl
selectivity in pigeons discriminating fentanyl, bremazocine and water, 168
Flumazenil
influence of chronic diazepam treatment on discriminative stimulus effects, 73
-Flunaltrexamine
effects on ethanol consumption in the rat, 241
pharmacological effects against selective opioid agonists in frogs, 87
Flunitrazepam, (CPDD 0032)
abuse potential, 75
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 433-434
drug discrimination in rhesus monkeys, 433-434
Fluoxetine
effects on cue-reactivity/cue-induced craving in cocaine dependence, 142
medication take-home doses and contingency management, 330
treatment of nicotine dependence, 66
treatment of smokable amphetamine dependence, 297
Flupenthixol
effects of chronic exposure on cocaine self-administration, 281
Flurothyl
PCP and diazepam-like discriminative stimulant effects of abused inhalants in mice, 234
GABA
apparent pA2 values of partial and selective antagonists with midazolam, 73
conformational topography of receptor subtypes, 72
relationship between reinforcing and discriminative effects of GABAergic drugs, 174
Gambling
influence on methadone treatment outcome, 260
pathological gambling in cocaine-dependent outpatients, 260
GBR12909
analogs as dopamine uptake inhibitors, 79
effects of chronic administration on dopamine transporter and receptor, 272
rotational behavior enhanced by morphine and naltrexone, 170
suppression of cocaine self-administration, 271
GR125487D
effects on cocaine-induced motor activity, 302
GR127935
effects on cocaine locomotor and discriminative stimulus effects, 301
(+)-HA-966
effect on tolerance to morphine’s discriminative stimulus effects, 110
Hepatitis B
infection in cocaine users, 203
infection in heroin users, 203
497
Hepatitis C
anergy and immune suppression in intravenous heroin users, 202
Heroin
anergy and immune suppression in intravenous users with hepatitis C, 202
effects on mesolimbic modulation of synaptic transmission in the dentate gyrus, 164
electrophysiological substrates of self-administration, 165
gender differences in crack use and HIV risk among non-injecting heroin users, 185
gender differences in use severity among non-injecting users, 335
hepatitis B infection in users, 203
HIV risk behavior in older male heroin addicts, 102
information dissemination about “bad” heroin, 206
outcomes for abusers following 3-day inpatient detoxification, 317
pharmacokinetics of intravenous administration in morphine-maintained humans, 221
reinforcing effects of intravenous and imranasal administration in humans, 172
relapse among stable methadone maintenance patients, 90
role of corticotropin-releasing factor in relapse to heroin-seeking, 107
role of delta receptors in reinforcing effects, 86
scopolamine detoxification for the treatment of heroin addicts, 307
screening for heroin use in hospitalized HIV-infected drug users, 196
sweat patch monitoring of use during treatment, 223
titration of drug dose in rats reinforced by intravenous cocaine or heroin, 210
See also Opioids
(+)-2,3,3a,4,5,9 -Hexahydro-1-methyl-1 H-pyrrolo[3,2- h )-isoquinoline HBr ((+)-Bridged
Nicotine, NIH 10917)
analgesia in mice, 405
analgesia in rhesus monkeys, 405
displacement of radiolabeled opioid binding, 405
physical dependence evaluation in rhesus monkeys, 405
(-)-2,3,3a,4,5,9 -Hexahydro-1-methyl-1 H -pyrrolo[3,2- h )-isoquinoline 2 HBr ((-)-Bridged
Nicotine, NIH 10918)
analgesia in mice, 405
displacement of radiolabeled opioid binding, 405
HIV
antecedent influences on vulnerability among African American men, 178
antisocial personality disorder in risk behaviors among cocaine users, 184
antisocial personality disorder, sociopathy and HIV risk in intravenous drug users, 183
community-based outreach as risk reduction strategy, 39
discriminating cognitive impairment from HIV versus chronic substance use, 198
drug abuse treatment and risky sex, 188
drug and sexual risk behaviors, 101
drug arrests and HIV risk behaviors in detainees in juvenile justice system, 262
drug treatment as prevention strategy, 39
effects of stage of change and risk-reduction counseling on crack/cocaine users, 189
effects on the brain, 52-54
gender differences in crack use and HIV risk among non-injecting heroin users, 185
impact of drug and alcohol treatment and disease intervention on risk behaviors, 187
influence of risk-reduction strategies on behavior of intravenous drug users, 183
intervention effectiveness among cocaine snorters at risk for HIV, 185
lamotrigine for cocaine abuse in HIV-seropositive patients, 197
morphine effects on reactivity to HIV peptides, 25
needle exchange availability and participation among women, 181
neurochemical changes in cocaine users with HIV-1, 197
preventing HIV/AIDS among middle-aged and elderly intravenous drug users, 181
498
prevention of HIV from unprotected sex and drug use by African-American women, 180
prevention with drug users: a database and synthesis of research, 186
psychosocial risk and protective factors and coping in female IDUs, 103
reaching and enrolling drug users for prevention, 194
real and perceived HIV risk by population density, 103
re-engagement of drop outs from a drug treatment program, 195
relationship between resistance to learning serostatus and disclosing cocaine use. 195
retention and risk-reduction in a national treatment sample, 187
risk behavior among Puerto Rican drug users, 186
