Table Of ContentThe Genetic Basis
of Alcohol and
Drug Actions
The Genetic Basis
of Alcohol and
Drug Actions
Edited by
JOHN C. CRABBE, JR.
Veterans Affairs Medical Center
Portland, Oregon
and
R. ADRON HARRIS
University of Colorado
Denver, Colorado
Springer Science+Business Media, LLC
Library of Congress Catalog1ng-1n-Publ1cat1on Data
The Genetic basis of alcohol and drug actions / edited by John C.
Crabbe, Jr. and R. Adron Harris,
p. cm.
Includes bibliographical references and Index.
1. Pharmacogenetics—Animal models. 2. Alcoholism—Animal models.
3. Drug abuse—Animal models. 4. Alcoholism—Genetic aspects.
5. Drug abuse—Genetic aspects. 6. Alcohol—Physiological effects.
I. Crabbe, John C. II. Harris, R. Adron.
[DNLM: 1. Alcoholism—genetics. 2. Pharmacogenetics.
3. Substance Abuse—genetics. WM 274 G327521
RM301.3.G45G46 1991
615' .78—dc20
DNLM/DLC
for Library of Congress 91-28926
CIP
ISBN 978-1-4899-2069-0 ISBN 978-1-4899-2067-6 (eBook)
DOI 10.1007/978-1-4899-2067-6
© Springer Science+Business Media New York 1991
Originally published by Plenum Press, New York in 1991
Softcover reprint of the hardcover 1st edition 1991
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Contributors
ANDREA M. ALLAN • Department of Psychiatry, Washington University
School of Medicine, St. Louis, Missouri 63110
J. K. BELKNAP. Research Service, Department of Veterans Affairs Medical
Center and Department of Medical Psychology, Oregon Health Sciences
University, Portland, Oregon 97201
ALLAN C. COLLINS • Department of Psychology and Institute for Behavioral
Genetics, University of Colorado, Boulder, Colorado 80309
JOHN C. CRABBE, JR. • Research Service, Department of Veterans Affairs
Medical Center and Departments of Medical Psychology and Pharmacology,
Oregon Health Sciences University, Portland, Oregon 97201
THOMAS V. DUNWIDDIE • Department of Pharmacology, University of Colo
rado Health Sciences Center, Denver, Colorado 80262 and Veterans Admin
istration Medical Center, Denver, Colorado 80220
HOWARD J. EDENBERG • Departments of Biochemistry and Molecular Biology
and of Medical and Molecular Genetics, Indiana University School of
Medicine, Indianapolis, Indiana 46202-5122
EDWARD J. GALLAHER • Research Service, Department of Veterans Affairs
Medical Center and Departments of Medical Psychology and Pharmacology,
Oregon Health Sciences University, Portland, Oregon 97201
KATHLEEN A. GRANT • Unit for Special Projects, Division of Intramural
Clinical and Biological Research, National Institute on Alcohol Abuse and
Alcoholism, Bethesda, MD 20892
R. AoRON HARRIS. Research Service, Veterans Administration Medical
Center and Department of Pharmacology, University of Colorado Health
Sciences Center, Denver, Colorado 80262
PAULA L. HOFFMAN. Department of Pharmacology, University of Colorado
Health Sciences Center, Denver, Colorado 80262
MICHAEL J. MARKS • Department of Psychology and Institute for Behavioral
Genetics, University of Colorado, Boulder, Colorado 80309
v
vi CONTRIBUTORS
GERALD E. MCCLEARN • Center for Developmental and Health Genetics and
the Intercollege Graduate Program in Genetics, The Pennsylvania State
University, University Park, Pennsylvania 16802
L. A. O'TOOLE • Research Service, Department of Veterans Affairs Medical
Center and Department of Medical Psychology, Oregon Health Sciences
University, Portland, Oregon 97201
TAMARA J. PHILLIPS. Research Service, Department of Veterans Affairs
Medical Center and Departments of Medical Psychology and Pharmacology,
Oregon Health Sciences University, Portland, Oregon 97201
CAROLYN S. RABE • Unit for Special Projects, Division of Intramural Clinical
and Biological Research, National Institute on Alcohol Abuse and Alcohol
ism, Bethesda, Maryland 20892
THOMAS W. SEALE • Departments of Pediatrics, Psychiatry, and Biochemis
try, University of Oklahoma Health Sciences Center, Oklahoma City, Okla
homa 73190
BORIS T ABAKOFF • Department of Pharmacology, University of Colorado
