Table Of ContentAlcohol and Opiates
NEUROCHEMICAL AND BEHAVIORAL
MECHANISMS
Edited by
Kenneth Blum
Chief, Division of Drug and Alcohol Abuse
and
Associate Professor
Department of Pharmacology
University of Texas
Health Science Center
San Antonio, Texas
Associate Ed/tors
Diana L. Bard and Murray G. Hamilton
Division of Drug and Alcohol Abuse
Department of Pharmacology'
University of Texas
Health Science Center
San Antonio, Texas
®
ACADEMIC PRESS, INC. New York San Francisco London 1977
A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT © 1977, BY ACADEMIC PRESS, INC.
ALL RIGHTS RESERVED.
NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR
TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC
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ACADEMIC PRESS, INC.
Ill Fifth Avenue, New York, New York 10003
United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
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Library of Congress Cataloging in Publication Data
Main entry under title:
Alcohol and opiates.
1. Alcohol-Physiological effect-Congresses.
2. Narcotics-Physiological effect-Congresses.
3. Neuropsychopharmacology-Congresses. 4. Neuro-
chemistry-Congresses. I. Blum, Kenneth.
II. Bard, Diana L. III. Hamilton, Murray G.
[DNLM: 1. Alcohol-Pharmacodynamics-Congresses.
2. Opium-Pharmacodynamics-Congresses. 3. Drug
dependence-Congresses. 4. Behavior-Drug effects
-Congresses. WM270 A355 1976]
QP801.A3A42 615'.782 77-1930
ISBN 0-12-108450-7
PRINTED IN THE UNITED STATES OF AMERICA
This book is dedicated to my wife, Arlene Carol, for her unselfish
love and magnificent devotion; and to our children, Jeffrey Harris and
Seth Howard, for whom we wish a life of pleasure inducement that tran
scends the hangups and misconceptions of our contemporary adult world.
List of Contributors
L. G. ABOOD, Center Brain Research and Biochemistry, University of Rochester Medical
Center, Rochester, New York 14642
KENNETH BLUM, Department of Pharmacology, University of Texas Health Science Center
at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284
HOWARD CAPPELL, Research Division, Addiction Research Foundation, 33 Russell Street,
Toronto, Ontario, Canada M5S 2S1
H. LEE CARDENAS, Departments of Pharmacology and Psychiatry, University of Texas Health
Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284
RAYMOND C.A. CHEN, Department of Pharmacology, Peoria School of Medicine, University
of Illinois at The Medical Center, Peoria, 1400 West Main Street, Peoria, Illinois 61606
DORIS H. CLOUET, New York State Drug Abuse Control Commission Research Laboratories,
Brooklyn, New York 11217
GERALD COHEN, Department of Neurology, Mount Sinai School of Medicine, New York,
New York 10029
ALLAN C. COLLINS, School of Pharmacy and Institute for Behavioral Genetics, University of
Colorado, Boulder, Colorado 80309
MICHAEL A. COLLINS, Department of Biochemistry and Biophysics, Stritch School of
Medicine, Loyola University of Chicago, 2160 South First Avenue, Maywood, Illinois 60153
RICHARD A. DEITRICH, Department of Pharmacology, School of Medicine, University of
Colorado, Denver, Colorado 80220
DONALD S. FABER, New York State Research Institute on Alcoholism, 1021 Main Street,
Buffalo, New York 14203
HOWARD J. FRIEDMAN, Center of Alcohol Studies, Rutgers University, New Brunswick,
New Jersey 08903
STEVEN R. GOLDBERG, Laboratory of Psychobiology, Department of Psychiatry, Harvard
Medical School, Boston, and New England Regional Primate Center, One Pine Hill Drive,
Southborough, Massachusetts 01772
AVRAM GOLDSTEIN, Department of Pharmacology, Stanford University, and Addiction
Research Foundation, Palo Alto, California 94304
MURRAY G. HAMILTON, Division of Drug and Alcohol Abuse, University of Texas Health
Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284, and
Department of Pharmacology, The University of Western Ontario, London, Ontario,
Canada
MAURICE HIRST, Department of Pharmacology, The University of Western Ontario, London,
Ontario, Canada
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x LIST OF CONTRIBUTORS
ANDREW K.S. HO, Department of Pharmacology, Peoria School of Medicine, University of
Illinois at the Medical Center, 1400 West Main Street, Peoria, Illinois 61606
MANFRED R. KLEE, Max Planck Institute for Brain Research, 6 Frankfure/m-Niederrad,
Deutschardenstr 46, West Germany
WERNER A. KLEE, Laboratory of General and Comparative Biochemistry, National Institute on
Mental Health, Public Health Service, Bethesda, Maryland 20014
PING-YEE LAW, Departments of Psychiatry and Pharmacology, University of California,
San Francisco, California 94122
A. EUGENE LeBLANC, Addiction Research Foundation, 33 Russell Street, Toronto, Ontario,
Canada M5S 2S1
DAVID LESTER, Center of Alcohol Studies, Rutgers University, New Brunswick, New
Jersey 08903
