Table Of ContentAnimal Models of Depression
Animal Models
of Depression
Edited by
George F. Koob
Cindy L. Ehlers
David 1. Kupfer
With 65 Illustrations
Birkhauser
Boston . Basel . Berlin
George F. Koob, PhD David J. Kupfer, MD
Cindy L. Ehlers, PhD Department of Research and Psychiatry
Department of Neuropharmacology University of Pittsburgh Medical School
Research Institute of the Scripps Clinic Pittsburgh, PA 15261, USA
La Jolla, CA 92037, USA
Library of Congress Cataloging-in-Publication Data
Animal models of depression / edited by George F. Koob, Cindy L.
Ehlers, David J. Kupfer.
p. cm.
Based on a conference held Sept. 1986 sponsored by the MacArthur
Foundation Research Network on the Psychobiology of Depression.
Bibliography: p.
1. Depression, Mental-Animal models-Congresses. I. Koob,
George F. II. Ehlers, Cindy L. III. Kupfer, David 1., 1941- .
IV. McArthur Foundation Research Network on the Psychobiology of
Depression.
RC537.A568 1989
616.85'27'00724-dcl9 88-7437
CIP-Titelaufnahme der Deutschen Bibliothek
Animal models of depression: [based in part on a conference
held in September 1986) / ed. by: George F. Koob
[Sponsored by the MacArthur Foundation Research Network on
the Psychobiology of Depression). - Boston; Basel:
Birkhauser, 1989
ISBN-13: 978-1-4684-6764-2 e-ISBN-13: 978-1-4684-6762-8
DOl: 10.1007/978-1-4684-6762-8
NE: Koob, George F. [Hrsg.J
Printed on acid-free paper
© Birkhauser Boston, 1989
Softcover reprint of the hardcover 1st edition 1989
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9 8 765 4 3 2 I
Contents
Introduction ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
List of Contributors. . . .. .. . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . xi
I. Animal Models
1. Basis of Development of Animal Models in Psychiatry: An Overview
William T. McKinney.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Animal Models: Promises and Problems
Conan Kometsky. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3. Non-Homologous Animal Models of Affective Disorders: Clinical
Relevance of Sensitization and Kindling
Robert M. Post and Susan R B. Weiss ...................... '" . . . . . . 30
II. Developmental Models
4. The HP A System and Neuroendocrine Models of Depression
Ned H Kalin .......................................................... 57
5. The Use of an Animal Model to Study Post-Stroke Depression
Robert G. Robinson .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6. Social Zeitgebers: A Peer Separation Model of Depression in Rats
Cindy L. Ehlers, Tamara L. Wal~ Stephen P Wyss, and
R Ian Chaplin .................................................. 99
7. Electrophysiology of the Locus Coeruleus: Implications for
Stress-Induced Depression
Jay M. Weiss and Peter E Simson....................................... III
8. Motor Activity and Antidepressant Drug: A Proposed Approach to
Categorizing Depression Syndromes and Their Animal Models
Martin H Teicher, Matacha L Barber, Janet M. Lawrence, and
Ross 1 Baldessarini .................................................... 135
9. Anhedonia as an Animal Model of Depression
George F. Koob........................................................ 162
vi Contents
III. PharmacQlogic Models
10. Models of Depression Used in the Pharmaceutical Industry
James L. Howard, Robert M Ferris, Barrett R Cooper, Francis E. Soroko,
Ching M Wang, and Gerald T. Pollard.................................. 187
II. Pharmacological, Biochemical, and Behavioral Analyses of Depression:
Animal Models
Robert M. Zacharko and Hymie Anisman ............................... 204
12. Pharmacologic Probes in Primate Social Behavior
R. Francis Schlemmer, Jr., Jennifer E Young, and John M Davis......... 239
13. The Neuropharmacology of Serotonin and Sleep: An Evaluation
John D. Fernstrom and Ross H Pastel................................... 261
Epilogue
Floyd E Bloom ............................................................ 281
Index.............. ..... ..................... ...... . ........ ...... 285
Introduction
Animal models represent experimental investigations developed in one species
for the purpose of studying phenomena in another species and provide
numerous advantages for preclinical research. They allow scientists greater
control and isolation of important experimental variables. Animal models are
safe, reproducible strategies by which to evaluate and design new pharma
cological treatment strategies, while also allowing direct central nervous
system intervention to alter the course of the aberrant behavior. Animal models
have been developed for a number of mental illnesses; in this particular domain,
they hold the promise to shed light on the still obscure etiologies of these
illnesses and ultimately to facilitate the development and testing of "cures."
Yet, true models of mental illness are difficult to develop, because mental
illness may be a uniquely human phenomenon.