Health Sciences Center, Denver, Colorado 80262
PETER VA LVERIUS • Section on Receptor Mechanisms, Laboratory of Physio
logic and Pharmacologic Studies, Division of Intramural Ciinical and Biolog
ical Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda,
Maryland 20892
Preface
HISTORICAL BACKGROUND
The use of genetic animal models in neuroscience and biomedical research is
showing dramatic growth. The earliest application of these models to research
on drug mechanisms was in the area of alcohol research. Mardones (1951)
reported successful selective breeding of rats preferring and not preferring to
drink alcohol under various conditions of dietary deficiency, suggesting
genetic control of alcohol drinking. McClearn and Rodgers (1959, 1961)
described differences among inbred mouse strains in preference for 10Ofo
ethanol solutions versus tap water. Active exploration of this phenomenon
continued until the early 1970s, eventually spawning the entire range of alcohol
genetic research reviewed in Chapters 2 and 3 of this volume. Notably, oral
alcohol self-administration has served as the basis for the development of
several rat lines bred for preference or aversion, and these lines are very
actively being investigated.
The pioneering research of Dr. McClearn and others was very wide
ranging in its conceptual scope and at least touched on all issues currently
under intense investigation. The basic approach was to identify high and low
preferrers among inbred strains of mice and to search for preference correlates
in other traits. One major thrust of early research was to attempt to explain
strain differences in preference as a function of underlying differences in
patterns of caloric utilization. Reviews of these studies concluded that
nutritional factors could not completely explain preference differences (Rod
gers, 1966; McClearn, 1968). A related early theme was the potential role of
differences in alcohol metabolism. For example, Rodgers and McClearn (1962)
found a relationship between strain mean preference and alcohol dehydroge
nase activity in six inbred strains of mice, and Schlesinger et al. (1967) reported
that C57BL mice metabolized ethanol more rapidly than did DBAl2 mice.
Although differences in alcohol dehydrogenase activity were small between the
strains, Sheppard et al. (1968) reported 300% more aldehyde dehydrogenase
activity in C57BL/6J than in DBAl2J mice. Most such studies compared only
C57 and DBA mice, and the utility of metabolic differences in explaining
alcohol drinking in rodents is currently thought to be small (see, for example,
Teichert-Kuliszewska et al., 1988). However, the advent of sophisticated
molecular genetic studies with alcohol-and acetaldehyde-dehydrogenase vari
ants (see Edenberg, Chapter 5) has maintained this as an active area of
vii
viii PREFACE
research in the description of gene function. Although this older literature on
preference drinking is not exhaustively reviewed, several aspects are described
in Chapters 2 and 3, where studies with the selectively bred rat lines are
thoroughly discussed.
GOALS OF THIS VOLUME
In 1978, P. L. Broadhurst surveyed the field he called "psychopharmacoge
netics" in a monograph. This review cited over 400 papers, most of which were
comparisons among inbred mouse strains. There have been no comprehensive
reviews since. Our goal in this volume was to provide comprehensive reviews
of research applications and future trends in the area of the genetic basis for
drug sensitivity. We have tried to evaluate the literature critically rather than
simply report raw results. In order to keep the volume to a manageable size,
we have narrowed our focus to those drugs that have demonstrated abuse
potential. Furthermore, we have generally restricted our reviews to genetic
animal models, although these models are frequently oriented toward a
specific aspect of drug responsiveness relevant to the human condition.
Finally, we have not systematically reviewed studies of drug metabolism.
