PSYCHOPHARMACOLOGYThe Fourth Generation of Progress

An Official Publication of theAmerican College of Neuropsychopharmacology

Editors-in-Chief

Floyd E. Bloom, M.D.Chairman

Department of NeuropharmacologyThe Scripps Research Institute

Lajolla, California

David J. Kupfer, M.D.Professor and ChairmanDepartment of Psychiatry

University of Pittsburgh School of MedicineWestern Psychiatric Institute and Clinic

Pittsburgh, Pennsylvania

Associate Editors

Benjamin S. Bunney, M.D.Charles B. G. Murphy Professor and Chairman

Department of PsychiatryProfessor of Pharmacology

Yale University School of MedicineNew Haven, Connecticut

Kenneth L. Davis, M.D.Professor and ChairmanDepartment of Psychiatry

Mount Sinai School of MedicineNew York, New York

Herbert Y. Meltzer, M.D.Douglas D. Bond ProfessorDepartment of Psychiatry

Case Western Reserve University School of MedicineUniversity Hospitals of Cleveland

Cleveland, Ohio

Richard I. Shader, M.D.Professor

Department of Pharmacology and Experimental Therapeuticsi Tufts University School of Medicine

Boston, Massachusetts

Roland D. Ciaranello, M.D.Nancy Friend Pritzker Professor

Department of Psychiatry and Behavioral SciencesStanford University School of Medicine

Stanford, California

George F. Koob, Ph.D.Professor

Department of NeuropharmacologyThe Scripps Research Institute

Lajolla, California

Charles R. Schuster, Ph.D.Intramural Research Program

National Institute on Drug AbuseNational Institutes of Health

Baltimore, Maryland

Stanley J. Watson, Jr., M.D., Ph.D.Associate Director

Mental Health Research InstituteAssociate Chair for Research

Department of PsychiatryUniversity of MichiganAnn Arbor, Michigan

RAVEN PRESS NEW YORK

Contents

CONTRIBUTORS xix

PREFACE TO THE THIRD EDITION xli

PREFACE xliii

PART I. PRECLINICAL SECTION

1. Introduction to Preclinical Neuropsychopharmacology 1Floyd E. Bloom

Critical Analysis of Methods

2. Basic Concepts and Techniques of Molecular Genetics 9Samuel H. Barondes

3. Cytology and Circuitry 13Stanley J. Watson, Jr. and William E. Cullinan

4. A Critical Analysis of Neurochemical Methods for MonitoringTransmitter Dynamics in the Brain 29Janet M. Finlay and Michael J. Zigmond

5. Electrophysiology 41Gary S. Aston-Jones and George R. Siggins

6. Behavioral Techniques in Preclinical NeuropsychopharmacologyResearch 65James E. Barrett and Klaus A. Miczek

Transmitter Systems

Amino Acids

7. Excitatory Amino Acid Neurotransmission 75Carl W. Cotman, Jennifer S. Kahle, Stephan E. Miller,Jolanta Was, and Richard J. Bridges

8. GABA and Glycine 87Steven M. Paul

Amines

9. Neuronal Nicotinic Acetylcholine Receptors: Novel Targets forCentral Nervous System Therapeutics 95Stephen P. Arneric, James P. Sullivan, and Michael Williams

vii

viii / CONTENTS

10. Molecular Biology, Pharmacology, and Brain Distribution ofSubtypes of the Muscarinic Receptor I l lFrederick J. Ehlert, William R. Roeske, and Henry I. Yamamura

11. Cholinergic Transduction 125Elliott Richelson

12. Structure and Function of Cholinergic Pathways in the CerebralCortex, Limbic System, Basal Ganglia, and Thalamus of theHuman Brain 135Marek-Marsel Mesulam

13. Functional Heterogeneity of Central Cholinergic Systems 147Peter B. Reiner and H. Christian Fibiger

14. Molecular Biology of the Dopamine Receptor Subtypes 155Olivier Civelli

15. Electrophysiological Properties of Midbrain Dopamine Neurons 163Anthony A. Grace and Benjamin S. Bunney

16. The Dopamine Transporter: Potential Involvement inNeuropsychiatric Disorders 179Michael J. Bannon, James G. Granneman, and Gregory Kapatos

17. Long- and Short-Term Regulation of Tyrosine Hydroxylase 189Menek Goldstein

18. Colocalization in. Dopamine Neurons 197Ariel Y. Deutch and Andrew J. Bean

19. Dopamine Receptor Expression in the Central Nervous System 207Alfred Mansour and Stanley J. Watson, Jr.

20. Dopamine Autoreceptor Signal Transduction and Regulation 221Louis A. Chiodo, Arthur S. Freeman, and Benjamin S. Bunney

