glutamate and addiction

GLUTAMATE
ADDICTION
and
EDITED BY
BARBARA H. HERMAN, PhD
CO-EDITED BY
JERRY FRANKENHEIM, PhD
RAYE Z. LITTEN, PhD
PHILIP H. SHERIDAN, MD
FORREST F. WEIGHT, MD
STEVEN R. ZUKIN, MD
HUMANA PRESS
G
LUTAMATE AND
A
DDICTION
Genetics and Genomics of Neurobehavioral Disorders, edited by Gene S.
Fisch, 2003
Sedation and Analgesia for Diagnostic and Therapeutic Procedures, edited
by Shobha Malviya, Norah N. Naughton, and Kevin K. Tremper, 2003
Neural Mechanisms of Anesthesia, edited by Joseph F. Antognini,
Earl E. Carstens, and Douglas E. Raines, 2002
Glutamate and Addiction
edited by Barbara Herman, 2002
Molecular Mechanisms of Neurodegenerative Diseases
edited by Marie-Françoise Chesselet, 2000
C ontemporary
C linical
N euroscience
Series Editors:
Ralph Lydic and

Helen A. Baghdoyan
G
LUTAMATE AND
A
DDICTION
HUMANA PRESS TOTOWA, NEW JERSEY
Edited by
BARBARA H. HERMAN, PhD
Clinical Medical Branch, Division of Treatment Research and Development
National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)
Bethesda, MD
Coeditors
Jerry Frankenheim, PhD
Pharmacology, Integrative & Cellular Neurobiology Research Branch (PICNRB)
Division of Neuroscience & Behavioral Research (DNBR), National Institute on Drug Abuse (NIDA)
National Institutes of Health (NIH), Bethesda, MD
Raye Z. Litten, PhD
Treatment Research Branch, Division of Clinical and Prevention Research
National Institute on Drug Abuse (NIAAA), National Institutes of Health (NIH), Bethesda, MD
Philip H. Sheridan, MD
Division of Neuropharmacological Drug Products, Center for Drug Evaluation and Research
Office of Drug Evaluation I, Food and Drug Administration, Rockville, MD
Forrest F. Weight, MD
Laboratory of Molecular and Cellular Neurobiology, Division of Intramural Clinical and Biological
Research, National Institute on Drug Abuse (NIAAA) National Institutes of Health (NIH)
Bethesda, MD
Steven R. Zukin, MD
Division of Treatment Research and Development, National Institute on Drug Abuse (NIDA)
National Institutes of Health (NIH), Bethesda, MD
Contemporary Clinical Neuroscience

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1. Substance abuse–Pathophysiology. 2. Glutamic acid–Physiological effect. I. Herman, Barbara H. II.
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RC564.G585 2002
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Acknowledgments
This book is dedicated to our families and collaborators who contributed and sup-
ported this effort to characterize the role of glutamatergic systems in addiction disorders
and to develop new technologies for the treatment of these brain disorders. This book is
also dedicated to Dr. Marian Fischman who died on October 23, 2001 during the final
review phase of this book. Dr. Fischman’s contributions to the medications development
of cocaine and opiate addiction were an outstanding influence in understanding the
biology and treatment of addiction disorders. Finally, this book is dedicated to the phy-

sicians Lawrence Kelley,
MD, Jacqueline R. Honig, MD, Marc S. Myerson, MD, and the
countless other valued medical personnel who brought one of us back from a near death
experience during its creation.
To Alexandra Samantha Herman, Robert H. Herman, Anita S. Herman
And our families
BHH, JF, RL, FW, SZ

Preface
vii
Assembling Glutamate and Addiction was a two-and-a-half year labor of love. As
editors, we all had the same goal in mind and pursued this with a fierce dedication. We
felt that it was now time for a volume clarifying for the first time the relationship between
glutamatergic systems and addiction. The past decade has seen a steady and escalating
progression of scientific advances that have implicated a pivotal role of glutamatergic
systems in cocaine, opiate, and alcohol dependence––both the etiology of these disorders
and their treatment. As editors, we met as a group several times a year to discuss the
progress and the ever emerging direction of the book. As senior editor, I am personally
indebted to the superb job of the coeditors attracting the very best scientists in this field
to contribute their important papers to this book.
To Philip H. Sheridan,
MD of the Food and Drug Administration (FDA), for his mar-
velous ability to attract internationally known scientists to contribute to the first section
of the book on the basic physiology and pharmacology of glutamate. The five stellar
chapters in this section include ones by Borges and Dingledine; Witkin, Kaminski and
Rogawski; Choi and Snider; Sanchez and Jensen; and Kaul and Lipton. A special thank
you to Michael A. Rogawski,
MD, PhD, Epilepsy Research Section, NINDS, NIH for being
an early and avid supporter of this effort and bringing to our attention valuable contribu-
tors to this book. It is our hope that these five introductory chapters will provide a level