It was based on these considerations that the MacArthur Foundation
Research Network on the Psychobiology of Depression set out to sponsor a
conference to review the status, problems, promises, and relevance of animal
models to the clinical conditions of affective disorders. The conference was
held in September 1986 and included participants from both within the
Network as well as scientists and scholars from various disciplines relevant to
the concerns of the conference. After the conference was held, it became clear
to the organizers that the material presented could be helpful to a broader field
of investigators, since a significant portion of the information has not been
presented elsewhere or in the unified context of a monograph. Thus, it was
decided to ask the participants to prepare book chapters based on their
presentations, and the current volume represents the outcome of these efforts.
The monograph follows the structural outline of the conference: The first
section is devoted to the presentation of an overview. Chapter 1 reviews the
basis of development of animal models in psychiatry. Dr. William T. McKinney
emphasizes that in order to understand and evaluate the rapidly expanding
literature on several areas of animal modeling research, a fundamental under
standing of the bases and the jurisdiction for using animal models to study
affective disorders must first be present. An animal model should simulate and
reproduce accurately the human syndrome it is designed to represent, or be
viii Introduction
considered a framework that dictates the direction that experimentation should
pursue.
Chapter 2 focuses on the problems and promises of animal models of mental
illness. Dr. Conan Kometsky addresses several basic questions: Do animal
models of mental illness hold the promise to determine the etiology of these
complex disorders? If it is possible to clarify the etiology, should it not be
relatively easy to also find a cure? Are there true animal models of mental
illness or are these conditions unique to humans?
Responding to some of these questions, Chapter 3 discusses the relevance of
animal models to the clinical condition. Its author, Dr. Robert Post, highlights
their potential utility in paralleling processes in the clinical situation that can be
conceptualized in new ways, perhaps leading to a new series of clinical research
formulations, testable hypotheses, and even pharmacotherapies.
The second and third sections of the monograph focus on two different
approaches to animal models-developmental and pharmacological models.
Contributors were asked to emphasize a single focus of study for a particular
model, with the idea that each would explore the strength and weaknesses of
the model and directions for future research.
Chapters 4 through 9 explore the potential of developmental models. They
demonstrate the degree to which development can be altered by early
childhood experiences and how it can lead to predictable behavioral and social
signs of depressive symptoms. The hypothalamic-pituitary-adrenal system and
neuroendocrine models are presented by Dr. Ned Kalin in Chapter 4. He
concludes his review with a series of proposed experiments to test these models
in primates. In Chapter 5, Dr. Robert Robinson explores the use of animal
models to study post-stroke depression and provides insights into the parallels
between human and animal studies. Chapter 6 presents a peer separation
model of depression by Dr. Cindy Ehlers and co-workers. She proposes a new
model of depression involving social zeitgebers and biological rhythms. In
Chapter 7, Dr. Jay Weiss and co-workers discuss the electrophysiology ofthe
locus coeruelus and implications for stress-induced depression. Their emphasis
is on the applications of such a model for aspects of depression in humans. A
proposed approach to categorizing depressive syndromes and their animal
models is undertaken in Chapter 8 by Dr. Martin Teicher. He applies the
techniques of motor activity to test this nosologic schema. Anhedonia as an
animal model of depression is discussed in Chapter 9 by Dr. George Koob. In
this chapter, he reviews specific measures in CNS reward, namely intracranial
self-stimulation, and applies this model to the neurobiology of reward.
Chapter 10 to 13 focus on pharmacologic models. Dr. James Howard and
co-workers review various models of depression used in the pharmacological
industry in Chapter 10 and provide an excellent critique of these various
models as they are used for new drug development. Dr. Zacharko and Dr.
Hymie Anisman present animal models used for the pharmacological,
biochemical, and behavioral analyses of depression (with an emphasis on the
Introduction ix
biogenic amines) in Chapter 11. Dr. R. Frances Schlemmer and co-workers
discuss pharmacologic probes in primate social interaction in Chapter 12,
focusing on biochemical-behavior relationships. Chapter 13 contains an
evaluation of the neuropharmacology of serotonin (5HT) and sleep by Dr. John
Fernstrom and Dr. Ross H. Pastel. In this critique, they point out that a simple
relationship between 5HT neuronal function and sleep does not exist and that
studies must be evaluated as acute or chronic investigations, and that the
activity of 5 HT neurons changes with the state of vigilance.
What we hope to present with this monograph are examples that dem
onstrate that animal models have the potential to make a critical difference in
the study of affective disorders. Of paramount importance, however, is the fact
that, even if the pathogenesis of affective diseases was known, it would still be
necessary to utilize animal models to monitor the symptoms or objective
measures of depression to predict the efficacy of drugs and other treatments.