risk behavior in cocaine-using methadone patients, 101
risk behavior in intravenous drug users in Los Angeles, 182
risk behavior in older male heroin addicts, 102
risk behaviors in African-American parturient women, 179
risk behaviors of crystal methamphetamine users, 102
risk outcomes by type of drug treatment, 190
risk reduction among homeless crack smokers completing treatment and aftercare, 191
risks for seroconversion in collaborative injection drug users, 184
screening for heroin use in hospitalized HIV-infected drug users, 196
seroprevalence and risk behavior changes in high risk drug users, 104
service differences by gender, modality and risk status in drug treatment, 188
service management and costs of managing infected substance abusers, 192
structured manual for improving drug counseling among HIV substance abusers, 191
Substance P upregulates expression in human macrophages, 26
two-way relational model between drug use and HIV/AIDS, 182
unprotected sex with infected drug users, 180
urine HIV-1 test methodology in DUF populations, 196
Human research
cocaine/opioid combinations, 56
ethical considerations, 41
functional versus competitive antagonism, 46
genetic studies, scientific and ethical considerations, 42
nicotine discrimination, 46
novel applications of drug discrimination, 45
population-based research, 43
relationship between discriminative-stimulus and subject-rated effects, 47
setting up a new laboratory, 41
studying ethanol pharmacology, 46
using drug discrimination to study abuse of opioids, 45
Hydromorphone
effects in opioid-withdrawn volunteers, 308
-Hydroxybuturic acid, sodium salt, (CPDD 0044)
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 435-437
drug discrimination in rhesus monkeys, 437
self-administration by monkeys, 438
reinforcing effects in rhesus monkeys, 435
7-Hydroxy-DPAT
effects on amphetamine-induced stereotypies and conditioned place preference, 289
11-(4-Hydroxy-4’-phenylpiperidin-1-yl)-2-mehyl-6,11-dihydrodibenz[b,e]oxepine
fumaric
acid,
(NIH 10901)
analgesia in mice, 400
analgesia in rhesus monkeys, 401
biological evaluation of physical-dependence potential and abuse liability, 359
499
displacement of radiolabeled opioid binding, 400
physical dependence evaluation in rhesus monkeys, 401
11-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-hydroxy-methyl-6,11-dihydrodibenz[b,e]oxepine
fumaric acid, (NIH 10903)
analgesia in mice, 403
analgesia in rhesus monkeys, 404
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 403
physical dependence evaluation in rhesus monkeys, 404
11-[4-Hydroxy-4-trifluoromethylphenyl)
piperidin-1-yl]-2-hydroxymethyl-6,11dihydrodibenz[b,e]oxepine fumaric acid, (NIH 10902)
analgesia in mice, 402
analgesia in rhesus monkeys, 402
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 402
physical dependence evaluation in rhesus monkeys, 403
11-[4-Hydroxy-4-(3-triflouromethylphenyl)piperidin-1-yl]-2-methyl-6,11dihydrodibenz[b,c]oxepine sulfuric acid, (NIH 10900)
analgesia in mice, 399
analgesia in rhesus monkeys, 400
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 399
physical dependence evaluation in rhesus monkeys, 400
Ibogaine
actions and interactions with cocaine in rhesus monkeys, 309
effects on ethanol intake and motivated responding in rats, 255
effects on nicotine preference and nicotine-induced dopamine release, 156
neurobiological effects compared to MK-801, 236
neurotoxic effects mediated through sigma, receptors, 235
reversal of cocaine withdrawal effects. 237
structure-activity studies for binding to sigma receptors, 236
ICI 204,448
antipruritic activity, 88
Immune function
differential opioid effects, 24-25
role of nitric oxide in opioid immunomodulation, 23
Impulsivity
effects of abused drugs on a laboratory model, 31
role in drug abuse, 30-32
traits and state characteristics, 31
Inhalants
use by 12-17 year olds, 248
See also specific agents
Intravenous drug users
AIDS-related drug and sexual risk behaviors, 101
antisocial personality disorder, sociopathy and HIV risk in users, 183
discriminating cognitive impairment from HIV versus chronic substance use, 198
gender differences in crack use and HIV risk among non-injecting heroin users, 185
health care need and utilization of intravenous drug uses and others, 330
influence of HIV risk-reduction strategies on behavior of intravenous drug users, 183
needle exchange availability and participation among women, 181
preventing HIV/AIDS among middle-aged and elderly intravenous drug users, 181
psychosocial risk and protective factors and coping in female IDUs, 103
500
risks for HIV seroconversion in collaborative injection drug users, 184
treatment entry and retention among out-of-treatment users, 194
[ 125 I]IOXY
visualization of a novel kappa2 receptor distribution in guinea pig brain, 162
Isobutyl nitrite
role in nitric oxide in immunotoxicity, 116
(±)-Isonicotine oxalate, (NIH 10886)
analgesia in mice, 392
analgesia in rhesus monkeys, 393
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 392, 425
inhibition of electrically stimulated mouse vas deferens, 425
physical dependence evaluation in rhesus monkeys, 393
(-)-Isonicotine dioxalate, (NIH 10895)
analgesia in mice, 394
analgesia in rhesus monkeys, 395
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 394, 427
physical dependence evaluation in rhesus monkeys, 395
(+)-Isonicotine oxalate, (NIH 10896)
