Molecular and Cellular Aspects of the Drug Addictions

253 Pages·1989·12.46 MB·English

by  Harold Kalant (auth.)

Molecular and Cellular
Aspects of the
Drug Addictions
A vram Goldstein
Editor
Molecular and Cellular
Aspects of the
Drug Addictions
Springer-Verlag
New York Berlin Heidelberg
London Paris Tokyo
Avram Goldstein, M.D.
Addiction Research Foundation Professor
Department of Pharmacology
School of Medicine
Stanford University
Stanford, California 94305
Library of Congress Cataloging-in-Publication Data
Molecular and cellular aspects of the drug addictions / Avram
Goldstein, editor.
p. em.
Based on an all-day symposium held on April 13, 1988.
Includes bibliographies.
ISBN-13:978-1-4613-8819-7 (U.S.)
1. Drug abuse-Physiological aspects-Congresses.
2. Neurochemistry-Congresses. 3. Drug receptors-Congresses.
4. Psychopharmacology-Congresses. 1. Goldstein, Avram.
[DNLM: 1. Substance Dependence-physiopathology--congresses. WM
270 M718 1988]
RC563.2.M64 1989
615'.78-dc20
DNLMlDLC
for Library of Congress 89-10061
CIP
© 1989 by Springer-Verlag New York Inc.
Softcover reprint of the hardcover 1st edition 1989
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ISBN -13: 978-1-4613-8819-7 e-ISBN -13 :978-1-4613-8817-3
DOl: 10.1007/978-1-4613-8817-3
Preface
In 1970 I gave up the chairmanship of the Department of Pharmacology at
Stanford University Schoel of Medicine to devote full time to basic and
clinical research on problems of drug addiction. In 1971 I developed the
method of radioligand binding that led to the important characterization of
opioid receptors in several laboratories. The extraordinary specificity of
these receptors for morphine and related opiates suggested the likelihood
that there were naturally occurring morphine-like molecules in the brain
and other tissues. The systematic search for these molecules culminated
in 1979 in the discovery, by my group, ofthe dynorphin peptides-one of
the three families of opioid peptides, the first of which (the enkephalin
family) had been discovered in Aberdeen, Scotland, in 1975. I also
became involved in clinical research on the pharmacologic treatment of
heroin addicts, for which I established the first large methadone mainte
nance treatment program in California. My basic and clinical research
experience convinced me that an institution encompassing laboratory
research, studies on normal human volunteers, and treatment research,
under a single roof, could expedite progress in understanding the drug
addictions.
That concept was transformed into reality by the founding, in 1974, of
the Addiction Research Foundation of Palo Alto, California. The funds
for construction of a laboratory were provided by a generous grant from
the Drug Abuse Council (a consortium of several foundations), the
president of which was Thomas L. Bryant. Strong community support,
both in Palo Alto and in San Francisco, came from a number of
community leaders, notably Agnes C. Robinson, Martin E. Packard,
Brooks Walker, Jr., Jean Kuhn Doyle, Emmett G. Solomon, Henry P.
Organ, Herbert Dwight, Jr., Alejandro Zaffaroni, David A. Fasken,
David and Lucile Packard, the Honorable Edward C. Scoyen, Leonard
Cornell, and Charles G. Schulz.
The Foundation operated independently-it was never affiliated with
Stanford-for 14 years. Its research activities were largely funded by the
National Institute on Drug Abuse. At the peak of its strength the staff
vi Preface
numbered 65, about equally divided between laboratory and clinical
research. Leaders of the research teams were Brian M. Cox in the
laboratory, Barbara A. Judson in the clinic, and Priscilla Grevert in
research on normal human volunteers. The chief administrator was Abbie
W. Freiley.
Participating in the Scientific Advisory Board at different times were:
Harold Kalant, Floyd E. Bloom, E. Leong Way, Doris H. Clouet, Jack H.
Mendelson, Walter M. Booker, William M. Harvey. Jerome H. Jaffe.
Murray E. Jarvik. Arnold J. Mandell, and Norman Weiner.
Leo E. Hollister served for many years as chairman of the Human
Subjects Committee, which was responsible for reviewing the ethical
aspects of all proposed human experiments, and whose membership
included numerous medical and lay members of the community.