We are grateful to the John D. and Catherine T. MacArthur Foundation for
supporting a meeting that provided to the participants many insights into the
usefulness of animal models for furthering research on affective disorders. We
are equally appreciative of their encouragement to share these insights with a
broader field of investigators through the publication of this monograph.
George F. Koob
Cindy L. Ehlers
David 1. Kupfer
Contributors
Hymie Anisman, Ph.D. Department of Psychology, Carleton University,
Ottawa, Ontario, Canada KIS 5B6
Ross J. Baldessarini, MD. Professor of Psychiatry and Neuroscience, Harvard
Medical School, Massachusetts General Hospital and Mailman Research
Center, McLean Hospital, Belmont, MA 02178, USA
Natacha l Barber, B.A. Department of Psychiatry, Harvard Medical School
and Mailman Research Center, McLean Hospital, Belmont, MA 02178,
USA
Floyd E Bloom, MD. Member, Research Institute of Scripps Clinic, 10666
North Torrey Pines Road, BCR1, La Jolla, CA 92037, USA
R. Ian Chaplin, B.S. Research Institute of Scripps Clinic, 10666 North Tor
rey Pines Road, BCR1, La Jolla, CA 92037, USA
Barrett R. Cooper, Ph.D. Department of Pharmacology, Burroughs Wellcome
Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709, USA
John M Davis, MD. Research Department, lllinois State Psychiatric
Institute, 1601 West Taylor Street, Chicago, IL 60612, USA
Cindy L. Ehlers, Ph.D. Associate Adjunct Professor of Psychiatry, Western
Psychiatric Institute Clinic, Pittsburgh, PA 15261, and Assistant Member,
Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, BCR1,
La Jolla, CA 92037, USA
John D. Fernstrom, Ph.D. Professor of Psychiatry ,Department of Psychiatry ,
University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
Robert M. Ferris, Ph.D. Department of Pharmacology, Burroughs Wellcome
Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709, USA
James L. Howard, Ph.D. Senior Research Scientist, Department of Pharma
cology, Burroughs Wellcome Co., 3030 Cornwallis Road, Research
Triangle Park, NC 27709, USA
xii Contributors
Ned H Kalin, MD. Director of R~search, Department of Psychiatry,
Middleton Memorial Veterans Hospital, University of Wisconsin Medical
School, Madison, WI 53705, USA
George F. Koob, PhD. Associate Member, Research Institute of Scripps
Clinic, 10666 North Torrey Pines Road, BCRl, La Jolla, CA 92037, USA
Conan Kometsky, PhD. Professor, Department of Pharmacology and
Psychiatry, Boston University School of Medicine, 80 E. Concord Street,
Room L602, Boston, MA 02118, USA
David 1. Kupfer, M.D. Professor and Chairman, Department of Psychiatry,
University of Pittsburgh Medical School, 3811 O'Hara Street, Pittsburgh,
PA 15261, USA
Janet M Lawrence, MD. Department of Psychiatry and Neuroscience
Program, Harvard Medical School, Massachusetts General Hospital and
Mailman Research Center, McLean Hospital, Belmont, MA 02178, USA
William T. McKinney, M.D. Professor of Psychiatry, Clinical Sciences Center,
D6/244, University of Wisconsin School of Medicine, 600 Highland
Avenue, Madison, WI 53792, USA
Ross H. Paste~ PhD. Sleep Research Laboratory, Physiology and Behavior
Branch, Department of Medical Neuroscience, Walter Reed Army Institute
of Research, Washington, DC 20307, USA
Gerald T. Pollard, PhD. Department of Pharmacology, Burroughs Wellcome
Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709, USA
Robert M. Post, MD. Chief, Biological Psychiatry Branch, NIMH, Room 3
N212 Building 10, 9000 Rockville Pike, Bethesda, MD 20892, USA
Robert G. Robinson, M.D. Professor of Psychiatry and Neuroscience, Johns
Hopkins University School of Medicine, Traylor Building Room 624,
Baltimore, MD 21205, USA
R Francis Schlemmer, Jr., PhD. Department of Pharmacodynamics, College
of Pharmacy, University of Illinois at Chicago, 833 South Wood Street,
Chicago, IL 60612, USA
Peter E Simson, PhD. Department of Psychiatry, Duke University Medical
Center, Box 3829, Durham, NC 27710, USA
Francis E Soroko, B.S. Department of Pharmacology, Burroughs Wellcome
Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709, USA
Martin H Teicher, M D., PhD. Assistant Professor of Psychiatry , Department
of Psychiatry, Harvard Medical School, and Mailman Research Center,
McLean Hospital, Belmont, MA 02178, USA
Tamara L. Wan B.S. Research Institute of Scripps Clinic, 10666 North
Torrey Pines Road, BCRl, La Jolla, CA 92037, USA