analgesia in mice, 395
analgesia in rhesus monkeys, 396
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 395
physical dependence evaluation in rhesus monkeys, 396
Isradipine
reversal of cocaine-induced changes in brain blood flow, 96
Job-seeking
psychological correlates, 257
Kappa opioids
discrimination in female versus male rats, 222
effects of agonists on cocaine self-administration by rhesus monkeys, 277
functional evidence for receptor subtypes in rhesus monkeys, 85
[ 3 5 S]GTP S autoradiography in monkey brain, 127
receptor distribution in guinea pig brain, 162
receptor expression during maturation of mouse immune cells, 113
repeated administration decreases dopamine transporter number, 275
LAAM
blood levels, 315
cimetidine adjunctive therapy for opioid dependence, 316
comparison with methadone maintenance, 314
discriminative stimulus effects of deprivation-induced withdrawal, 109
dose comparison during maintenance therapy, 89
maintenance treatment with twice weekly dosing, 90
opioid cross-tolerance and withdrawal during maintenance, 314
preference for opioid treatment, 315
self-report instruments for measuring environments of patients, 318
Lamotrigine
for cocaine abuse in HIV-seropositive patients, 197
Leshner, Alan
Drug abuse and addiction, 3-8
Levorphanol
pA2 analysis of opioid antinociceptive effects in rats, 224
501
Lithium chloride
conditioned taste aversion, a comparison of rat strains, 214
LM-39
training drug in rats, 290
Lofexidine
assisted methadone withdrawal, 306, 307
treatment for opioid withdrawal, 306
Lorazepam
comparison of the acute effects of diazepam, lorazepam and zolpidem, 174
Luteinizing hormone
cocaine effects on, 275
Marijuana
aggressive behavior following discontinuation of long-term use, 70
assessment and treatment of dependence in adults, 69
effect of monetary alternative on marijuana self-administration, 70
effect on cognition, heart rate and subjective mood when combined with ethanol, 72
effect on success in quitting smoking, 68
fetal outcomes when mothers used early in pregnancy, 125
genes encoding receptors, 238
group therapy on readiness to change scores in substance abusers, 240
initial opportunity to use, 68
motor coordination and balance impairment by acute administration, 71
predictors of cessation of use, 69
rewarding abstinence in methadone maintenance, 326
sibling risk for substance use and dependence, 246
smooth pursuit eye tracking and light reflex, 71
See also Tetrahydrocannabinol and Cannabinoid
Mazindol
dopamine transporter availability in mazindol-treated cocaine addicts, 152
MDMA
LM-39 as a training drug in rats, 290
pharmacological effects in humans, 290
Mecamylamine
reduces conditioned cocaine craving in cocaine-dependent subjects, 142
Memantine
influence on “binge” cocaine-induced elevation of dynorphin mRNA, 232
reinforcing and discriminative stimulus effects, 232
Met-enkephalin
synergism with azidothymidine in retarding murine retrovitus infection, 26
Methadone
effects of naloxone on responses reinforced by oral methadone, 109
d -isomer has NMDA antagonist activity, 87
Methadone maintenance
cognitive-behavioral therapy for cocaine-using methadone patients, 329
co-morbid psychiatric diagnosis and personality dimensions in patients, 287
comparison of morphine and methadone maintenance in pregnant opioid addicts, 343
comparison with buprenorphine in opioid addicts, 313
comparison with LAAM, 314
discriminating cognitive impairment from HIV versus chronic substance use, 198
dynorphin A(1-13) subjective responses in controls and maintenance patients, 111
effectiveness of psychosocial treatment, 320
financial incentive to reduce drug use during maintenance, 325
gambling influence on methadone treatment outcome, 260
502
gender differences in patients, 179
health status of employed patients, 263
HIV prevention strategy, 39
HIV risk behaviors in cocaine-using methadone patients, 101
hyperalgesia in patients, 228
incentive program for sustaining post-detox abstinence, 325
lofexidine-assisted methadone withdrawal, 306, 307
maintenance during pregnancy, relationship between dose and infant outcome, 133
maternal and fetal effects of withdrawal during pregnancy, 133
medication take-home doses and contingency management, 330
methadone dose response in opioid/cocaine dependent patients, 328
patient satisfaction survey, 319
prediction of treatment response by four measure of antisociality, 91
prediction of treatment response by week 2 performance, 318
personality effects on treatment compliance and drug use in treatment, 327
program quality effects on patient drug use during maintenance, 319
quality of life under substitution treatments, 313
reduces hospital utilization, 92
reinforcing effects of methadone/ethanol combinations, 333
relapse to heroin in stable patients, 90
rewarding marijuana abstinence, 326
self-report instruments for measuring environments of patients, 318
voucher-based reinforcement of brief cocaine abstinence in methadone patients, 327
Methamphetamine
characteristics of stimulant abusers and their response to treatment, 298
DADLE attenuation of methamphetamine neurotoxicity, 289
drug discrimination and physiological effects, 291
effects of prenatal exposure on CNS development. 28
long-term outcomes from abuse, 299
reversal of ethanol-induced body sway in standing humans, 292
reversible and rapid effects on dopamine transporters, 288
