Integrating the Neurobiology of Schizophrenia (eBook)

Front Cover 1
Integrating the Neurobiology of Schizophrenia 4
Copyright Page 5
Contents 6
Contributors 12
Preface 14
References 17
Chapter 1: Neurobiology of Dopamine in Schizophrenia 18
I. Introduction 18
II. Dopaminergic System in the Brain 20
A. Dopaminergic Projections 20
B. Dopaminergic Receptors 23
III. Evidence Supporting Alterations of DA Systems in Schizophrenia 26
A. Pharmacological Evidence 26
B. Postmortem Studies 30
C. Imaging Studies 32
IV. Conclusions 42
References 43
Chapter 2: The Dopamine System and the Pathophysiology of Schizophrenia: A Basic Science Perspective 58
I. Introduction 59
II. Neuroanatomy of DA Systems 59
III. DA Neuron Activity and Release 62
IV. Cellular Actions of DA 66
V. Roles of DA on Cognitive and Affective Functions 68
VI. Development and Maturation of the DA System 70
VII. DA Deficits in Schizophrenia 72
VIII. Conclusions 75
References 75
Chapter 3: Glutamate and Schizophrenia: Phencyclidine, N-Methyl-D-Aspartate Receptors, and Dopamine–Glutamate Interactions 86
I. Introduction 87
II. Glutamatergic Physiology 88
A. Glutamate-Dopamine Comparisons 89
B. Glutamate Receptors 89
C. NMDA Receptors 89
D. AMPA/Kainate Receptors 91
E. Metabotropic Receptors 92
III. Glutamatergic Models of Schizophrenia 92
A. Symptom Patterns Following NMDA Antagonist Administration 93
B. Cognitive Deficits Following NMDA Antagonist Treatment 95
C. In Vivo Findings in Schizophrenia Based on Dopamine Receptor Occupancy 96
D. Postmortem Findings 98
IV. Clinical Studies with NMDA Agonists 98
A. NMDA Receptor Glycine-Site Agonists 100
B. Glycine Transport Inhibitors 103
C. Other Ionotropic Targets 105
D. Metabotropic Receptors 106
E. Group I Receptors 106
F. Group II Metabotropic Agonists 107
V. Potential Causes of Glutamatergic Dysfunction in Schizophrenia 107
A. Dopamine-Glutamate Interactions 108
B. Linkage-Association Studies in Schizophrenia 111
C. Environmental and Neurochemical Factors 112
VI. Future Research and Treatment Implications 113
Acknowledgments 113
References 113
Chapter 4: Deciphering the Disease Process of Schizophrenia: the.Contribution of Cortical Gaba Neurons 126
I. Working Memory Impairments: A Core Feature of Schizophrenia 126
II. Working Memory Impairments and Altered GABA Neurotransmission in the DLPFC 127
III. Potential Pathogenetic Mechanisms for Cell Type-Specific Alterations in GABA Neurons 135
A. Reduced Excitatory Drive via NMDA Receptors 135
B. Reduced Neurotrophin Signaling 136
IV. Connecting Alterations in PV-Positive Neurons to Working Memory Impairments: Decreased Gamma Band Synchrony in Schizophrenia 139
V. Treatment Implications 140
Acknowledgments 141
References 141
Chapter 5: Alterations of Serotonin Transmission in Schizophrenia 150
I. Introduction 150
II. Alteration of 5-HT Receptors in Schizophrenia 151
A. 5-HT Transporters 151
B. 5-HT1A Receptors 158
C. 5-HT2 Receptors 159
D. Other Receptors 161
III. Pharmacological Manipulation of 5-HT Transmission in Schizophrenia 158
A. 5-HT Precursors 158
B. 5-HT Depleting Agents 158
C. 5-HT2A Agonism: LSD and "Model" Psychosis 159
D. 5-HT2A Antagonism, Clozapine, and Atypicality 161
E. Action of Antipsychotic Drugs at Other Serotonergic Receptors 164
IV. 5-HT-DA Interactions Relevant to Schizophrenia 166
A. VTA DA Neurons Activity 166
V. Discussions 168
References 170
Chapter 6: Serotonin and Dopamine Interactions in Rodents and Primates: Implications for Psychosis and Antipsychotic Drug Development 182
I. Introduction 183
II. Dopamine and 5-HT Receptors 184
III. Psychomotor Stimulants: A Dopamine-Serotonin Interaction "Case Study" 185
IV. Monoaminergic Nuclei Interactions 187
V. Serotonin and Dopamine in the Thalamus 189
VI. Dopamine and Serotonin in the Striatum 191
VII. Dopamine and Serotonin in the Hippocampal Formation 193
VIII. Dopamine and Serotonin in the Prefrontal Cortex/Neocortex 194
IX. Animal Models 198
X. Conclusions 200
References 200
Chapter 7: Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia 210
I. Introduction 211
II. ACh in Brain Regions Implicated in Schizophrenia 212
A. Cholinergic Pathways Within the Ventral Striatum 214
B.Cholinergic Projections in Prefrontal Cortex and Hippocampus 215
III. Physiology of ACh Circuits and Signaling in Brain Regions Implicated in Schizophrenia Pathology 215
A. ACh Receptors in the CNS 215
B. Physiology of ACh Circuits in Striatum 217
C. Physiology of ACh Circuits in PFC and Hippocampus 219
IV. Developmental and Genetic Deficits in Schizophrenia That May Influence Function and Assembly of Cholinergic Systems 220
A. Development of Cholinergic Systems 220
B. Potential Role of Neuregulin 1 221
V. Clinical and Preclinical Evidence for Deficits in Components of Brain Cholinergic Systems in Schizophrenia 223
