Animal Models of Drug Addiction

448 Pages·1993·34.54 MB·English

by  Alan A. Boulton, Glen B. Baker, Robert B. Stewart, Larry A. Grupp (auth.), Peter H. Wu (eds.)

NEUROMETHODS q 24
Animal Models of Drug Addiction
NEUROMETHODS
Program Editors: Alan A. Boulton and Glen B. Baker
24. Animal Models of Drug Addiction
Edlted by Alan A. Boulton, Glen B. Baker, and Peter H. Wu, 1992
23. Practical Cell Culture Techniques
Edlted by Alan A. Boulton, Glen 8. Baker, and Wolfgang Walz, 1992
22. Animal Models of Neurological Disease, II:
Metabolic Encephalopathies and the Epilepsies
Edited by Alan A. Boulton, Glen B. Baker, and Roger F.
Butterworth, 1992
21. Animal Models of Neurological Disease, I: Neurodegenerative Disease
Edited by Alan A. Boulton, Glen B. Baker, and Roger F.
Butterworth, 1992
20. Intracellular Messengers
Edlted by Alan A. Boulton, Glen B. Baker, and Colin W. Taylor, 1992
19. Animal Models in Psychiatry, II
Edited by Alan A. Boulton, Glen B. Baker, and Mathew T.
Martin-loerson, 199 1
18. Animal Models in Psychiatry, I
Edited by Alan A. Boulton, Glen B. Baker, and Mathew T.
Martin-loerson, 199 1
17. Neuropsychology
Edlted by Alan A. Boulton, Glen B. Baker, and Merrill Hlscock, 1990
16. Molecular Neurobiological Techniques
Edlted by Alan A. Boulton, Glen B. Baker, and Anthony 7.
Campagnoni, 1990
15. Neurophysiological Techniques: Applications to Neural Systems
EdIted by Alan A. Boulton, Glen B. Baker, and CaseH . Vanderwolfi 1990
14. Neurophysiological Techniques: Basic Methods and Concepts
E&ted by Alan A. Boulton, Glen B. Baker, and CaseH . Vande~olfi 1990
13. Psychopharmacology
EdIted by Alan A. Boulton, Glen B. Baker, and Andrew J. Gmenshaw, 1989
12. Drugs as Tools in Neurotransmitter Research
Edited by Alan A. Boulton, Glen 8, Baker, and August0 V. Juorio, 1989
11. Carbohydrates and Energy Metabolism
Edrted by Alan A. Boulton, Glen B. Baker, and Roger F. But&worth, 1989
10. Analysis of Psychiatric Drugs
Edited by Alan A. Boulton, Glen B. Baker, and Ronald T. Coutts, 1988
9. The Neuronal Microenvironment
Edrted by Alan A. Boulton, Glen B. Baker, and Wolfgang Walz, 1988
8. Imaging and Correlative Physicochemical Techniques
Edkd by Alan A. Boulton, Glen B. Baker, and Donald P. Bolsuert, 1988
7. Lipids and Related Compounds
Ed&xi by Alan A. Boulton, Glen B. Baker, and Lloyd A. Hon-ocks, 1988
6. Peptides
Edlted by Alan A. Boulton, Glen B. Baker, and Quentin Pittman, 1987
NEUROMETHODS 0 24
Animal Models
of Drug Addiction
Edited by
Alan A. Boulton
Uniuersity ofSaskatchewan, Saskatoon, Canada
Glen B. Baker
Unioersity of Alberta, Edmonton, Canada
and
Peter If. Wu
Uniuersity of Toronto, Toronto, Canada
Humana Press l Totowa, New Jersey
0 1992 The Humana Press Inc.