R-Methanandamide
effect on conditioned responding before and after daily THC dosing, 94
effects on open-field behavior in rats, 95
Methaqualone (CPDD 0007)
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 433
drug discrimination in rhesus monkeys, 432-433
18-Methoxy-coronaridine
effects on nicotine preference and nicotine-induced dopamine release, 156
Methoxyflurane
PCP and diazepam-like discriminative stimulant effects of abused inhalants in mice, 234
Methylecgonidine
effect in sheep, 81
3-O-Methylmorphindole HCl, (NIH 10821)
analgesia in mice, 372
analgesia in rhesus monkeys, 372
biological evaluation of physical dependence potential and abuse liability, 353
displacement of radiolabeled opioid binding, 372, 416
inhibition of electrically stimulated mouse vas deferens, 416
physical dependence evaluation in rhesus monkeys, 372
N-Methylmorphine
role of nitric oxide in immunomodulation, 23
503
3-O-Methylnaltrindole fumarate, (NIH 10822)
analgesia in mice, 373
analgesia in rhesus monkeys, 373
biological evaluation of physical dependence potential and abuse liability, 353
displacement of radiolabeled opioid binding, 373, 416
inhibition of electrically stimulated mouse vas deferens, 416
physical dependence evaluation in rhesus monkeys, 373
Methylphenidate
analogs for cocaine treatment, 76
relationship between discriminative-stimulus and subject-rated effects, 47
relationship of ADHD to abuse and dependence, 130
2-Methyl-5-(3-pyridyl)morphan, 2 oxalate, (NIH 10899)
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 427
drug discrimination in rhesus monkeys, 427
Midazolam
apparent pA2 values of partial and selective GABAA antagonists, 73
pharmacokinetics and pharmacodynamics, 219
Miferpristone
effect on morphine-induced immunosuppression, 200
Modafinil
comparison of preclinical pharmacology with amphetamine, 295
Morphine
antipruritic activity, 88
behavioral and physiological effects in non-drug abusing volunteers, 111
chronic exposure attenuates expression of interleukin-1 converting enzyme, 114
comparison of morphine and methadone maintenance in pregnant opioid addicts, 343
CTOP injections into the ventral pallidum block development of sensitization, 165
deprenyl prevents behavioral and neurochemical changes after withdrawal, 108
differential opioid effects on the immune system, 24-25
discriminative stimulus effects of naloxone following acute morphine pretreatment, 110
effects of injection into the periaqueductal gray matter on macrophage functions, 199
effects on reactivity to HIV peptides, 25
elevated splenic catecholamines and immunosuppression following PAG injections, 115
enhancement of GBR12909 rotational behavior, 170
enhancement of macrophage apoptosis, 113
euphoria in males, 334
immunomodulatoty effects following natural withdrawal, 201
irnmunosuppression correlated with activation of the HPA axis, 200
involvement of cAMP-dependent protein kinase in spinal cord during withdrawal, 163
genetic differences in food and morphine operant reinforced behavior, 171
modulation of hypothalamus-pituitary-adrenal axis in rats with and without stress, 166
motor effects enhanced in rats discriminating cocaine but not amphetamine, 304
NMDA antagonists attenuate tolerance to morphine’s discriminative stimulus, 110
pA2 analysis of opioid antinociceptive effects in rats, 224
prevention of antinociceptive tolerance by nitric oxide synthase inhibitors, 128
quality of life under substitution treatments, 313
renal interstitial scarring, 202
response of two [ 3 5 S]GTP S binding sites to chronic morphine treatment, 127
role of delta receptors in naloxone-induced place aversion in dependent mice, 171
scopolamine effects on reinforcement and reinstatement of responding by monkeys, 173
sex differences in antinociception, 88
state-dependent learning is affected by drug dose, 170
504
subjective, psychomotor, and analgesic effects in healthy volunteers, 228
sweat patch monitoring of use during treatment, 223
Motivation
distinguishing motivational and motor effects of drugs, 267
group therapy on readiness to change scores in substance abusers, 240
Mu opioid receptor
developmental comparison of G-protein coupling to mu opioid receptors, 126
[ 3 5 S]GTP S autoradiography in monkey brain, 127
immune alterations in mice lacking the receptor gene, 112
knockout transgenic mice, 268
molecular characterization of ligand-receptor interactions with RTI-4614-4, 163
phosphorylation of the receptor, 164
protein kinase C involvement in receptor down-regulation, 128
Naloxone
antipruritic activity, 88
buprenorphine interactions in dependent patients stabilized on buprenorphine, 310
cycloserine effect on naloxone-precipitated opioid withdrawal, 308
discriminative stimulus effects in morphine-treated monkeys, 168
effects in opioid-withdrawn volunteers, 308
effects on responses reinforced by oral methadone, 109
urine toxicology with buprenorphine/naloxone combination treatment, 312
Naltrexone
discriminative stimulus effects following acute morphine pretreatment, 110
discriminative stimulus effects in morphine-treated monkeys, 168
effects on ethanol consumption in the rat, 241
enhancement of GBR12909 rotational behavior, 170
failure to block behavioral effects of pentobarbital in humans, 242
pA2 analysis of opioid antinociceptive effects in rats, 224
Naltrindole
analogs potentiate T cell proliferation, 113