playing field for all readers of this book to upgrade their basic understanding of glutamate
before proceeding to the other research chapters focused on the relationship between
glutamate and various addictive disorders.
To Jerry Frankenheim,
PhD of the National Institute on Drug Abuse, the National
Institutes of Health (NIH) for his wonderful role, as senior editor of Section II, in illus-
trating the role of glutamatergic systems in stimulant drugs of abuse including cocaine,
amphetamine, and methamphetamine. Dr. Frankenheim displayed considerable care in
editing this section. In addition, I am personally indebted to Dr. Frankenheim for his
seamless job in serving as Acting Senior Editor of this volume for a two-month period
when I was unavailable for this task. Section II is a truly remarkable part of the book in
its thoroughness in covering virtually every aspect of the role of glutamate in stimulant
drugs of abuse, with outstanding chapters by Pert, Post, and Weiss; Karler, Thai, and
Calder; Wolf; Baker, Cornish, and Kalivas; Wang, Mao, and Lau; Pulvirenti; Vezina and
Suto; Cadet; Burrows and Yamamoto; Itzhak, Martin, and Ali; Matsumoto and Pouw;
Bisaga and Fischman; and Epping-Jordan. As we state in our dedication of this book, this
effort also coincided with the tragic death of one of our beloved colleagues in the addic-
tion field, Marian Fischman,
PhD of Columbia University School of Medicine. Dr. Fis-
chman was a vibrant human being, and one of the most vital forces in the research field
of addiction medicine. A personal thank you to Adam Bisaga,
MD who took over the task
of writing and editing this chapter with Dr. Fischman in an extremely gracious and
responsible fashion in the face of tragic circumstances.
We are extremely grateful to the authors who contributed to the valued third section
of the book on glutamate and opiate drugs of abuse including heroin. The world-renown
scientists in this section included Mao; Trujillo; Popik; and Rasmussen. An overview of
this important topic is provided by Jianren Mao,
MD, PhD of Harvard University School
viii Preface

of Medicine. It is of interest to note that the researchers in this section were some of the
first to provide evidence of a relationship between glutamate and various aspects of the
addiction process.
In the final section, the relationship between glutamate and alcohol abuse and alcohol-
ism is explored. Our superb editors of Section IV are Forrest F. Weight,
MD and Raye
Litten,
PhD, both of the National Institute of Alcohol Abuse and Alcoholism (NIAAA).
Personally, I am particularly grateful for the continuous role provided by Dr. Litten, who
managed to come to virtually every editorial meeting across building lines and to quickly
get his section collated into a deliverable form to our publisher, Humana Press.
I would like to thank Craig Adams and Elyse O’Grady of Humana Press for their
superb editorial and publishing skills and their tireless efforts in cheering this effort on
to its completion. Craig and Elyse supported this effort from the beginning and until its
completion, with a compassion and expertise that I will forever admire.
Finally, I would like to thank my institute, the National Institute on Drug Abuse, NIH,
for being supremely generous in allowing me the time to pursue this effort for the last two
and a half years. Particular thanks goes to Alan Leshner, Ph.D., former Director, NIDA,
Glen R. Hanson,
PhD, DDS, current and Acting Director, NIAA, Frank Vocci, PhD, Director,
Division of Treatment Research and Development (DTR&D), NIDA and Ahmed Elkashef,
MD, Chief, Clinical Medical Branch (CMB), DTR&D, NIDA for permitting this effort to
occur. We also thank the institute directors of NIAAA, Enoch Gordis,
MD (former director)
and the present top official of the FDA Bernard A. Schwertz,
DVM, PhD, Acting Principal
Deputy Commissioner and the past commissioner of the FDA, Jane E. Henney,
MD for
enabling the participation of individuals from their respective institutions.
I am personally touched by the numerous cards, letters and flowers that I received from

family, friends, professional colleagues, and folks from Humana while in the hospital.
Our interest in glutamatergic systems and drug abuse disorders stems back to at least
1991, when the first preclinical evidence was presented for a role of this system in the
development of opiate tolerance and withdrawal (cf. 1, 2). Indeed, a few years earlier,
research in the late 1980s suggested a role of glutamate in stimulant drug addiction (3).
From there, we as a group launched several efforts to try to synthesize the knowledge
base that was quickly accumulating in this exciting area. Thanks to the efforts of the
National Institutes of Health (NIH) and the Food and Drug Administration (FDA),
approaches to understanding the biological and behavioral basis of drug addiction and
developing new modalities for the treatment of drug addiction are now attaining some
level of consistency across the world. A highlight in this trend for unification in theory
and practice, is illustrated by the conceptual writings of Alan I. Leshner,
PhD former
Director, National Institute on Drug Abuse, who has tirelessly pioneered to increase the
research and scientific basis for understanding drug addiction as a disorder of the brain
(e.g., 4, 5). A similar emphasis on drug abuse as a brain disorder is noted in the very basic
preclinical research of Stephen E. Hyman,
MD, former Director, National Institute on
Mental Health (e.g., 6, 7). Similarly, in a monthly letter developed by the National
Institute on Alcohol Abuse and Treatment (NIAAA), Enoch Gordis,
MD, former Direc-
tor, NIAAA has describe numerous scientific advances detailing the role of various
biochemical systems in alcohol dependence and the role of medication treatment in
alcohol dependence (cf., 8, 9). An esteemed partner in this endeavor is Jane Henney,
MD,
former Commissioner, FDA whose institute is responsible for making certain that the
medications that are developed for this indication are both efficacious and safe. We very
much value the superb contributions of the authors in Section IV on glutamate and
alcohol, who include Peoples; Crew, Rudolph, and Chandler; Becker and Redmond;
Krystal, Petrakis, D’Souza, Mason, and Trevisan; Zieglgänsberger, Rammes, Spanagel,