HORACE H. LOH, Department of Pharmacology, University of California, San Francisco, Cal
ifornia 94122
SHERWOOD C. LYNN, JR., Departments of Pharmacology and Psychiatry, University of Texas
Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284
ALICE M. MARSHALL, Department of Pharmacology, The University of Western Ontario,
London, Ontario, Canada
J. MICHAEL MORRISON, National Institute on Drug Abuse, 11400 Rockville Pike, Rockville,
Maryland 20852
HERBERT MOSKOWITZ, Southern California Research Institute, 2033 Pontius Avenue, Los
Angeles, California 90025
STEVEN H. POLLOCK, Division of Drug and Alcohol Abuse, University of Texas Health
Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284
CARRIE L. RANDALL, Department of Psychiatry and Behavioral Sciences, Medical University
of South Carolina, Charleston, South Carolina 29401
DAVID H. ROSS, Department of Pharmacology and Psychiatry, University of Texas Health
Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284
N. SALEM, JR., Center Brain Research and Biochemistry, University of Rochester Medical
Center, Rochester, New York 14642
SATANAND SHARMA, Southern California Research Institute, 2033 Pontius Avenue, Los
Angeles, California 90025
ERIC J. SIMON, Experimental Medicine, New York University School of Medicine, New York,
New York 10016
ALFRED A. SMITH, Department of Psychiatry, New York Medical College, New York, New
York 10019
BORIS TABAKOFF, Department of Physiology, College of Medicine, University of Illinois,
901 South Woleoh Street, Chicago, Illinois 60680
F. TAKEDA, Center Brain Research and Biochemistry, University of Rochester Medical Center,
Rochester, New York 14642
ANDREW H. TANG, The Upjohn Company, Kalamazoo, Michigan 49001
JACK E. WALLACE, Department of Pathology, University of Texas Health Science Center at
San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284
KENNETH ZIEDMAN, Southern California Research Institute, 2033 Pontius Avenue, Los
Angeles, California 90025
Foreword
Part I—Alcohol*
Alcohol abuse is one of the greatest problems facing our modern-day
society. An estimated 9 million people in the United States alone are
alcoholics or problem drinkers. Each year alcohol abuse costs the United
States economy an estimated 25 billion dollars and the human suffering
exacted by alcohol cannot be translated into monetary terms. As the use of
alcohol increases, as more young people take up drinking, the incidence of
alcohol-related problems also increases. Clearly there is an urgent need to in
tensify current efforts of treating and preventing alcohol abuse. To maximize
the effectiveness of these efforts, a base of reliable, objective, and scientific
facts needs to be established.
The subject of alcohol abuse is exceedingly complex. Alcoholism affects
all segments of our society and its amelioration poses a real challenge to
people concerned with improving the quality of life. Significant strides have
been made to help alcoholic people, but the area of alcoholism is fraught
with too much heat and too little light. Too much reliance has sometimes
been placed on conventional wisdom and dogma. I point this out not to
belittle in any way the significant advances that have been made in the past.
Rather, I believe that realistic appraisal of the current state of our knowledge
lends a hopeful note to the opportunities that lie ahead.
The way to address problems of alcoholism is to ask the difficult
questions and probe deeply for answers. We do not know so many essential
facts about alcoholism. What is the nature of addiction? What are the
precise effects of alcohol on the brain, the liver, the pancreas, and the heart?
We need a much greater emphasis on the effects of alcohol on the central
* This foreword was prepared by Ernest P. Noble, Ph.D., M.D. in his private capacity. No
official support or endorsement by the ADAM HA or NIAAA is intended or should be inferred.
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xii FOREWORD-ALCOHOL
nervous system. We do not yet know the neurochemical bases of the
behavioral changes produced by alcohol. What are the mechanisms un
derlying tolerance, adaptation, and dependence? What is the withdrawal
reaction and are there drugs that can mitigate it?
The social and psychological aspects of drinking and alcohol abuse
urgently need exploration. What stresses of modern-day life impel certain
people toward excessive drinking? What role does drinking play for the
poor, for minorities such as Indians, Hispanics, and Blacks, for youth
and the elderly? Why are more and more women using alcohol? What will
be the results of increased drinking in women for their likelihood of
becoming alcoholics and what is the effect of increased drinking among
women on their offspring? One of the facts that adds to the complexity of
the problem is that alcohol use has been a part of our society for so long.