999 hverview Drive, Suite 208
Totowa, New Jersey 07512
Ail rights reserved
No part of this book may be reproduced, stored m a retrieval system, or transmitted m any
form or by any means, electronic, mechanical, photocopying, microfilming, recording, or
otherwise without written permission from the Publisher.
printed m the united States of America
Library of Congress Cataloging-in-Publication Data
Mam entry under htle
Anunal models of drug addictron / ecbted by Alan A Boulton, Glen B
Baker, and Peter Wu
p. cm - (Neuromethods , 24)
Includes brbliograpmcal references and mdex
ISBN O-89603-217-5
1 Drug abuse-Animal models 2 Alcoholism-Animal models
I. Boulton, A. A (Alan A) 11. Baker, Glen B, 1947- III. Wu,
Peter. IV Series
[DNLM* 1. Alcohol, Ethyl-pharmacology 2 Disease Models,
Ammal 3 Drug Tolerance 4 Models, Genetic 5. Substance
Dependence-physiopathology Wl NE337G v 24 / QV 77 A59921
RC564 A56 1992
616 86’27--dc20
DNLM/DLC
for Library of Congress 9449180
CIP
Preface to the Series
When the President of Humana Press first suggested that
a series on methods in the neurosciences might be useful,
one of us (AAB) was quite skeptical; only after discussions
with GBB and some searching both of memory and library
shelves did it seem that perhaps the publisher was right.
Although some excellent methods books have recently
appeared, notably in neuroanatomy, it is a fact that there is a
dearth in this particular field, a fact attested to by the alac-
rity and enthusiasm with which most of the contributors to
this series accepted our invitations and suggested additional
topics and areas. After a somewhat hesitant start, essentially
in the neurochemistry section, the series has grown and will
encompass neurochemistry, neuropsychiatry, neurology,
neuropathology, neurogenetics, neuroethology, molecular
neurobiology, animal models of nervous disease, and no
doubt many more “neuros.” Although we have tried to
include adequate methodological detail and in many cases
detailed protocols, we have also tried to include wherever
possible a short introductory review of the methods and/or
related substances, comparisons with other methods, and the
relationship of the substances being analyzed to neurologi-
cal and psychiatric disorders. Recognizing our own limita-
tions, we have invited a guest editor to join with us on most
volumes in order to ensure complete coverage of the field.
These editors will add their specialized knowledge and
competencies. We anticipate that this series will fill a gap;
we can only hope that it will be filled appropriately and with
the right amount of expertise with respect to each method,
substance or group of substances, and area treated.
Alan A. Boulton
Glen B. Baker
Preface
to the Animal Models Volumes
This volume describes animal models of drug addiction.
Because of increasing public concern over the ethical treatment
of animals in research, we felt it incumbent upon us to include
this general preface in order to indicate why we think further
research using animals is necessary.
Animals should only be used when suitable alternatives are
not available, and humans can only be experimented upon in
severely proscribed circumstances. Alternative procedures using
cell or tissue culture are inadequate in any models requiring
assessments of behavioral change or of complex in vivo pro-
cesses. However, when the distress, discomfort, or pain to the
animals outweighs the anticipated gains for human welfare, the
research is not ethical and should not be carried out.
It is imperative that each individual researcher examine his/
her own research from a critical moral standpoint before engag-
ing in it, and take into consideration the animals’ welfare as well
as the anticipated gains. Furthermore, once a decision to pro-
ceed with research is made, it is the researcher’s responsibility
to ensure that the animals’ welfare is of prime concern in terms
of appropriate housing, feeding, and maximum reduction of any
uncomfortable or distressing effects of the experimental conditions.
Frequentjhmalized
Preface
The theme of this volume, the use of animal models in the
study of addiction, is one that has found wide acceptance in
behavioral pharmacology. Yet it is also one that carries the
inherent risk of ambiguity, because it contains two concepts that
are frequently ill-defined or, perhaps worse, left undefined.
These are the concepts of addictiun and of modeLThe first is
important because it tells us exactly what it is that we are trying
to model. The second is equally important, because it tells us
exactly what we are trying to do in relation to addiction. Unfor-
tunately, neither is easy to define in a way that will be univer-
sally acceptable.
Corrigall’s chapter in this volume comes squarely to grips
with the first question, by citing the definitions of addiction that
are offered in the 1988 Report of the US Surgeon General on
Nicotine Addiction, and the 1989 Committee Report of the Royal
Society of Canada, on Tobacco, Nicotine and Addiction. Both of
these reports define the central problem of addiction as drug-
seeking and drug-taking behavior that is very strongly moti-
vated by the reinforcing psychoactive effects of a drug, and that
is very difficult to give up, even when the user is also strongly
motivated to do so.