Danysz, and Parsons; Pasternak and Kolesnikov; and Potgieter. We all work together
with these institutes and with the creative and brilliant scientists who undertake both the
preclinical and clinical research to develop a rigorous science of drug addiction. It is our
hope that this research will result in innovative treatments for drug abuse and addiction,
and for understanding the basis of these disorders in the central nervous system.
The job of characterizing the role of glutamatergic systems in addiction disorders is now
off to a solid beginning. With the recent advance and approval of glutamatergic antago-
nists for the indication of alcohol abuse and addiction in a variety of European countries,
we have already started to witness some clinical payoff for the superbly innovative and
thorough research of both preclinical and clinical sciences. We hope that this effort will
launch a new decade starting in the year 2001, that will see yet even further advances in
the glutamatergic field, both in the etiology and treatment of addiction disorders.
Barbara H. Herman,
PhD
References
1. Herman, B.H., Vocci, F., Bridge, P. The effects of NMDA receptor antagonists and nitric
oxide synthase inhibitors on opioid tolerance and withdrawal. Neuropsychopharmacology 13:
269–292, 1995.
2. Herman, B.H. and O’Brien, C.P. Clinical medications development for opiate ad-
diction: focus on nonopioids and opioid antagonists for the amelioration of opiate with-
drawal symptoms and relapse prevention. Seminars in Neuroscience 9: 158–172, 1997.
3. Karler, R., et al., Blockade of “reverse tolerance” to cocaine and amphetamine by
MK-801. Life Sci 45: 599–606, 1989.
4. Leshner A.I., Koob G.F. Drugs of abuse and the brain. Proc Assoc Am Physicians
111:99–108, 1999.
5. Leshner A.I. Addiction is a brain disease, and it matters. Science 278: 45–47, 1997.
6. Hyman S.E., Hyman S.E., Malenka R.C. Addiction and the brain: the neurobiology
of compulsion and its persistence. Nat Rev Neurosci.2: 695–703, 2001.
7. Berke J.D., Hyman S.E. Addiction, dopamine, and the molecular mechanisms of
memory. Neuron 25: 515–532, 2000.

8. Gordis E. Advances in research on alcoholism and what they promise for future
treatment and prevention. Med Health R I 82:121, 1999.
9. Gordis E. The neurobiology of alcohol abuse and alcoholism: building knowledge,
creating hope. Drug Alcohol Depend. 51:9–11, 1998.
Preface ix

Preface vii
Contributors xv
I. INTRODUCTION: PHYSIOLOGY AND PHARMACOLOGY OF GLUTAMATE
Philip H. Sheridan, Forrest F. Weight, and Barbara H. Herman
Section Editors
1 Molecular Pharmacology and Physiology
of Glutamate Receptors 3
Karin Borges and Raymond Dingledine
2 Pharmacology of Glutamate Receptors 23
Jeffrey M. Witkin, Rafal Kaminski,
and Michael A. Rogawski
3 Glutamate and Neurotoxicity 51
B. Joy Snider and Dennis W. Choi
4 Maturational Regulation of Glutamate Receptors
and Their Role in Neuroplasticity 63
Russell M. Sanchez and Frances E. Jensen
5 Role of the NMDA Receptor in Neuronal Apoptosis
and HIV-Associated Dementia 71
Marcus Kaul and Stuart A. Lipton
II. GLUTAMATE: STIMULANT DRUGS OF ABUSE (COCAINE, AMPHETAMINE, METHAMPHETAMINE)
Jerry Frankenheim and Barbara H. Herman, Section Editors
6 Role of Glutamate and Nitric Oxide in the Acquisition
and Expression of Cocaine-Induced Conditioned
Increases in Locomotor Activity 83

Agu Pert, Robert M. Post, and Susan R. B. Weiss
7 Interactions of Dopamine, Glutamate, and GABA Systems
in Mediating Amphetamine- and Cocaine-Induced
Stereotypy and Behavioral Sensitization 107
Ralph Karler, David K. Thai, and Larry D. Calder
8 Addiction and Glutamate-Dependent Plasticity 127
Marina E. Wolf
9 Glutamate and Dopamine Interactions in the Motive Circuit:
Implications for Craving 143
David A. Baker, Jennifer L. Cornish, and Peter W. Kalivas
10 Glutamate Cascade from Metabotropic Glutamate Receptors
to Gene Expression in Striatal Neurons: Implications
for Psychostimulant Dependence and Medication 157
John Q. Wang, Limin Mao, and Yuen-Sum Lau
Contents
xi
11 Glutamate Neurotransmission in the Course of Cocaine
Addiction 171
Luigi Pulvirenti
12 Glutamate and the Self-Administration of
Psychomotor-Stimulant Drugs 183
Paul Vezina and Nobuyoshi Suto
13 Roles of Glutamate, Nitric Oxide, Oxidative Stress, and
Apoptosis in the Neurotoxicity of Methamphetamine 201
Jean Lud Cadet
14 Methamphetamine Toxicity: Roles for Glutamate, Oxidative
Processes, and Metabolic Stress 211
Kristan B. Burrows and Bryan K. Yamamoto
15 Nitric Oxide-Dependent Processes in the Action
of Psychostimulants 229