21. Biochemical Pharmacology of Midbrain Dopamine Neurons 227Robert H. Roth and John D. Elsworth

22. Dopaminergic Neuronal Systems in the Hypothalamus 245Kenneth E. Moore and Keith J. Lookingland

23. Electron Microscopy of Central Dopamine Systems 257Virginia M. Picket and Susan R. Sesack

24. Development of Mesencephalic Dopamine Neurons in the NonhumanPrimate: Relationship to Survival and Growth Following NeuralTransplantation 269John R. Sladek, Jr., Barbara Blanchard, T. J. Collier,John D. Elsworth, Jane R. Taylor, Robert H. Roth,and D. Eugene Redmond, Jr.

25. Mesocorticolimbic Dopaminergic Neurons: Functional and RegulatoryRoles 283Michel Le Moal

26. Dopamine Receptors: Clinical Correlates 295Philip Seeman

27. Signal Transduction Pathways for Catecholamine Receptors 303Ronald S. Duman and Eric J. Nestler

CONTENTS / ix

28. Norepinephrine and Serotonin Transporters: Molecular Targets ofAntidepressant Drugs 321Eric L. Barker and Randy D. Blakely

29. Pharmacology and Physiology of Central Noradrenergic Systems 335Stephen L. Foote and Gary S. Aston-Jones

30. Coexisting Neurotransmitters in Central Noradrenergic Neurons 347Philip V. Holmes and Jacqueline N. Crawley

31. Modification of Central Catecholaminergic Systems by Stress andInjury: Functional Significance and Clinical Implications 355Elizabeth D. Abercrombie and Michael J. Zigmond

32. Central Norepinephrine Neurons and Behavior 363Trevor W. Robbins and Barry J. Everitt

33. Physiological and Anatomical Determinants of Locus CoeruleusDischarge: Behavioral and Clinical Implications 373Rita J. Valentino and Gary S. Aston-Jones

34. Noradrenergic Neural Substrates for Anxiety and Fear: ClinicalAssociations Based on Preclinical Research 387Dennis S. Charney, J. Douglas Bremner, and D. Eugene Redmond, Jr.

35. Histamine 397Jean-Charles Schwartz, Jean-Michel Arrang, Monique Garbarg,and Elisabeth Traiffort

36. Molecular Biology of Serotonin Receptors: A Basis forUnderstanding and Addressing Brain Function 407Jean Chen Shih, Kevin J.-S. Chen, and Timothy K. Gallaher

37. Serotonin Receptor Subtypes 415Richard A. Glennon and Malgorzata Dukat

38. Serotonin Receptors: Signal Transduction Pathways 431Elaine Sanders-Bush and Herve Canton

39. Anatomy, Cell Biology, and Plasticity of the Serotonergic System:Neuropsychopharmacological Implications for the Actions of"Psychotropic Drugs 443Efrain C. Azmitia and Patricia M. Whitaker-Azmitia

40. Electrophysiology of Serotonin Receptor Subtypes and SignalTransduction Pathways 451George K. Aghajanian

41. Serotonin and Behavior: A General Hypothesis 461Barry L. Jacobs and Casimir A. Fornal

42. Indoleamines: The Role of Serotonin in Clinical Disorders 471George R. Heninger

Peptides

43. General Overview of Neuropeptides 483Tomas G. M. Hdkfelt, Marie-Noelle Castel, Patrizia Morino,Xu Zhang, and Ake Dagerlind

x / CONTENTS

44. Thyrotropin-Releasing Hormone: Focus on Basic Neurobiology 493George A. Mason, James C. Garbutt, and Arthur J. Prange, Jr.

45. Corticotropin-Releasing Factor: Physiology, Pharmacology, and Rolein Central Nervous System and Immune Disorders 505Errol B. De Souza and Dimitri E. Grigoriadis

46. Neuropharmacology of Endogenous Opioid Peptides 519John J. Wagner and Charles I. Chavkin

47. Vasopressin and Oxytocin in the Central Nervous System 531Linda Rinaman, Thomas G. Sherman, and Edward M. Strieker

48. Neuropeptide Y and Related Peptides 543Claes Wahlestedt and Markus Heilig

49. Somatostatin in the Central Nervous System 553David R. Rubinow, Candace L. Davis, and Robert M. Post

50. Galanin: A Neuropeptide with Important Central Nervous SystemActions 563Tamas Bartfai

51. The Neurobiology of Neurotensin 573Garth Bissette and Charles B. Nemeroff

52. Cholecystokinin/Gastrin 585Margery C. Beinfeld

New Transmitters

53. Arachidonic Acid 595Daniele Piomelli

54. Nitric Oxide and Related Substances as Neural Messengers 609Solomon H. Snyder and Ted M. Dawson

55. Neuronal Growth and Differentiation Factors and Synaptic Plasticity . . . 619Paul H. Patterson

56. Proto-Oncogenes: Beyond Second Messengers 631James I. Morgan and Thomas E. Curran

57. Purinoceptors in Central Nervous System Function: Targets forTherapeutic Intervention 643Michael Williams

Integrative Concepts

58. Brain Energy Metabolism: An Integrated Cellular Perspective 657Pierre J. Magistretti, Luc Pellerin, and Jean-Luc Martin