The Foundation, in its 14 years of existence, had many significant
research accomplishments, recorded in more than 200 publications. The
major laboratory contributions concerned the dynorphin opioid peptides
-their structure, tissue distribution, mode of processing from a large
precursor peptide, and their physiologic functions. Human volunteer
studies dealt primarily with the natural regulation of pain through the
opioid systems, using as a tool the opioid receptor blocker naloxone.
Clinical research established optimal dosage regimens for methadone and
for the long-acting methadone congener LAAM, developed a practical
naloxone test for opiate dependence, worked out effective procedures for
drug testing in urine, and advanced our understanding of the principles
and efficacy of treating heroin addiction with surrogate opiates or opiate
antagonists.
As federal research support faced increasing budgetary constraints.
with a resulting instability and unpredictability of research funding by the
federal agencies, and with increasing difficulty experienced in fund
raising from the private sector, it became painfully obvious that the dream
of a nationally significant multidisciplinary center for addiction research,
with its own building and a sufficient endowment to ensure its perma
nence, was not to be realized. The Board of Directors decided, therefore,
to phase out and dissolve the Foundation, but to perpetuate its purpose by
transferring all of its cash assets to Stanford University for the purpose of
establishing a chair in addiction research in the medical school. The
holder of this chair, it was specified, is to have "a demonstrated
commitment to teaching and research on the biologic. chemical. and
genetic basis of addictive disorders."
All the Foundation's laboratory equipment and supplies were donated
to the Department of Physiology of the Beijing Medical University, the
People's Republic of China's designated "key" medical university. There
Professor J .-S. Han, the department chairman, has carried out important
investigations into the functions of the opioid peptides, and !1aS had a long
collaborative relationship with the Foundation's scientists. This gift,
Preface vii
therefore, will support further research on addiction, pain regulation, and
other opioid-related phenomena-research along lines similar to those we
followed at Palo Alto.
An all-day symposium was held on April 13, 1988, to mark the
dissolution of the Foundation. It was followed by a dinner, at which the
Addiction Research Foundation Professorship was presented to Stanford
by Martin E. Packard, President of the Foundation, and accepted by
Donald Kennedy, President of the University. The symposium speakers
were all world-renowned scientists, working either directly on the biologi
cal aspects of drug addiction, or on biologic problems germane to the
study of the drug addictions. The chapters in this book are based on the
lectures presented at the symposium.
A vram Goldstein
Stanford, California
March 3, 1989
Contents
Introduction .............................................. xiii
A vram Goldstein
1. The Nature of Addiction: An Analysis of the Problem ........... 1
Harold Kalant
2. Neuroanatomical and Neurochemical Substrates of
Drug-Seeking Behavior: Overview and Future Directions ....... 29
Stanley J. Watson, Keith A. Trujillo, James P. Herman, and
Huda Akil
3. Bradykinin and Pain ........................................ 92
Solomon H. Snyder, Donald C. Manning, and Larry R. Steranka
4. Neurochemical Aspects of Addiction: Opioids and
Other Drugs of Abuse ...................................... 111
A. Herz and T.S. Shippenberg
5. Which Molecular and Cellular Actions of
Ethanol Mediate Reinforcement? ........................... 142
Floyd E. Bloom
6. Presynaptic Inhibition, Presynaptic Facilitation, and the
Molecular Logic of Second-Messenger Systems ............... 159
Andrea Volterra, Steven A. Siegelbaum, J. David Sweatt, and
Eric R. Kandel
7. Applications of Molecular Genetics to
Neuropsychiatric Disorders ................................. 198
Joseph B. Martin
Index .................................................... 223
Contributors
Huda Akil, Ph.D., Professor and Director of Research, Department of
Psychiatry, Research Scientist, Mental Health Research Institute,
Ann Arbor, Michigan 48109-0720, USA
Floyd E. Bloom, M.D., Director, Division of Pre-Clinical Neuroscience
and Endocrinology, Research Institute of Scripps Clinic, La Jolla,