Yossef Itzhak, Julio L. Martin, and Syed F. Ali
16 Effects of Novel NMDA/Glycine-Site Antagonists
on the Blockade of Cocaine-Induced Behavioral
Toxicity in Mice 243
Rae R. Matsumoto and Buddy Pouw
17 Clinical Studies Using NMDA Receptor Antagonists
in Cocaine and Opioid Dependence 261
Adam Bisaga and Marian W. Fischman
18 The Role of mGluR5 in the Effects of Cocaine:
Implications for Medication Development 271
Mark P. Epping-Jordan
III. G
LUTAMATE AND OPIATE DRUGS (HEROIN) OF ABUSE
Barbara H. Herman and Jerry Frankenheim, Section Editors
19 Role of the Glutamatergic System in Opioid Tolerance
and Dependence: Effects of NMDA Receptor Antagonists 281
Jianren Mao
20 The Role of NMDA Receptors in Opiate Tolerance,
Sensitization, and Physical Dependence: A Review
of the Research, A Cellular Model, and Implications
for the Treatment of Pain and Addiction 295
Keith A. Trujillo
21 Modification of Conditioned Reward by
N-Methyl-
D-aspartate Receptor Antagonists 323
Piotr Popik
22 Morphine Withdrawal as a State of Glutamate Hyperactivity:
The Effects of Glutamate Receptor Subtype Ligands
on Morphine Withdrawal Symptoms 329
Kurt Rasmussen

xii Contents
IV. GLUTAMATE AND ALCOHOL ABUSE AND ALCOHOLISM
Forrest F. Weight and Raye Z. Litten, Section Editors
23 Alcohol Actions on Glutamate Receptors 343
Robert W. Peoples
24 Glutamate and Alcohol-Induced Neurotoxicity 357
Fulton T. Crews, Joseph G. Rudolph,
and L. Judson Chandler
25 Role of Glutamate in Alcohol Withdrawal Kindling 375
Howard C. Becker and Nicole Redmond
26 Alcohol and Glutamate Neurotransmission in Humans:
Implications for Reward, Dependence, and Treatment 389
John H. Krystal, Ismene L. Petrakis, D. Cyril D’Souza,
Graeme Mason, and Louis Trevisan
27 Mechanism of Action of Acamprosate Focusing
on the Glutamatergic System 399
W. Zieglgänsberger, G. Rammes, R. Spanagel, W. Danysz,
and Ch. Parsons
28 The NMDA/Nitric Oxide Synthase Cascade in Opioid
Analgesia and Tolerance 409
Gavril W. Pasternak and Yuri Kolesnikov
29 Overview of Clinical Studies for Acamprosate 417
Adriaan S. Potgieter
Index 427
Contents xiii

SYED F. ALI, PhD • Neurochemistry Laboratory, Division of Neurotoxicology, National
Center for Toxicological Research, Food and Drug Administration, Jefferson, AR
DAVID A. BAKER, PhD • Department of Physiology and Neuroscience, Medical School
of South Carolina, Charleston, SC

H
OWARD C. BECKER, PhD • Charleston Alcohol Research Center, Center for Drug and
Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Physiology,
and Neuroscience, Department of Veterans Affairs Medical Center, Medical University
of South Carolina, Charleston, SC
A
DAM BISAGA, MD • Division on Substance Abuse, Department of Psychiatry, Columbia
University College of Physicians and Surgeons, New York, NY
K
ARIN BORGES, PhD • Department of Pharmacology, Emory University School of Medicine,
Atlanta, GA
K
RISTAN B. BURROWS, PhD • Program in Basic and Clinical Neuroscience, Department
of Psychiatry, Case Western Reserve University Medical School, Cleveland, OH
J
EAN LUD CADET, MD • Molecular Psychiatry Division, National Institute on Drug
Abuse, National Institutes of Health, Baltimore, MD
LARRY D. CALDER, PhD • Department of Pharmacology, University of Utah School
of Medicine, Salt Lake City, UT
L. J
UDSON CHANDLER, PhD • Department of Physiology/Neuroscience and Psychiatry,
Medical University of South Carolina, Charleston, SC
DENNIS W. CHOI, MD, PhD • Center for the Study of Nervous System Injury and Department
of Neurology, Washington University School of Medicine, St. Louis, MO
JENNIFER L. CORNISH, PhD • National Institute on Drug Abuse, National Institutes
of Health, Baltimore, MD
F
ULTON T. CREWS, PhD • Director, Center for Alcohol Studies, University of North
Carolina at Chapel Hill, Chapel Hill, NC
W. DANYSZ • Merz Co., Frankfurt, Germany