59. Molecular and Cellular Mechanisms of Brain Development 671David A. Morilak, Matthew H. Porteus, and Roland D. Ciaranello

60. The Development of Brain and Behavior 683Thomas R. Insel

61. Intracellular Messenger Pathways as Mediators of Neural Plasticity 695Eric J. Nestler and Ronald S. Duman

CONTENTS / xi

62. Neuroendocrine Interactions 705Bruce S. McEwen

63. Interactions Between the Nervous System and the Immune System:Implications for Psychopharmacology 719Adrian J. Dunn

64. Adaptive Processes Regulating Tolerance to Behavioral Effects ofDrugs 733Alice M. Young and Andrew J. Goudie

65. The Psychopharmacology of Sexual Behavior 743James G. Pfaus and Barry J. Everitt

66. Animal Models of Drug Addiction 759George F. Koob

67. Stress 773Huda A. Akil and M. Ines Morano

68. Animal Models of Psychiatric Disorders 787Mark A. Geyer and Athina Markou

69. Genetic Strategies in Preclinical Substance Abuse Research 799John C. Crabbe, Jr. and Ting-Kai Li

PART II. CLINICAL SECTION

70. Introduction to Clinical Neuropsychopharmacology 813David J. Kupfer

Critical Analysis of Methods

71. The DSM-IV Classification and Psychopharmacology 823Allen Frances, Avram H. Mack, Ruth Ross,and Michael B. First

72. Clinical Study Design—Critical Issues 829Donald S. Robinson and Robert F. Prien

73. Short- and Long-Term Psychopharmacological Treatment Strategies .. 839Ira D. Glick, David L. Braff, and David S. Janowsky

74. Pharmacokinetics and Pharmacodynamics 849David J. Greenblatt, Jerold S. Harmatz, Lisa L. von Moltke,and Richard I. Shader

75. Methodological Issues in the Neuropathology of Mental Illness 859Joel E. Kleinman, Thomas M. Hyde, and Mary M. Herman

76. Positron and Single Photon Emission Tomography: Principles andApplications in Psychopharmacology 865Robert T. Malison, Marc Laruelle, and Robert B. Innis

77. In Vivo Structural Brain Assessment 881Kelvin O. Lim, Margaret Rosenbloom, and Adolf Pfefferbaum

78. Methodological Issues in Event-Related Brain Potential and MagneticField Studies 895Walton T. Roth, Judith M. Ford, Adolf Pfefferbaum,and Thomas R. Elbert

xii / CONTENTS

Psychiatric Disorders

Mood Disorders

79. Recent Studies on Norepinephrine Systems in Mood Disorders 911Alan F. Schatzberg and Joseph J. Schildkraut

80. Dopaminergic Mechanisms in Depression and Mania 921Paul Willner

81. The Serotonin Hypothesis of Major Depression 933Michael Maes and Herbert Y. Meltzer

82. The Role of Acetylcholine Mechanisms in Mood Disorders 945David S. Janowsky and David H. Overstreet

83. Neuroendocrinology of Mood Disorders 957Florian Holsboer

84. Neuropeptide Alterations in Mood Disorders 971Paul M. Plotsky, Michael J. Owens, and Charles B. Nemeroff

85. Psychoneuroimmunology of Depression 983Michael Irwin

86. Biological Rhythms in Mood Disorders 999Anna Wirz-Justice

87. Brain Imaging in Mood Disorders 1019Godfrey D. Pearlson and Thomas E. Schlaepfer

88. Mood Disorders Linked to the Reproductive Cycle in Women 1029Barbara L. Parry

89. Selective Serotonin Reuptake Inhibitors in the Acute Treatment ofDepression 1043Stuart A. Montgomery

90. Short-Term Treatment of Mood Disorders With StandardAntidepressants 1053Michael J. Burke and Sheldon H. Preskorn

91. Long-Term Treatment of Mood Disorders 1067Robert F. Prien and James H. Kocsis

92. Treatment-Resistant Depression 1081Michael E. Thase and A. John Rush

93. Lithium and the Anticonvulsants in the Treatment of BipolarDisorder 1099Joseph R. Calabrese, Charles Bowden, and Mark J. Woyshville