Although this metabolism is clearly under substantial genetic influence, the
bulk of the existing literature has concluded that such differences cannot
generally explain differences in drug responses.
We have made every effort to be comprehensive. Given the rapidly
increasing number of studies in this area, however, we have doubtless fallen
short of this ideal in some cases. For many of the drugs, there exist selective
reviews covering some aspects of drug sensitivity; these are cited in the
individual chapters. It is our hope that studies we have overlooked are
generally from the older literature, but some issues may be handled more fully
in selective reviews. We thank our many colleagues for sharing freely with us
preprints and hard-to-obtain reprints. Although we have made every effort to
cite results of experiments accurately, inevitably we will not have completely
attained this ideal. Errors of fact are our responsibility alone. We would
appreciate hearing from our readers about additional references and/or
factual errors.
We offer special thanks to Diane Snell, who provided technical editorial
assistance. Without her substantial efforts, this volume could not have been
completed in timely fashion.
REFERENCES
Broadhurst, P. L., 1978, The Inheritance oj Behaviour. New York, Plenum Press.
Mardones, J., 1951, On the relationship between deficiency of B vitamins and alcohol intake in
rats, Q. J. Stud. Alcoho/1l:563-575.
PREFACE ix
McClearn, G. E., 1968, Genetics and motivation of the mouse, in: Nebraska Symposium on
Motivation (W. J. Arnold, ed.), University of Nebraska Press, Lincoln, pp. 47-83.
McClearn, G. E., and Rodgers, D. A., 1959, Differences in alcohol preference among inbred
strains of mice, Q. J. Stud. Alcohol 20:691-695.
McClearn, G. E., and Rodgers, D. A., 1961, Genetic factors in alcohol preference of laboratory
mice, J. Compo Physiol. Psychol. 54:116-119.
Rodgers, D. A., 1966, Factors underlying differences in alcohol preference among inbred strains
of mice, Psychosom. Med. 28:498-513.
Rodgers, D. A., and McClearn, G. E., 1962, Alcohol preference of mice, in: Roots oj Behavior
(E. L. Bliss, ed.), Harper & Row, New York, pp. 68-95.
Schlesinger, K., Bennett, E. L., and Hebert, M., 1967, Effects of genotype and prior consumption
of alcohol on rates of ethanol-l-14C metabolism in mice, Q. J. Stud. Alcohol 29:231-235.
Sheppard, J. R., Albersheim, P., and McClearn, G. E., 1968, Enzyme activities and ethanol
preference in mice, Biochem. Genet. 2:205-212.
Teichert-Kuliszewska, K., Israel, Y., and Cinader, B., 1988, Alcohol dehydrogenase is not a major
determinant of alcohol preference in mice, Alcohol 5:45-47.
John C. Crabbe, Jr.
R. Adron Harris
Contents
CHAPTER 1. The Tools of Pharmacogenetics 1
Gerald E. MeClearn
Some Basic Considerations 2
The Quantitative Genetic Model 3
The Classical Methods 6
Inbred Strains and Derived Generations 6
Genetically Heterogeneous Stocks 13
Team-Yoking Molecular and Quantitative
Genetics in Alcohol Research 18
Conclusion 22
References 22
CHAPTER 2. Behavioral Studies of Genetic Differences in
Alcohol Action 25
Tamara J. Phillips and John C. Crabbe, Jr.
Inbred Strains 25
Preference Drinking 25
Reinforcing and Aversive Effects 28
Effects on Ambulation 29
Discoordinating and Sedative Effects 30
Tolerance 33
Dependence and Withdrawal 34
Other Studies 35
Summary of Work with Inbred Strains 38
Recombinant Inbred Strains and Other Single-Gene
Techniques 38
Correlational Studies with Genetically
Heterogeneous Stocks 41
Selected Lines 44
Lines Selected for Ethanol-Induced Loss of
Righting Reflex 44
Lines Selected for Ethanol Consumption S4
Lines Selected for Ethanol Withdrawal Severity 62
HOT and COLD Mouse Lines 70
xi