differential opioid effects on the immune system, 24-25
effects on ethanol consumption in the rat, 241
effects on ethanol-reinforced responding in rhesus monkeys, 118
pharmacological effects against selective opioid agonists in frogs, 87
4-phenolic analogs as delta-selective opioid ligands, 79
synthesis of derivatives, 80
Nathan B. Eddy Memorial Award
Introduction of recipient, 9-10
Award lecture by M.W. Adler, 11-22
National Treatment Outcome Research Study
treatment outcomes for drug abusers in the United Kingdom, 91
Needle exchange
availability and participation among intravenous drug-using women, 181
Nicotine
ADHD and depression in substance using delinquents, relationship to nicotine, 251
cognitive task-induced brain activation during withdrawal, 66
comparison with intravenous caffeine in cocaine abusers, 285
discriminative and reinforcing effects, 64
drug discrimination and self-administration, 46
effects of price increases and brief abstinence on smoking, 65
fetal outcomes when mothers used early in pregnancy, 125
ibogaine effects on nicotine preference and nicotine-induce dopamine release, 156
mechanism of acute tolerance in mice, 65
505
rat models of drug-seeking relapse, 157
self-administration studies in rats, 64
synthesis of epibatidine analogs as potential PET and SPECT ligands, 157
time-of-day relapse during nicotine-patch-smoking-cessation treatment, 158
transdermal nicotine replacement therapy in smokers with co-morbid mental illness, 160
treatment of dependence with fluoxetine, nicotine patch and group therapy, 66
See also Tobacco
NIH 8068, (Etorphine HCl)
analgesia in mice, 369
biological evaluation of physical dependence potential and abuse liability, 352
displacement of radiolabeled opioid binding, 369
physical dependence evaluation in rhesus monkeys, 370
self-administration by monkeys, 370
NIH 10820, (NIH 10398) (-)-Eseroline (L)-ascorbate
analgesia in mice, 370
analgesia in rhesus monkeys, 371
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 370, 415
inhibition of electrically stimulated mouse vas deferens, 415
physical dependence evaluation in rhesus monkeys, 371
NIH 10821, (3-O-Methylmorphindole HCl)
analgesia in mice, 372
analgesia in rhesus monkeys, 372
biological evaluation of physical dependence potential and abuse liability, 353
displacement of radiolabeled opioid binding, 372, 416
inhibition of electrically stimulated mouse vas deferens, 416
physical dependence evaluation in rhesus monkeys, 372
NIH 10822, (3-O-Methylnaltrindole fumarate)
analgesia in mice, 373
analgesia in rhesus monkeys, 373
biological evaluation of physical dependence potential and abuse liability, 353
displacement of radiolabeled opioid binding, 373, 416
inhibition of electrically stimulated mouse vas deferens, 416
physical dependence evaluation in rhesus monkeys, 373
NIH 10833, (N-[(R,S)-2-Benzyl-3[(S)(2-amino-4-methylthio)butyldithiol-l-oxopropyl]-Lphenylalanine benzyl ester methyl sulfite)
analgesia in mice, 374
analgesia in rhesus monkeys, 374
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 374, 417
inhibition of electrically stimulated mouse vas deferens, 417
physical dependence evaluation in rhesus monkeys, 375
self-administration by monkeys, 375
NIH 10838, (2-Phenyl-1,3-propanediol dicarbamate (Felbamate)
analgesia in mice, 375
analgesia in rhesus monkeys, 376
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 375, 418
inhibition of electrically stimulated mouse vas deferens, 417
physical dependence evaluation in rhesus monkeys, 376
NIH 10839, (3,5-Dimethyltricyclo[3.3.1.1 3,7 ]decan-1-amine (Memantine))
analgesia in mice, 377
analgesia in rhesus monkeys, 377
506
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 377, 418
inhibition of electrically stimulated mouse vas deferens, 418
physical dependence evaluation in rhesus monkeys, 377
NIH 10840, (1-Aminocyclopropane carboxylic acid (ACPC))
analgesia in mice, 378
analgesia in rhesus monkeys, 378
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 378, 419
inhibition of electrically stimulated mouse vas deferens, 419
physical dependence evaluation in rhesus monkeys, 378
NIH 10841, (D-Phenylalanine)
analgesia in mice, 379-381
analgesia in rhesus monkeys, 381-382
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 379, 419
inhibition of electrically stimulated mouse vas deferens, 419
physical dependence evaluation in rhesus monkeys, 382
NIH 10846, (Dihydroetorohine•HCl)
analgesia in mice, 382
analgesia in rhesus monkeys, 384
biological evaluation of physical dependence potential and abuse liability, 352
displacement of radiolabeled opioid binding, 382, 420
inhibition of electrically stimulated mouse vas deferens, 420
physical dependence evaluation in rhesus monkeys, 384
self-administration by monkeys, 384
NIH 10860, ((-)-5,9 -Dimethyl-2-heptyl-2’-propionoxy-6,7-benzomorphan
HCl)
analgesia in mice, 385
analgesia in rhesus monkeys, 386
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 385
physical dependence evaluation in rhesus monkeys, 386
NIH 10864, ((-)-5,9 -Dimethyl-2’-hydroxy-2-(2-hydroxyethyl)-6,7-benzomorphan
oxalate)
analgesia in mice, 386
analgesia in rhesus monkeys, 387
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 386
physical dependence evaluation in rhesus monkeys, 387
NIH 10867, (7-Nitroindazole (7-Nitro-1H-indazole)
analgesia in mice, 387
analgesia in rhesus monkeys, 388