R
AYMOND DINGLEDINE, PhD • Department of Pharmacology, Emory University School
of Medicine, Atlanta, GA
D. C
YRIL D’SOUZA, MD • Department of Psychiatry, Yale University School of
Medicine, New Haven, CT; Alcohol Research Center, VA Connecticut Healthcare
System, West Haven, CT; and NIAAA Center for the Translational Neuroscience
of Alcoholism, Ribicoff Research Facilities, Connecticut Mental Health Center,
New Haven, CT
M
ARK P. EPPING-JORDAN, PhD • Addex Pharmaceuticals, Institut de Biologie Cellulaire
et du Morphologie, Universit de Lausanne, Lausanne, Switzerland
M
ARIAN W. FISCHMAN, PhD (deceased)•Division on Substance Abuse, Department
of Psychiatry, Columbia University College of Physicians and Surgeons,
New York, NY
J
ERRY FRANKENHEIM, PHD • DNBR, National Institute on Drug Abuse (NIDA), Bethesda, MD
B
ARBARA H. HERMAN, PHD • Clinical Medical Branch, Division of Treatment Research
and Devlopment, National Institute on Drug Abuse (NIDA), National Instiutes
of Health (NIH), Bethesda, MD
Contributors
xv
xvi Contributors
YOSSEF ITZHAK, PhD • Department of Psychiatry and Behavioral Sciences, University
of Miami School of Medicine, Miami, FL
F
RANCES E. JENSEN, MD • Children’s Hospital, Boston, MA, and Harvard Medical School,
Boston, MA

P
ETER W. KALIVAS, PhD • Department of Physiology and Neuroscience, Medical School
of South Carolina, Charleston, SC
R
AFAL KAMINSKI, MD, PhD • Drug Development Group, Intramural Research Program,
National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD
RALPH KARLER, PhD • Department of Pharmacology, University of Utah School of Medicine,
Salt Lake City, UT
M
ARCUS KAUL, PhD • Center for Neuroscience and Aging, The Burnham Institute,
La Jolla, CA
YURI KOLESNIKOV, MD, PhD • The Laboratory of Molecular Neuropharmacology, Memorial
Sloan-Kettering Cancer Center, New York, NY
J
OHN H. KRYSTAL, MD • Department of Psychiatry, Yale University School of
Medicine, New Haven, CT; Alcohol Research Center, VA Connecticut Healthcare
System, West Haven, CT; and NIAAA Center for the Translational Neuroscience
of Alcoholism, Ribicoff Research Facilities, Connecticut Mental Health Center,
New Haven, CT
Y
UEN-SUM LAU, PhD • Division of Pharmacology, School of Pharmacy, University
of Missouri–Kansas City, Kansas City, MO
S
TUART A. LIPTON, MD, PhD • Center for Neuroscience and Aging, The Burnham Institute,
La Jolla, CA
RAYE Z. LITTEN, PhD • Division of Clinical and Prevention Research, National Institute
on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD
J
IANREN MAO, MD, PhD • MGH Pain Center, Department of Anesthesia and Critical
Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA

L
IMIN MAO, MD • Division of Pharmacology, School of Pharmacy, University of Missouri–
Kansas City, Kansas City, MO
J
ULIO L. MARTIN, PhD • Department of Psychiatry and Behavioral Sciences, University
of Miami School of Medicine, Miami, FL
G
RAEME MASON, PhD • Department of Psychiatry, Yale University School of
Medicine, New Haven, CT; Alcohol Research Center, VA Connecticut Healthcare
System, West Haven, CT; and NIAAA Center for the Translational Neuroscience
of Alcoholism, Ribicoff Research Facilities, Connecticut Mental Health Center,
New Haven, CT
R
AE R. MATSUMOTO, PhD • Department of Pharmaceutical Sciences, College of Pharmacy,
University of Oklahoma Health Sciences Center, Oklahoma City, OK
C
H. PARSONS • Merz Co., Frankfurt, Germany
G
AVRIL W. PASTERNAK, MD, PhD • The Laboratory of Molecular Neuropharmacology,
Department of Anesthesiology, Memorial Sloan-Kettering Cancer Center,
New York, NY
R
OBERT W. PEOPLES, PhD • Unit on Cellular Neuropharmacology, Laboratory of Molecular
and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health, Bethesda, MD
A
GU PERT, PhD • Biological Psychiatry Branch, National Institute of Mental Health,
National Institutes of Health, Bethesda, MD
Contributors xvii
ISMENE L. PETRAKIS, MD • Department of Psychiatry, Yale University School