94. Psychosocial Predictors of Outcome in Depression 1113Robert M. A. Hirschfeld

95. Electroconvulsive Therapy 1123Harold A. Sackeim, D. P. Devanand, and Mitchell S. Nobler

96. Novel Pharmacological Approaches to the Treatment of Depression .. 1143Dennis L. Murphy, Philip B. Mitchell, and William Z. Potter

97. The Neurobiology of Treatment-Resistant Mood Disorders 1155Robert M. Post and Susan R. B. Weiss

CONTENTS / xiii

Schizophrenia

98. Neurodevelopmental Perspectives on Schizophrenia 1171Daniel R. Weinberger

99. Functional Brain-Imaging Studies in Schizophrenia 1185Raquel E. Gur

100. New Developments in Dopamine and Schizophrenia 1193Rene S. Kahn and Kenneth L. Davis

101. Schizophrenia and Glutamate 1205Blynn Garland Bunney, William E. Bunney, Jr.,and Arvid Carlsson

102. The Role of Serotonin in Schizophrenia 1215Bryan L. Roth and Herbert Y. Meltzer

103. The Effects of Neuroleptics on Plasma Homovanillic Acid 1229Arnold J. Friedhoff and Raul R. Silva

104. Neurophysiological and Psychophysiological Approaches toSchizophrenia 1235Keith H. Nuechterlein and Michael E. Dawson

105. Neurocognitive Functioning in Patients with Schizophrenia: AnOverview 1245Terry E. Goldberg and James M. Gold

106. Acute Treatment of Schizophrenia 1259William C. Wirshing, Stephen R. Marder, Theodore Van Putten,and Donna Ames

107. Maintenance Drug Treatment for Schizophrenia 1267John G. Csernansky and John G. Newcomer

108. Atypical Antipsychotic Drugs 1277Herbert Y. Meltzer

Anxiety Disorders

109. Neuroimaging Studies of Human Anxiety Disorders: Cutting Paths ofKnowledge through the Field of Neurotic Phenomena 1287Lewis R. Baxter, Jr.

110. Anxiety and Serotonin1A Receptor 1301Jeremy D. Coplan, Susan I. Wolk, and Donald F. Klein

111. Pharmacological Challenges in Anxiety Disorders 1311Lawrence H. Price, Andrew W. Goddard, Linda C. Barr,and Wayne K. Goodman

112. Environmental Factors in the Etiology of Anxiety 1325Karrie J. Craig, Kelly J. Brown, and Andrew Baum

113. The Pharmacotherapy of Acute Anxiety: A Mini-Update 1341Richard I. Shader and David J. Greenblatt

114. Issues in the Long-Term Treatment of Anxiety Disorders 1349Edward Schweizer, Karl Rickels, and Eberhard H. Uhlenhuth

xiv / CONTENTS

Geriatric Disorders

115. Towards an Understanding of the Genetics of Alzheimer's Disease . . . 1361Corinne L. Lendon and Alison M. Goate

116. Amyloidogenesis in Alzheimer's Disease and Animal Models 1371Sangram S. Sisodia and Donald L. Price

117. Neuropsychological Assessment of Patients with Alzheimer'sDisease 1377Richard C. Mohs

118. Biological' Markers in Alzheimer's Disease 1389Trey Sunderland, Susan E. Molchan, and George S. Zubenko

119. Anatomic and Functional Brain Imaging in Alzheimer's Disease 1401; Stanley I. Rapoport

? 120. Experimental Therapeutics 1417Deborah B. Marin and Kenneth L. Davis

121. Alzheimer's Disease: Treatment of Noncognitive BehavioralAbnormalities 1427Murray A. Raskind

122. Late-Onset Schizophrenia and Other Related Psychoses 1437Dilip V. Jeste, Jane S. Paulsen, and M. Jackuelyn Harris

123. Cognitive Impairment in Geriatric Schizophrenic Patients: Clinicaland Postmortem Characterization 1447Michael Davidson and Vahram Haroutunian

124. Psychotropic Drug Metabolism in Old Age: Principles and Problemsof Assessment 1461Lisa L. von Moltke, David J. Greenblatt, Jerold S. Harmatz,and Richard I. Shader