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 387,420
inhibition of electrically stimulated mouse vas deferens, 421
physical dependence evaluation in rhesus monkeys, 388
NIH 10869, ((-)-2-Cyanomethyl-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan
HCl)
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 421
inhibition of electrically stimulated mouse vas deferens, 421
NIH 10870, ((+)-2-Cyanomethyl-5.9 -dimethyl-2’-hydroxy-6,7-benzomorphan HCl)
analgesia in mice, 388
analgesia in rhesus monkeys, 389
biological evaluation of physical dependence potential and abuse liability, 354
507
displacement of radiolabeled opioid binding, 388, 422
inhibition of electrically stimulated mouse vas deferens, 422
physical dependence evaluation in rhesus monkeys, 388
NIH 10871, ((-)-Cyanopentyl-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan HCl)
analgesia in mice, 389
analgesia in rhesus monkeys, 390
biological evaluation of physical dependence potential and abuse liability, 354
displacement of radiolabeled opioid binding, 389
physical dependence evaluation in rhesus monkeys, 390
NIH 10874, (7-Benzoyl-2-piperidineomethyl-1,4-benzodioxane HCl)
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 423
inhibition of electrically stimulated mouse vas deferens, 423
NIH 10875, (Pseudocodeine HC)
biological evaluation of physical dependence potential and abuse liability, 353
displacement of radiolabeled opioid binding, 423
inhibition of electrically stimulated mouse vas deferens, 424
NIH 10884, ((-)-2-(3-Cyanopropyl)-5,9a-dimethyl-2’hydroxy-6,7-benzomorphan)
analgesia in mice, 390
analgesia in rhesus monkeys, 391
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 390, 424
inhibition of electrically stimulated mouse vas deferens, 424
physical dependence evaluation in rhesus monkeys, 391
NIH 10885, ((+)-2-(3-Cyanopropyl)-5,9 -dimethyl-2’hydroxy-6,7-benzomorphan)
analgesia in mice, 391
analgesia in rhesus monkeys, 392
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled ooioid binding, 391,
physical dependence evaluation in rhesus monkeys, 392
NIH 10886, ((±)-Isonicotine oxalate)
analgesia in mice, 392
analgesia in rhesus monkeys, 393
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 392, 425
inhibition of electrically stimulated mouse vas deferens, 425
physical dependence evaluation in rhesus monkeys, 393
N I H 1 0 8 8 7 , -Conotoxin MVIIA (reduced, cyclic (1-16), (8-20), (15-25))
analgesia in mice, 393
analgesia in rhesus monkeys, 394
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 393, 425
inhibition of electrically stimulated mouse vas deferens, 426
physical dependence evaluation in rhesus monkeys, 393
reinforcing effects in rhesus monkeys, 426
self-administration by monkeys, 394, 426
NIH 10895, ((-)-Isonicotine dioxalate)
analgesia in mice, 394
analgesia in rhesus monkeys, 395
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 394, 427
physical dependence evaluation in rhesus monkeys, 395
508
NIH 10896, ((+)-Isonicotine oxalate)
analgesia in mice, 395
analgesia in rhesus monkeys, 396
biological evaluation of physical dependence potential and abuse liability, 358
displacement of radiolabeled opioid binding, 395
physical dependence evaluation in rhesus monkeys, 396
NIH 10897, (-)-6-(Chlorohexyl)-5,9 -dimethyl-2’-hydroxy-6,7-benzomorphan HCl)
analgesia in mice, 396
analgesia in rhesus monkeys, 397
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 396
physical dependence evaluation in rhesus monkeys, 397
NIH 10898, (2S,5S,9S-(+)-2-(6-Chlorohexyl)-5-9 -dimethyl-2’-hydroxy-benzomorphan
HCl)
analgesia in mice, 398
analgesia in rhesus monkeys, 398
biological evaluation of physical dependence potential and abuse liability, 355
displacement of radiolabeled opioid binding, 398
physical dependence evaluation in rhesus monkeys, 398
NIH 10899, (2-Methyl-5-(3-pyridyl)morphan, 2 oxalate)
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 427
drug discrimination in rhesus monkeys, 427
NIH 10900, (11-[4-Hydroxy-4-(3-triflouromethylphenyl)piperidin-1-yl]-2-methyl-6, 11dihydrodibenz[b,c]oxepine sulfuric acid)
analgesia in mice, 399
analgesia in rhesus monkeys, 400
biological evaluation of physical-dcpendence potential and abuse liability. 359
displacement of radiolabeled opioid binding, 399
physical dependence evaluation in rhesus monkeys, 400
NIH 10901, 11-(4-Hydroxy-4-phenylpiperidin-1-y1)-2-methy1-6,11-dihydrodibenz[b,e]oxepine
fumaric acid
analgesia in mice, 400
analgesia in rhesus monkeys, 401
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 400
physical dependence evaluation in rhesus monkeys, 401
NIH 10902, 11-[4-Hydroxy-4-(trifluoromethylphenyl) piperidin-1-yl]-2-hydroxymethyl-6,11dihydrodibenz[b,e]oxepine fumaric acid
analgesia in mice, 402
analgesia in rhesus monkeys, 402
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 402
physical dependence evaluation in rhesus monkeys, 403
NIH 10903, 11-(4-Hydroxy-4-phenylpiperidin-l-y])-2-hydroxymethyl-6,11dihydrodibenz[b,e]oxe-pine fumaric acid
analgesia in mice, 403
analgesia in rhesus monkeys, 404
biological evaluation of physical-dependence potential and abuse liability, 359
displacement of radiolabeled opioid binding, 403
physical dependence evaluation in rhesus monkeys, 404
NIH 10917, (+)-2,3,3a,4,5,9 -Hexahydro-1-methyl-1 H - p y r r o l o [ 3 , 2 - h )-isoquinoline HBr,
(+)-Bridged nicotine
analgesia in mice, 405