of Medicine, New Haven, CT; Alcohol Research Center, VA Connecticut Healthcare
System, West Haven, CT; and NIAAA Center for the Translational Neuroscience
of Alcoholism, Ribicoff Research Facilities, Connecticut Mental Health Center,
New Haven, CT
P
IOTR POPIK, MD, PhD • Institute of Pharmacology, Polish Academy of Sciences, Kraków,
Poland
R
OBERT M. POST, PhD • Biological Psychiatry Branch, National Institute of Mental
Health, National Institutes of Health, Bethesda, MD
A
DRIAAN S. POTGIETER, MD • Marketing and Business Development, European Society
of Cardiology
B
UDDY POUW, MD • Department of Pharmaceutical Sciences, College of Pharmacy,
University of Oklahoma Health Sciences Center, Oklahoma City, OK
L
UIGI PULVIRENTI, MD • Department of Neuropharmacology, The Scripps Research
Institute, La Jolla, CA
G. R
AMMES • Max-Planck Institute of Psychiatry, Munich, Germany
K
URT RASMUSSEN, PhD • Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate
Center, Indianapolis, IN
NICOLE REDMOND • Charleston Alcohol Research Center, Center for Drug and
Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Physiology,
and Neuroscience, Department of Veterans Affairs Medical Center, Medical University
of South Carolina, Charleston, SC
M
ICHAEL A. ROGAWSKI, MD, PhD • Epilepsy Research Section, National Institute

of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
J
OSEPH G. RUDOLPH, PhD • NIH/NIAAA/DICBR/LNG, Rockville, MD
R
USSELL M. SANCHEZ, PhD • Children’s Hospital, Boston, MA, and Harvard Medical
School, Boston, MA
P
HILIP H. SHERIDAN, MD • Division of Neuropharmacological Drug Products, Center
for Drug Evaluation and Research, Office of Drug Evaluation I, Food and Drug
Administration, Rockville, MD
B. J
OY SNIDER, MD, PhD • Center for the Study of Nervous System Injury and Department
of Neurology, Washington University School of Medicine, St. Louis, MO
R. S
PANAGEL • Central Institute of Mental Health, Mannheim, Germany
N
OBUYOSHI SUTO, MA • Department of Psychiatry, The University of Chicago, Chicago, IL
D
AVID K. THAI, PhD • Department of Pharmacology, University of Utah School of Medicine,
Salt Lake City, UT
L
OUIS TREVISAN, MD • Department of Psychiatry, Yale University School of Medicine,
New Haven, CT; Alcohol Research Center, VA Connecticut Healthcare
System, West Haven, CT
K
EITH A. TRUJILLO, PhD • Department of Psychology, California State University San
Marcos, San Marcos, CA
P
AUL VEZINA, PhD • Department of Psychiatry, The University of Chicago, Chicago, IL
J

OHN Q. WANG, MD, PhD • Division of Pharmacology, School of Pharmacy, University
of Missouri–Kansas City, Kansas City, MO
F
ORREST F. WEIGHT, MD • Division of Intramural Clinical and Biological Research,
National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD
SUSAN R. B. WEISS, PhD • Biological Psychiatry Branch, National Institute of Mental
Health, National Institutes of Health, Bethesda, MD
J
EFFREY M. WITKIN, PhD • Neuroscience Discovery Research, Lilly Research Laboratories,
Lilly Corporate Center, Indianapolis, IN
M
ARINA E. WOLF, PhD • Department of Neuroscience, FUHS/The Chicago Medical
School, North Chicago, IL
B
RYAN K. YAMAMOTO, PhD • Department of Pharmacology, Boston University School
of Medicine, Boston, MA
W. ZIEGLGÄNSBERGER, MD, PhD • Max-Planck Institute of Psychiatry, Munich, Germany
S
TEVEN R. ZUKIN, MD • DTRD, National Institute on Drug Abuse, Bethesda, MD
xviii Contributors
I
Introduction
Physiology and Pharmacology of Glutamate
Section Editors
Philip H. Sheridan
Forrest F. Weight
Barbara H. Herman

1
Molecular Pharmacology and Physiology

of Glutamate Receptors
Karin Borges, PhD and Raymond Dingledine, PhD
1. INTRODUCTION
Glutamate receptors represent the main excitatory receptors in synaptic transmission in the brain
and have been intensively studied over the last 15 yr. Although clinical settings involving glutamate
receptor modulators or antagonists usually involve stroke, acute brain injury, epilepsy, and neuropathic
pain, both metabotropic and ionotropic classes of glutamate receptor also appear to play a role in
addiction and cognition. For example, sensitization to cocaine upon chronic exposure to this stimulant
appears to be mediated in part by Ca
2+
influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propi-
onic acid (AMPA) receptors (1), and an mGluR2 agonist attenuates the disruptive effects of phencycli-
dine on working memory (2). We will provide an overview of the molecular and physiological
properties of glutamate receptors and review their subunit-specific pharmacology. As much as possi-
ble, we will focus on features of glutamate receptor activation and desensitization that may be most
relevant to addiction and cognitive processing. More extensive information on glutamate receptor
pharmacology can be found in the literature (3–5).
2. METABOTROPIC RECEPTORS
2.1. Introduction into mGluR Classifications and Their Classical
G-Protein-Coupled Signaling Pathways
The metabotropic receptors all contain seven transmembrane domains (TM) and are coupled to G-
proteins. They are classified into three groups according to their pharmacology (Table 1). Many excel-
lent extensive reviews for the mGluRs are avaible (e.g., refs. 6–9). Metabotropic glutamate receptors
are widely expressed in the brain, except for mGluR6, which only occurs in the retina. Group II
mGluRs are found in presynaptic membranes or extrasynaptically, group III receptors function as
autoreceptors in the presynaptic terminal membrane, and group I mGluRs are often expressed perisy-
naptically, near the postsynaptic density (10). Astrocytes can express mGluR3 and mGluR5 (reviewed
in ref. 11) and outside the brain, mGluRs occur, for example, in the heart (12). Group I receptors are
coupled to G
q