California 92037, USA
Avram Goldstein, M.D., Addiction Research Foundation, Professor,
Department of Pharmacology, School of Medicine, Stanford
University, Stanford, California 94305, USA
James P. Herman, Ph.D., Postdoctoral Research Fellow, Mental
Health Research Institute, University of Michigan, Ann Arbor,
Michigan 48109-0720, USA
A. Herz, M.D., Director, Department of Neuropharmacology, Max
Planck Institute for Psychiatry, Planegg-Martinsried,
Federal Republic of Germany
Harold Kalant, M.D., Ph.D., Professor, Department of Pharmacology,
University of Toronto; Associate Research Director (Biobehavioral
Studies), Addiction Research Foundation of Ontario, Tor:onto, Ontario,
Canada
Eric R. Kandel, M.D., University Professor, Center for Neurobiology
and Behavior; Senior Investigator, Howard Hughes Medical Institute,
Columbia University, College of Physicians and Surgeons, New York,
New York 10032, USA
xii Contributors
Donald C. Manning, M.D., Ph.D., Department of Neuroscience, Johns
Hopkins University School of Medicine, Baltimore, Maryland
21205, USA
Joseph B. Martin, M.D., Ph.D., Julieanne Dorn Professor of
Neurology, Harvard Medical School, Boston, Massachusetts
02114, USA
T. S. Shippenberg, Ph.D., Research Assistant, Department of
Neuropharmacology, Max Planck Institute for Psychiatry,
Planegg-Martinsried, Federal Republic of Germany
Steven A. Siegelbaum, Ph.D., Associate Professor, Department of
Pharmacology; Assistant Investigator, Howard Hughes Medical
Institute, Columbia \.1niversity, College of Physicians and Surgeons,
New York, New York 10032, USA
Solomon H. Snyder, M.D., Director, Department of Neuroscience,
Johns Hopkins Medical School, Baltimore, Maryland 21205, USA
Larry R. Steranka, Ph.D., Nova Pharmaceutical Corporation,
Baltimore, Maryland 21224-2788, USA
J. David Sweatt, Ph.D., Associate, Howard Hughes Medical Institute,
Columbia University, College of Physicians and Surgeons, New York,
New York 10032, USA
Keith A. Trujillo, Ph.D., Postdoctoral Research Fellow, Mental Health
Research Institute, University of Michigan, Ann Arbor, Michigan
48109-0720, USA
Andrea Volterra, Ph.D., Associate Research Scientist, Department of
Pharmacology; Associate, Howard Hughes Medical Institute, Columbia
University, College of Physicians and Surgeons, New York, New York
10032, USA
Stanley J. Watson, Ph.D., M.D., Professor of Psychiatry; Associate
Director, Mental Health Research Institute, University of Michigan,
Ann Arbor, Michigan 48109, USA
Introduction
A vram Goldstein
Addiction is "a behavioral pattern of drug use, characterized by over
whelming involvement with the use of a drug (compulsive use),
the securing of its supply, and a high tendency to relapse after with
drawal" (I).
An expert committee of the World Health Organization (2,3) has for
many years struggled with questions of nomenclature in this field. In my
opinion, its dogmatic proscribing of the term "addiction" as supposedly
imprecise has not been a useful exercise, and the several alternative terms
proposed seem to miss the point. "Addiction," as defined above, brings
the problem into good focus. It is a behavior, and it concerns th'e
compulsive use of a drug. Thus modern basic research on addiction draws
upon the remarkable recent advances in understanding the molecular and
cellular bases of two neurobiologic disciplines-psychology and pharma
cology.
Discussion of drug addiction in some circles still provokes the fruitless
"biology versus psychology" debate-fruitless because we now under
stand, with ample experimental proofs, that life experiences and environ
mental stresses alter the neurochemistry of the brain, not only during
embryogenesis but also throughout the life span. In short, behavior is a
consequence of neurochemistry; psychology is biology. Both the hard
ware and the software could contribute to addictive behavior, and we
need to understand both, in concrete terms, for each addicting drug.
There is obviously no single, simple, cause of addiction. The net
contributions ofthree main factors will determine, at a particular time and
place, the incidence and prevalence of addiction to a given drug:
I. Availability of the drug.
2. Individual predisposition to use the drug repeatedly and become
addicted.
3. External facilitatory and inhibitory factors such as societal, family,
religious, and cultural traditions and attitudes, legal restraints, stressful
or tranquil conditions of life, and alternative sources of satisfaction.