509
analgesia in rhesus monkeys, 405
displacement of radiolabeled opioid binding, 405
physical dependence evaluation in rhesus monkeys, 405
NIH 10918, (-)-2,3,3a,4,5,9 -Hexahydro-1-methyl-1 H -pyrrolo[3,2- h )-isoquinoline 2 HBr,
(-)-Bridged nicotine
analgesia in mice, 405
displacement of radiolabeled opioid binding, 405
Nitric oxide
effects on pain response in healthy volunteers, 229
role in isobutyl nitrite immunotoxicity, 116
7-Nitroindazole (7-Nitro-1H-indazole, (NIH 10867)
analgesia in mice, 387
analgesia in rhesus monkeys, 388
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 387, 420
effects on cocaine discrimination in rats, 279
inhibition of electrically stimulated mouse vas deferens, 421
physical dependence evaluation in rhesus monkeys, 388
NMDA
role of NMDA receptors in the expression of diazepam withdrawal signs, 173
Norepinephrine transporter
affinity of cocaine and phenyltropane analogs for, 77
characterization of substrate transport, 33
cocaine medication development, 33
regulation of cocaine and antidepressant-sensitive transporters, 34
Olanzapine
attenuation of cocaine’s discriminative stimulus and reinforcing effects, 278
Opioids
craving and attitudinal changes in addicts in 30-day ambulatory detoxification, 317
differences among intravenous and intranasal abusers, 316
discriminative effects of cocaine/opioid combinations, 55
drug discrimination in humans, 45
immune function and host defense against retroviruses, 23
lofexidine-assisted methadone withdrawal, 306
lofexidine treatment for opioid withdrawal, 306
medications development, 56
morphological changes in dependence, 155
mu opioid receptor binding during early and prolonged cocaine abstinence, 107
neurobiology of abuse, 55
opioid abusers seeking smoking cessation treatment, 67
PCK involvement in receptor down-regulation, 128
rat strain differences in sensitivity to antinociceptive effects, 269
role of nitric oxide in immunomodulation, 23
See also individual drugs
Orphanin FQ
blocks opioid antinociception in cold-water tail-flick test, 224
peptide biotransformation in human blood, 225
8-Oxatropanes
inhibitors of monoamine transport systems, 78
Parenting skills
questionnaire revised, test-retest reliability, 342
Pentobarbital
effects on symbolic delayed matching performance in rats, 178
510
effects on temporal discrimination in rats, 176
euphoria in males, 334
failure of naltrexone to block behavioral effects in humans, 242
matching-to-sample performance of pigeons, 177
Phencyclidine
acquisition of oral self-administration, 230
antibody-based medications development, 231
chronic exposure produces apoptosis in olfactory tubercle and piriform cortex, 230
developmental exposure produces attenuated responses to PCP and MK-801, 229
discriminative stimulant effects of abused inhalants in mice, 234
effects on symbolic delayed matching performance in rats, 178
effects on temporal discrimination in rats, 176
matching-to-sample performance of pigeons, 177
pharmacokinetic antagonist, 231
Phentermine
detection in hair and nails, 223
effects in monkeys under progressive-ratio schedules of cocaine and food delivery, 141
effects of reacquisition of cocaine self-administration, 140
D-Phenylalanine, (NIH 10841)
analgesia in mice, 379-381
analgesia in rhesus monkeys, 381-382
biological evaluation of physical dependence potential and abuse liability, 357
displacement of radiolabeled opioid binding, 379, 419
inhibition of electrically stimulated mouse vas deferens, 419
physical dependence evaluation in rhesus monkeys, 382
Phenyldecahydroisoquinoline
synthesis of an analog related to morphine, 162
2-Phenyl-1,3-propanediol dicarbamate (Felbamate), (NIH 10838)
analgesia in mice, 375
analgesia in rhesus monkeys, 376
biological evaluation of physical dependence potential and abuse liability, 356
displacement of radiolabeled opioid binding, 375, 418
inhibition of electrically stimulated mouse vas deferens, 417
physical dependence evaluation in rhesus monkeys, 376
Phenytoin
effects on cocaine self-administration in humans, 138
Pimozide
effects on subjective responses to ethanol in humans, 242
Post-traumatic stress disorder
characterized among treatment-seeking substance abusers, 48
neurobiology of, 50
relationship to substance abuse, 48
risk factors common with drug abuse/dependence, 50
Pregnancy
buprenorphine maintenance in opioid addicts, 134
comparison of morphine and methadone maintenance in pregnant opioid addicts, 343
EEG abnormalities in children exposed to cocaine in utero, 135
methadone maintenance, relationship between dose and infant outcome, 133
maternal and fetal effects of methadone withdrawal during, 133
outcome in women consuming drugs and vitamin/mineral supplements, 134
predictors of development in prenatal drug-exposed toddlers, 135
predictors of treatment outcomes for pregnant women, 340
psychiatric symptomatology in drug dependent pregnant women, 341
511
risk factors: a birth cohort of preadolescents, 136
type A and type B clusters in substance-dependent treatment-seeking women, 341
Preproenkephalin
cocaine alterations in mRNA levels in guinea pig brain, 83
cocaine effects on mRNA levels and nest building in pregnant rats, 122
Procaine
cerebral blood flow following procaine in cocaine addiction, 151
Prolactin
elevation of serum levels by dynorphin A1-13 , 167
2 -Propanoyl-3 -(4-tolyl)-tropane
behavioral effects in monkeys, 284