Use of the beverage alcohol is part of our sociocultural heritage and this
makes for difficult research.
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
addressing some of these questions. When I was appointed Director of the
NIAAA, I brought with me the clear realization of the high priority that must
be given to research. To facilitate the basic and applied research activities of
NIAAA, we have had to undergo some reorganization. We have elevated In
tramural Research to division status with three proposed branches:
Biochemistry, Psychobiology, and Clinical Studies. We have also created a
separate Division of Extramural Research with two branches: Epidemiology
and Special Studies, and Extramural Studies. This reorganization is for
tuitous for a healthy exchange of information and will facilitate the
development of a knowledge base for maximally effective treatment and
prevention.
Through research it is possible to answer some of the crucial and fun
damental questions about alcohol. Many scientists, such as the contributors
to this book, have already begun to address the challenging area of alcohol
abuse. This volume illustrates the kinds of issues that basic research is con
cerned with. From reading these chapters, one can clearly see that
significant advances are being made in understanding the addictive
processes, the nature of dependence and withdrawal, and the mechanisms
of tolerance. The similarities and differences between alcohol and other
drugs such as the opiates need to be determined. Their delineation will
have beneficial spinoffs both for the areas of alcohol abuse and drug depen
dence.
This volume also illustrates the concern of scientists with establishing
viable models for assessing the effects of alcohol. Some of the most basic
and fundamental questions about drug actions depend upon refined model
systems for answers. The nature of tolerance, for example, needs to be ex
plored at the level of the single cell as well as in the intact animal. With
sophisticated model systems, scientists can examine one question at a time
FOREWORD-ALCOHOL xiii
with a high degree of control not possible in studies of man. The knowledge
derived from basic studies will lead to progress in the applied sciences.
Readers of this book will discover some of the exciting advances that
are being made in basic research on alcohol and drug dependence. In the
coming years, we will see continuing advances in these areas. This is a
challenging area for investigation, and we must proceed in the spirit of ex
cellence. Endeavors to improve the quality of life for the millions of victims
of alcoholism is a task worthy of our most compassionate attention.
ERNEST P. NOBLE
National Institute on Alcohol Abuse
and Drug Addiction
Rockville, Maryland 20852
Foreword
Part II—Opiates
The last few years have produced exciting and important new develop
ments in opiate research as the result of various outstanding studies by in
vestigators in a number of different laboratories. The seemingly puzzling
demonstration that electrical stimulation-produced analgesia in rats could be
counteracted by injection of the narcotic antagonist naloxone, in the ab
sence of any exogenous narcotic, was one of the first suggestions of an en
dogenous opioid action. In vitro binding studies with radioactively labeled
potent narcotics and narcotic antagonists were found to provide an effective
technique for determining the tissue distribution and concentration of the
opiate receptors. Probably the most active and fascinating new avenue of
research has been in the multidisciplinary area of the isolation, synthesis,
and pharmacological characterization of the various endogenous peptides,
such as the enkephalins and other endorphins, which apparently act as
ligands for opiate receptors. Although at the present time it appears that the
endorphins probably produce tolerance and dependence similar to morphine
itself, and from a practical standpoint would lead only to a more expensive
morphine-like substance, the vast potential of molecular modification may
still allow for the synthesis of new derivatives with less addictiveness,
greater resistance to hydrolytic or other types of inactivation, longer
duration of action, and improved effectiveness by intravenous and other
routes of administration outside the central nervous system. Recent work
suggests that some of the beneficial analgesic effect of acupuncture may be
related to the action of the endogenous opioids, as indicated by the fact that
naloxone has been reported to decrease acupuncture analgesia. The expand
ing studies in the field of the endogenous opioids may lead to the
elucidation of many mechanisms of action which are of fundamental phar
macological importance.
Other recent studies have resulted in advances in the understanding of
opiate neurochemistry, the nature and purification of opiate receptors,
possible differences in opiate receptors, the complex effects of narcotics on
behavior, and metabolic aspects of opiate agonists and antagonists. The
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xvi FOREWORD-OPIATES
following articles present new contributions in many of these areas of opiate
research and provide additional scientific knowledge which should assist in
the efforts to achieve solutions to the problems of opiate abuse and addic
tion, and at the same time improve the safety of the valuable legitimate
medical uses of the opiates and opioid narcotics.
HAROLD BLUMBERG
Department of Pharmacology
New York Medical College
Valhalla, New York 10595