The phenomena of tolerance and physical dependence
(identifiable only as a withdrawal reaction when drug use is
abruptly terminated) are recognized as frequent, or even char-
acteristic, cunsequenceso f addiction, but not intrinsic parts of it.
Similarly, the harm that may result from addiction is a legitimate
social concern and a major reason for studying addiction, but
not an essential defining feature of it.
The definition of “model” is perhaps more difficult to
agree on, yet it is essential for an understanding of what we
can and cannot hope to learn from the use of animal models
of addiction. In everyday language, the word “model” has
various meanings. It may mean an ideal example to be cop-
ied, such as a model student, or a role model. Sometimes it
ix
X Preface
means a prototype, such as a new model of car. It may mean
a miniature but perfect copy, such as a model airplane, and
in that sense a rat model of addiction might be a tiny perfect
copy of addiction in humans. The most relevant meaning,
however, is a description or analogy that will help us to visu-
alize the structure or function of something that we cannot
otherwise study.
An animal model of addiction, in that sense, should b e
one that replicates all the factors contributing to the produc-
tion of addiction in humans, that reproduces in the animals
the essential components of the picture of addiction as seen
in humans, and that therefore permits a valid and detailed
analysis of the underlying mechanisms, and their possible
prevention or treatment, by interventions that are not
physically or ethically possible in humans.
Extensive study of addiction in humans, however, has
revealed many important aspects that are not included in the
definition given above. In alcoholism, for example, there is
an important genetic component of risk, or predisposition,
that has been the subject of a great deal of recent research in
animal models. But there are also very important social, finan-
cial, occupational, and psychiatric factors contributing to
individual risk of alcoholism, especially in those who do not
have an apparent genetic predisposition. Moreover, the genetic
predisposition does not invariably lead to alcoholism in
humans, so that these same external factors can also exert
impor tan t modulatory influences that may facilitate or deter
the actual occurrence of alcoholism in those at genetic risk.
What, then, can we reasonably expect to learn from the
study of animal “models”? Clearly, we are unlikely ever to
have a complete animal model of alcoholism, because no
experimental animals, even primates, are subject to all of the
social influences that act on humans and their drug use.
However, it is possible to model many of these influences.
For example, the demonstrated effect of variation in price
on the level of consumption of alcohol by humans could be
modeled by systematic variation of the amount of work the
animal must perform to obtain the drug, as has been done
Preface xi
with other reinforcers. The role of social environmental
stresses has to some extent been modeled by studies of drug
consumption in animals living in group cages, and occupy-
ing different rungs of the dominance ladder. Much more
could be done to examine the effects of other external influ-
ences, but it may be an impossible task to build a sufficiently
complex model to test all the recognized external factors and
study their interactions with endogenous or genetic deter-
minants.
It is much more probable that animal models will yield
valuable information about individual components of the
overall picture. The various chapters of the present volume
make clear that animal models can be used fruitfully to exam-
ine the reinforcing and discriminative stimulus properties
of psychoactive drugs, the production of tolerance and vari-
ous components of physical dependence, and the risk of organic
complications from heavy use. Animal models may there-
fore also help to explore the neural circuitry and the neuro-
nal and other cellular mechanisms underlying these various
aspects of addiction. They can permit studies of the interac-
tions among behavioral, genetic, and environmental influ-
ences acting on these components of addiction.
But it is important to recognize that these are not mod-
els of addiction. As Harris and Crabbe point out, it is certain
that a great many genes contribute to the total risk of ad-
diction, and to the expression of its individual features.
Moreover, the role of each gene is not specific for addiction,
but for a biological function that may participate in addic-
tion. For example, animals genetically selected for prone-
ness to seizures induced by alcohol withdrawal are also prone
to seizures induced by withdrawal of other depressant drugs,
or by administration of seizure-provoking drugs. Therefore,
there is no guarantee that the overall risk of addiction, even
to a specific drug, is determined by exactly the same set of
genes in all cases. Indeed, it has been proposed that there are
multiple forms of human alcoholism, for example, that reflect
different combinations of genetic and environmental influ-
ences.