125. Pharmacological Treatment of Depression in Late Life 1471Carl Salzman, Lon S. Schneider, and George S. Alexopoulos

Neurologic Disorders

126. Parkinson's Disease 1479Amos D. Korczyn

127. Tardive Dyskinesia: Epidemiological and Clinical Presentation . . . 1485John M. Kane

128. Tardive Dyskinesia: Pathophysiology 1497Daniel E. Casey

129. The Treatment of Tardive Dyskinesias 1503George Gardos and Jonathan O. Cole

130. Multi-Infarct Dementia 1513David S. Geldmacher and Peter J. Whitehouse

131. Prion Diseases 1521Stephen J. DeArmond and Stanley B. Prusiner

CONTENTS / xv

132. Amyotrophic Lateral Sclerosis, Glutamate, and Oxidative Stress 1531Andreas Plaitakis and P. Shashidharan

133. Neuropsychiatric Manifestations of HIV-1 Infection and AIDS 1545Robert A. Stern, Diana O. Perkins, and Dwight L. Evans

134. Potential Mechanisms of Neurologic Disease in HIV Infection 1559Melvyn P. Heyes

Personality Disorders

135. The Neuropsychopharmacology of Personality Disorders 1567Emil F. Coccaro and Larry J. Siever

Eating Disorders

136. Psychopharmacology of Anorexia Nervosa, Bulimia Nervosa, andBinge Eating 1581B. Timothy Walsh and Michael J. Devlin

137. Obesity, Fat Intake, and Chronic Disease 1591George A. Bray

138. Basic Biological Overview of Eating Disorders 1609Katherine A. Halmi

Sleep Disorders

139. Disordered Sleep: Developmental and Biopsychosocial Perspectiveson the Diagnosis and Treatment of Persistent Insomnia 1617Charles F. Reynolds III, Daniel J. Buysse, and David J. Kupfer

Childhood Disorders

140. Early-Onset Mood Disorder 1631David A. Brent, Neal Ryan, Ronald Dahl, and Boris Birmaher

141. The Interface of Genetics, Neuroimaging and Neurochemistry inAttention-Deficit Hyperactivity Disorder 1643Monique Ernst and Alan Zametkin

142. Autism and Pervasive Developmental Disorders 1653Linda J. Lotspeich

143. Tic Disorders 1665James F. Leckman, David L. Pauls, and Donald J. Cohen

144. Eating Disturbances and Eating Disorders in Childhood 1675Regina C. Casper

Substance Abuse

145. Cocaine 1685Chris-Ellyn Johanson and Charles R. Schuster

xvi / CONTENTS

146. Caffeine—A Drug of Abuse? 1699Roland R. Griffiths and Geoffrey K. Mumford

147. Pathophysiology of Tobacco Dependence 1715Jack E. Henningfield, Leslie M. Schuh, and Murray E. Jarvik

148. Opioids 1731George E. Bigelow and Kenzie L. Preston

149. Pharmacotherapy of Alcoholism 1745Charles P. O'Brien, Michael J. Eckardt, and V. Markku I. Linnoila

150. Marijuana 1757Billy R. Martin

151. Phencyclidine 1767David A. Gorelick and Robert L. Bolster

152. Abuse and Therapeutic Use of Benzodiazepines andBenzodiazepine-Like Drugs 1777James H. Woods, Jonathan L. Katz, and Gail Winger

153. Genetic Influences in Drug Abuse 1793George R. Uhl, Gregory I. Elmer, Michele C. LaBuda,and Roy W. Pickens

154. Behavioral Treatment of Drug and Alcohol Abuse 1807Maxine L. Stitzer and Stephen T. Higgins

Integrative Concepts

155. Genetics 1821Raymond R. Crowe

156. Strategies for Multimodality Research 1835Ellen Frank, David J. Kupfer, and Jordan Karp

157. Methodological and Statistical Progress in Psychiatric ClinicalResearch: A Statistician's Perspective 1849Helena Chmura Kraemer

PART III. SPECIAL TOPICS

158. New Drug Design in Psychopharmacology: The Impact of MolecularBiology 1861John F. Tollman and Svein G. Dahl

159. Ethical Issues in Genetic Screening and Testing, Gene Therapy, andScientific Conduct 1875Lisa S. Parker and Elizabeth Gettig

160. The Economics of Psychotropic Drug Development 1883Joseph A. DiMasi and Louis Lasagna

161. Economic Evaluation of Drug Treatment for Psychiatric Disorders:The New Clinical Trial Protocol 1897Gary A. Zarkin, Henry G. Grabowski, Josephine Mauskopf,Heather A. Bannerman, and Richard H. Weisler

CONTENTS / xvii

162. Ethnicity, Culture, and Psychopharmacology 1907Keh-Ming Lin and Russell E. Poland

163. Violence and Aggression 1919J. John Mann

SUBJECT INDEX 1929