A. Deficits in Components of Muscarinic Cholinergic Transmission 223
B. Deficits in Components of Nicotinic Cholinergic Transmission 224
C. Deficits in Cholinergic Innervation 224
D. Summary 224
VI. Evidence for Cholinergic Contributions to Schizophrenia Pathophysiology from Clinical and Preclinical Psychopharmacology 225
A. ACh Release, Muscarinic Blockade, Partial Agonists, and "Atypicality" 225
B. Both Procholinergic and Anticholinergic Compounds May Ameliorate or Worsen Different Symptom Domains 226
C. Nicotine Ameliorates a Wide Range of Deficits Seen in Schizophrenia 228
D. Despite Clear Effects of Other Cholinergic Compounds, Cholinesterase Inhibitors Are Not Proven Adjuncts in the Treatment of Schizophrenia 229
VII. Conclusions 230
References 231
Chapter 8: Schizophrenia and the alpha7 Nicotinic Acetylcholine Receptor 242
I. Introduction 243
II. Neurobiological and Neurogenetic Evidence for a Link Between the alpha7 Nicotinic Acetylcholine Receptor and Schizophrenia 243
III. The Prototypic alpha7 Nicotinic Agonist, Nicotine, and Schizophrenia 245
IV. The Search for an alpha7 Nicotinic Acetylcholine Receptor Agonist 250
V. The Phase 1 Study of DMXBA in Schizophrenia 251
References 254
Chapter 9: Histamine And Schizophrenia 264
I. Introduction 265
II. The Histaminergic Neuronal System 266
A. Organization 266
B. Metabolism of Histamine 268
C. Histamine Receptors 271
D. Histaminergic Neuron Activity and Its Control 277
E. Physiological Roles of Histaminergic Neurons 279
III. Changes in the Histaminergic System in Schizophrenia 281
A. Genetic Studies 281
B. Histamine Neuron Activity 282
IV. Interactions of Antipsychotic Drugs with the Histaminergic System 284
A. Interactions of APDs with Histamine Receptors 284
B. Modulation of Histamine Neuron Activity by APDs 286
V. Role of Histaminergic Neurons in Schizophrenia 286
VI. Conclusions 289
References 289
Chapter 10: Cannabinoids and Psychosis 306
I. Introduction 307
II. Ancedotal Reports 308
A. Autobiographical Accounts 308
B. Surveys of Cannabis Users 310
C. Psychosis in Cannabis Users from Community Samples 311
D. Naturalistic Case Series 311
III. Epidemiological Studies 314
IV. Pharmacological Studies 320
V. Cannabis and Psychosis: Causality 329
VI. Cannabinoid Receptor Dysfunction and Psychotic Disorders 331
VII. Summary and Conclusions 334
Acknowledgments 335
References 335
Chapter 11: Involvement of Neuropeptide Systems in Schizophrenia: Human Studies 344
I. Introduction 345
II. Cholecystokinin 346
III. Corticotropin-Releasing Factor 354
IV. Interleukins 361
V. Neurotensin 363
VI. Neuropeptide Y 365
VII. Opioid Peptides 366
A. Endorphins 366
B. Dynorphin 367
C. Enkephalins 367
VIII. Secretin 368
IX. Somatostatin 368
X. Vasoactive Intestinal Peptide 369
XI. Tachykinins 369
XII. Thyrotropin-Releasing Hormone 370
XIII. Other Peptides 371
XIV. Conclusions 373
Acknowledgments 374
References 374
Chapter 12: Brain-Derived Neurotrophic Factor in Schizophrenia and Its Relation With Dopamine 394
I. Introduction 394
II. Genetic Studies 396
III. BDNF in the Serum of Patients with Schizophrenia 399
IV. BDNF and TrkB Receptor in the Brain of Patients with Schizophrenia 399
V. Dopamine-BDNF Interactions 402
A. BDNF Supports the Survival and the Differentiation of Dopaminergic Neurons 402
B. BDNF in the GABA-Containing Local Circuit Neurons of the Prefrontal Cortex 402
C. Functional Interplay Between BDNF and Dopamine 403
D. BDNF Controls the Expression of the Dopamine D3 Receptor 403
VI. Conclusions 405
References 406
Chapter 13: Schizophrenia Susceptibility Genes: in Search of A Molecular Logic and Novel Drug Targets for A Devastating Disorder 414
I. The Genetic Component of Schizophrenia 415
II. Genes Identified Through Systematic Follow-Up of Linkage Signals 416
A. Proline Dehydrogenase 416
B. Dystrobrevin-Binding Protein 1 418
C. Neuregulin 1 419
D. G72 420
E. Disrupted in Schizophrenia 1 420
F. Carboxyl-Terminal PDZ Ligand of Neuronal Nitric Oxide Synthase 421
G. ZDHHC8 421
H. Trace Amine Receptor 6 422
I. Epsin 4 422
J. (GABA)A Receptor Subunit Gene Cluster 422
III. Other Candidate Genes 423
A. Catechol-O-Methyltransferase 423
B. Regulator of G-Protein Signaling 4 423
C. Calcineurin Gamma Catalytic Subunit 424
D. AKT1 424
IV. Areas of Caution in the Interpretation and Generalization of Genetic Findings 425
V. Future Directions of the Genetic Research: Advancing Our Understanding of How the Specific Genetic Factors Contribute Biologically to the Disease Process 426
A. Animal Models 427
B. Genetic Interactions 428
C. Understanding Disease Pathophysiology 429
D. Mechanism-Based Therapies 430
Acknowledgments 431
References 431
Index 440
Contents of Recent Volumes 456