-proteins, which, by activating phospholipase C, produce inositol triphosphate (IP
3
),
which then activates the endoplasmic IP
3
receptor and triggers the release of calcium from intracellular
stores. Group I receptors also activate or inhibit voltage-gated ion channels. Group II and III receptors
couple to G
i
/G
0
proteins that either block adenylate cyclase or calcium channels or activate potassium
channels. An example of the different signaling pathways as occurring in the CA1 area of the hip-
pocampus is shown in Fig. 1. The figure also displays the interaction of mGluRs with other receptors
and ion channels.
From: Contemporary Clinical Neuroscience: Glutamate and Addiction
Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ
3
Table 1
Established and Commonly Used Compounds That Can Distinguish Among mGluR Receptor
Groups and Between mGluR1 and mGluR5
Receptor Effectors Agonists Antagonists
Group1 mGluR1 Gq DHPG LY367385,CPCCOEt
mGluR5 Gq CHPG, CBPG, DHPG MPEP
GroupII mGluR2 G
i
/G
0
LY354740, APDC, DCG-IV LY341495
a

mGluR3 G
i
/G
0
GroupIII mGluR4 G
i
/G
0
L-AP4, L-SOP, PPG MAP4
mGluR6 G
i
/G
0
mGluR7 G
i
/G
0
mGluR8 G
i
/G
0
Note: For further information, see, for example, 9. The full names of the abbreviated compounds in alphabetical order
are as follows: L-AP4, L-(+)-amino-4-phosphonobutyric acid; APCD, 4-aminopyrrolidine-2,4-dicarboxylic acid; CBPG,
(S)-(+)-2-(3′-dicarboxycyclopropyl(1.1.1)pentyl)-glycine; CHPG, (R,S)-2-chloro-5- hydroxyphenylglycine; CPCCOEt,
cyclopropan[b]chromen-1a-carboxylate; DCG-VI, (2′S,2′R,3′R)-2-(2′3′-dicarboxycyclopropyl)glycine; DHPG,
3,5-dihydroxyphenylglycine; LY341495, 2S-2 amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-xanth-9-yl)propanoic
acid; LY354740,(1S,2S,5R,6S)-(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY367385, (+)-2-methyl-4-
carboxy-phenylglycine; MAP4, α-methyl-
L
-amino-4-phosphonobutyrate; PPG, (R,S)-4-phosphonophenylglycine;

L-SOP,
L
-serine O-phosphate.
a
Note that at high concentrations, the group II mGluR antagonist LY341495 can also block group III and I receptors.
Fig. 1. Example of physiological roles of mGluRs at the Schaffer collateral synapse in CA1 in the hippocam-
pus. mGluR5 and mGluR7 are located in the presynaptic terminal, where they inhibit glutamate release directly by
effects on the release machinery or indirectly by inhibiton of voltage-gated calcium channels. mGluR5 is
expressed at the postsynaptic terminal which increases pyramidal cell excitability by reducing potassium currents.
Moreover, mGluR5 activation can potentiate NMDA receptor-mediated currents. Inhibitory GABA-ergic terminals
express group I mGluRs, and by inhibiting GABA release, they can indirectly increase pyramidal cell excitability.
Finally, glial cells express mGluR3. There is evidence that glial mGluR stimulation leads to release of a neuropro-
tective factor. Also, mGluR3 activation can potentiate β-adrenergic responses, leading to release of cAMP or
adenosine, which stimulates A1 adenosine receptors and reduces glutamate release from the presynaptic terminal.
(From ref. 13, with permission.) (Color illustration in insert following p. 142.)
4
Molecular Pharmacology/Physiology of Glutamate Receptors 5
Some mGluRs are alternatively spliced. Alternative splicing in translated regions occurs only at the
C-termini in mGluR1, 4, 5, 7, and 8, as shown Fig. 2. In some cases, alternative splicing leads to dif-
ferent interactions with other signaling molecules (see Section 2.2.).
2.2. Association with Other Intracellular Signaling Proteins and Targeting Proteins
In addition to mGluR signaling via G-protein cascades, mGluR interactions with other signaling
molecules are being discovered. For example, group I mGluRs with homologous C-termini (mGluR1a
and mGluR5) couple to Homer proteins (16). Constitutively expressed Homer proteins (the long forms
of Homer 1b, 1c, 2, and 3) physically link mGluR1a or mGluR5 to the endoplasmic IP
3
receptor. This
signaling complex can be disrupted by the truncated Homer 1a, which is up-regulated as an immediate
early gene after certain forms of long-term potentiation and after seizures. Similarly, the long Homer
forms inhibited group I mGluR-mediated regulation of N-type calcium channels and M-type potas-