Pseudocodeine HCl, (NIH 10875)
biological evaluation of physical dependence potential and abuse liability, 353
displacement of radiolabeled opioid binding, 423
inhibition of electrically stimulated mouse vas deferens, 424
Quinelorane
dopamine receptor blockade, effects on self-administration, 279
Rational Emotive Behavior Therapy
process evaluation methods for treatment programs, 329
Retroviruses
opioids and neuropeptides in immune function and host resistance to, 23
Rimcazole
irreversible ligands for the dopamine transporter, 272
Rohypnol
abuse in Florida, 175
RTI-113
pharmacotherapy of cocaine abuse, 278
RTI-4614-4
molecular characterization of ligand-receptor interactions, 163
SCAN
test-retest reliability of the alcohol and drug sections, 240
SCH23390
effects of chronic exposure on cocaine self-administration, 281
effects of injection into ventral tegmental area on cocaine-induced sensitization, 302
Schema-Focused Therapy
personality disordered substance abusers, 259
Scopolamine
detoxification for the treatment of heroin addicts, 307
effects on morphine reinforcement and reinstatement of responding by monkeys, 173
Serotonin
affinity of cocaine and phenyltropane analogs for, 77
regulation of cocaine and antidepressant-sensitive transporters, 34
Sevoflurane
effects on pain response in healthy volunteers, 229
Sibutramine
abuse liability assessment, 297
SIV
rhesus monkey behavioral battery, 198
SKF 83959
behavioral effects in monkeys, 282
SNC80
antipruritic activity, 88
behavioral effects in rhesus monkeys, 86
512
search for selective delta antagonists, 161
synthesis of affinity labeling analogs for delta opioid receptors. 80
SoRI 9331
potentiates T cell proliferation, 113
SoRI 9340
potentiates T cell proliferation, 113
SR 141716A
effect on conditioned responding before and after daily THC dosing, 94
enhances radial arm maze performance in rats, 96
suppression of operant responding in THC chronically treated rats, 95
State-dependent learning
performance in a complex maze task is affected by drug dose, 170
Substance abuse
See Drug abuse
Substance P
upregulates HIV expression in human macrophages, 26
3 -(Substituted
phenyl)tropane-2 -carboxylic acid esters
synthesis and transporter binding properties, 273
Subutex
quality of life under substitution treatments, 313
Tetrahydrocannabinol
abstinence symptoms following THC administration in men and women, 239
effects of SR 141716A on diazepam substitution in THC discrimination in rats, 239
effects on conditioned responding before and after daily THC dosing, 94
effects on open-field behavior in rats, 95
SR 141716A effect on conditioned responding before and after daily THC dosing, 94
SR 141716A suppression of operant responding in chronically treated rats, 95
See also Cannabinoid and Marijuana
Tobacco
ACCU DROP, an aid for smoking cessation, 158
alternative reinforcer and response requirement on smoking by schizophrenics, 161
cigarette smoking during early cocaine abstinence, 159
cortisol synthesis inhibitors in heavy smokers, 159
effect of substance abuse treatment, alcohol and marijuana use on quitting, 68
effects of price increases and brief abstinence on smoking, 65
maternal and child predictors of the onset of use, 156
opioid abusers seeking smoking cessation treatment, 67
quitters and non-quitters differ in their pretreatment reactivity, 67
recovering alcoholic versus non-alcoholic smokers, 160
sibling risk for substance use and dependence, 246
time-of-day relapse during nicotine patch smoking cessation treatment, 158
transdermal nicotine replacement therapy in smokers with co-morbid mental illness, 160
See also Nicotine
Toluene
effects on recombinant NMDA receptors, 233
effects on VTA dopamine and non-dopamine neurons, 233
PCP and diazepam-like discriminative stimulant effects of abused inhalants in mice, 234
Triazolam
relationship between discriminative-stimulus and subject-rated effects, 47
1,1,1-Trichloroethane
PCP and diazepam-like discriminative stimulant effects of abused inhalants in mice, 234
Tuberculous
preventive therapy for active drug users, 205
513
tuberculin reactivity among drug users, 205
Tumor Necrosis Factordevelopment of a central component to persistent pain, 227
increases inulin and HIV-1 permeability across the blood-brain barrier, 117
U50,488
effects on cocaine self-administration by rhesus monkeys, 277
U69,593
discrimination in female versus male rats, 222
effects on dopamine induced inhibition of dopamine dynamics in dorsal striatum, 276
repeated administration decreases dopamine transporter number, 275
Venlafaxine
treatment of major depression and cocaine dependence, 255
-Vinyl GABA
attenuation of cocaine self-administration in rats, 280
Wender Utah Rating Scale
comparison of current and former stimulant abusers’ scores, 298
Zipeprol[4-(2-methoxy-2-phenylethyl)-(methoxyphenylmethyl)-1-piperazineethanol 2 HCl,
(CPDD 0042)
biological evaluation of physical-dependence potential and abuse liability, 360
discriminative stimulus effects in rhesus monkeys, 435
drug discrimination in rhesus monkeys, 434 - 435
Zolpidem
comparison of the acute effects of diazepam, lorazepam and zolpidem, 174
physical dependence, 74
selective effects on human memory functions, 74
514
*U.S. Government Printing Office: 1998 - 432-965/60003
NIDA
NATIONAL INSTITUTE
ON DRUG ABUSE
NIH Publication No. 98-4305
Printed March 1998