sium channels, whereas the truncated forms did not (17). Moreover, Homer interacts with the scaffold
protein Shank, which links Homer to many other cytoplasmic and membrane proteins. By virtue of its
ability to bridge receptors and cytoplasmic proteins, Homer controls the trafficking of mGluR1a and
mGluR5 into and out of synapses (18).
In addition to linking mGluRs to signaling molecules, the mGluR C-termini can be involved in
receptor targeting, as observed in other receptors. For example, the last 60 amino acids target mGluR7
to axons and dendrites, whereas mGluR2 is excluded from axons (19). Calmodulin binds to C-termi-
nal regions of mGluR5 and mGluR7, which are also phosphorylated by protein kinase C (PKC)
(20–22). Calcium/calmodulin binding and PKC phosphorylation are mutually occlusive, similar to
their roles at NMDA receptors (see Section 3.7.). Moreover, mGluR7 seems to be able to associate
with the PKC α-subunit and protein interacting with C-kinase 1 (PICK1), because they can be coim-
munoprecipitated from transfected COS cells and PICK1 can reduce phosphorylation of mGluR7a in
Fig. 2. Schematic representation of splice variants of mGluR proteins. Only translated regions are depicted;
alternative splicing in untranslated regions is not shown. The seven transmembrane domains are shown in black.
The different C-terminal domains are indicated by different patterns. (A) Group I mGluRs. The mGluR1a C-tail is
homologous to those of mGluR5a and mGluR5b (all shown in gray). The C-terminal domains of mGluR5a and
mGluR5b are the same. (B) Within the group III mGluRs, no homology between C-terminal domains is found.
Adapted from ref. 7; new splice variants for mGluR7 and mGluR8 (14,15) are added.
6 Borges and Dingledine
vitro (23). PICK1 also interacts with AMPA receptors (see Section 3.6.). Thus, an extensive network
of cytoplasmic proteins exists that serve to anchor, target, and modulate metabotropic glutamate
receptors. As described in the following section, many of these proteins play similar roles for the
ionotropic glutamate receptors.
The mitogen-activated protein (MAP) kinase ERK2 can be activated by mGluR stimulation, by a
G-protein-mediated mechanism (24,25). However, a G-protein-independent mGluR1 signaling path-
way appears to occur in CA3 pyramidal cells, because a transient activation of a cation conductance
follows activation of a Src-family kinase (26).
3. IONOTROPIC RECEPTORS
3.1. Ionotropic Receptor Classes and Their Subunits
The main features of ionotropic glutamate receptors will be discussed here. Additional information

can be found in more extensive reviews (e.g. refs. 3, 27, and 28). Studies on glutamate receptor
knock-out and transgenic mice are summarized in other reviews (29,30) and information on the
ionotropic glutamate receptor promoters can be found in ref. 30. The mammalian ionotropic gluta-
mate receptors are divided into three classes according to their subunit composition and pharmacol-
ogy. They are named after their high-affinity agonists: AMPA receptors containing the GluR1–4 or
GluRA–D subunits; kainate receptors comprising GluR5-7, KA1, and KA2 subunits; and N-methyl-
D
-
aspartate (NMDA) receptors with the subunits NR1, NR2A–D, and NR3A (Table 2). The two dis-
tantly related orphan receptors, δ1 and δ2, do not form functional homomeric channels. However,
neurodegeneration in the Lurcher mouse is caused by a δ2 mutation that produces a constitutively
active, Ca
2+
-permeable channel resembling an AMPA or kainate receptor (31,32).
Table 2
Glutamate Receptor Subunits and Their Genes
Receptor Chromosome
GenEmbl accession numbers
Group Family Subunit Gene (human) Mouse Rat Human
1 AMPA GluR1 GRIA1 5q33 X57497 X17184 157354
1 AMPA GluR2 GRIA2 4q32–33 X57498 M85035 A46056
1 AMPA GluR3 GRIA3 Xq25–26 M85036 X82068
1 AMPA GluR4 GRIA4 11q22–23 M36421 U16129
2 Kainate GluR5 GRIK1 21q21.1–22.1 X66118 M83560 U16125
2 Kainate GluR6 GRIK2 6q16.3–q21 D10054 Z11715 U16126
2 Kainate GluR7 GRIK3 1p34–p33 M83552 U16127
3 Kainate KA-1 GRIK4 11q22.3 X59996 S67803
a
3 Kainate KA-2 GRIK5 19q13.2 D10011 Z11581 S40369
4 NMDA NR1 GRIN1 9q34.3 D10028 X63255 X58633

5 NMDA NR2A GRIN2A 16p13.2 D10217 D13211 U09002
5 NMDA NR2B GRIN2B 12p12 D10651 M91562 U28861
a
5 NMDA NR2C GRIN2C 17q24–q25 D10694 D13212
5 NMDA NR2D GRIN2D 19q13.1qter D12822 D13214 U77783
6 NMDA NR3A GRIN3A
b
L34938
7Orphan δ1 GRID1 D10171 Z17238
7Orphan δ2 GRID2 4q22 D13266 Z17239
a
Partial sequence.
b
as proposed in ref. 3.
Source: ref. 3, with permission