Neve The Dopamine Receptors

2. Auflage 2010
ISBN: 978-1-60327-333-6
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 648 Seiten

Reihe: The Receptors

As sites of action for drugs used to treat schizophrenia and Parkinson’s disease, dopamine receptors are among the most validated drug targets for neuropsychiatric disorders. Dopamine receptors are also drug targets or potential targets for other disorders such as substance abuse, depression, Tourette’s syndrome, and attention deficit hyperactivity disorder. Updated from the successful first edition, "The Dopamine Receptors" serves as a reference work on dopamine receptors while also highlighting the areas of research that are most active today. To achieve this goal, authors have written chapters that set a broad area of research in its historical context, rather than focusing on the research output of their own laboratories.

Autoren/Hrsg.

Neve, Kim

Inhaltsverzeichnis

1;The Dopamine Receptors;1
2;Preface;5
3;Contents;6
4;Contributors;8
5;1 Historical Overview: Introduction to the Dopamine Receptors;12
5.1;1.1 Introduction;12
5.2;1.2 Membrane Stabilization by Antipsychotics;13
5.3;1.3 Therapeutic Concentrations of Antipsychotics;14
5.4;1.4 Discovery of the Antipsychotic Dopamine Receptor;15
5.5;1.5 Nomenclature of Dopamine Receptors;16
5.6;1.6 Antipsychotic Accelerated Turnover of Dopamine;19
5.7;1.7 The Dopamine Hypothesis of Schizophrenia, and Dopamine Receptors in the Human Brain;20
5.8;1.8 Key Advances Related to Dopamine Receptors;22
5.9;1.9 Is D2High the Unifying Mechanism for Schizophrenia?;24
5.10;References;27
6;2 Gene and Promoter Structures of the Dopamine Receptors;33
6.1;2.1 Dopamine Receptors;34
6.2;2.2 D2-Like Dopamine Receptor Genes ;37
6.2.1;2.2.1 D2 Dopamine Receptor Genes;37
6.2.1.1;2.2.1.1 Gene Structure and Organization;37
6.2.1.2;2.2.1.2 Promoter Structure and Transcriptional Regulation;38
6.2.2;2.2.2 D3 Dopamine Receptor Genes;40
6.2.2.1;2.2.2.1 Gene Structure and Organization;40
6.2.2.2;2.2.2.2 Promoter Structure and Transcriptional Regulation;41
6.2.3;2.2.3 D4 Dopamine Receptor Genes;43
6.2.3.1;2.2.3.1 Gene Structure and Organization;43
6.2.3.2;2.2.3.2 Promoter Structure and Transcriptional Regulation;44
6.3;2.3 D1-Like Dopamine Receptor Genes ;46
6.3.1;2.3.1 Gene Structure and Organization of D 1 -Like Dopamine Receptors;46
6.3.2;2.3.2 Promoter Region of the D1Dopamine Receptor Gene;47
6.3.3;2.3.3 Promoter Region of the D5 Dopamine Receptor Gene;49
6.4;References;50
7;3 Structural Basis of Dopamine Receptor Activation;57
7.1;3.1 Introduction;57
7.2;3.2 Transmembrane Segments and Activation;59
7.3;3.3 The Binding Site;60
7.4;3.4 Extracellular Loop 2;62
7.5;3.5 GPCR Oligomerization;64
7.5.1;3.5.1 GPCR Oligomerization and Signaling;65
7.5.2;3.5.2 GPCR Oligomers -- Structural Considerations;67
7.5.3;3.5.3 Oligomer Rearrangements upon Activation;68
7.5.4;3.5.4 GPCR Oligomerization and GPCR--G Protein Interactions;69
7.5.5;3.5.5 Consequences of GPCR Oligomerization;70
7.6;References;70
8;4 Dopamine Receptor Subtype-Selective Drugs: D1-LikeReceptors;84
8.1;4.1 Introduction;84
8.2;4.2 Apomorphine;85
8.3;4.3 1-Phenyl-3-Benzazepines;86
8.4;4.4 4-Phenyltetrahydroisoquinolines;88
8.5;4.5 Benzo[a]phenanthridines ;89
8.6;4.6 Abbott Isochromans;91
8.7;4.7 Dinapsoline;93
8.8;4.8 Dinoxyline;94
8.9;4.9 Doxanthrine;94
8.10;4.10 Aminomethylfluorenes;95
8.11;4.11 Defining the D1 Agonist Pharmacophore ;95
8.11.1;4.11.1 The Embedded Dopamine Fragment;96
8.11.2;4.11.2 Design Limitations: The Catechol Moiety;96
8.11.3;4.11.3 Relative Orientation of the Catechol and Pendant Phenyl Rings;98
8.11.4;4.11.4 Linking the Conceptual Model to the 3D Receptor Structure;99
8.12;4.12 The Future;104
8.13;References;104
9;5 Dopamine Receptor Subtype-Selective Drugs: D2-LikeReceptors;109
9.1;5.1 Drugs on the Market and Classical Pharmacological Tools;109
9.2;5.2 D3-Selective Ligands ;111
9.2.1;5.2.1 Aminotetralins and Analogs;112
9.2.1.1;5.2.1.1 Aminotetralins;112
9.2.1.2;5.2.1.2 DPAT Bioisosteres;113
9.2.2;5.2.2 Aminoindans;115
9.2.3;5.2.3 Arylcarboxamidobutyl Substituted Aminotetralins and Analogs Thereof;116
9.2.3.1;5.2.3.1 2-Methoxybenzamides and Analogs Thereof;116
9.2.4;5.2.4 Phenylpiperazines;117
9.2.4.1;5.2.4.1 Variations at x2 ;117
9.2.4.2;5.2.4.2 Variations of the Linker Unit;118
9.2.4.3;5.2.4.3 Variations at x1 ;118
9.2.5;5.2.5 Structural Hybrids;119
9.2.6;5.2.6 D3-Selective Radioligands ;120
9.3;5.3 D4-Selective Ligands ;122
9.3.1;5.3.1 Selective D4Agonists;122
9.3.2;5.3.2 Selective D4 Antagonists;127
9.3.3;5.3.3 Selective D4 Radioligands;130
9.4;References;132
10;6 Dopamine Receptor Signaling: Intracellular Pathwaysto Behavior;144
10.1;6.1 Dopamine Receptor Overview;144
10.1.1;6.1.1 Introduction;144
10.1.2;6.1.2 Expression;145
10.2;6.2 Dopamine Receptor Coupling to G Proteins;146
10.3;6.3 Regulation of Adenylate Cyclase;147
10.3.1;6.3.1 D1-Like Receptor Regulation of Adenylate Cyclase;147
10.3.2;6.3.2 D2-Like Receptor Regulation of Adenylate Cyclase;149
10.3.3;6.3.3 Cyclic AMP-Dependent Signaling and Behavior;149
10.4;6.4 Regulation of Phospholipase C;150
10.4.1;6.4.1 D1-Like Receptor Regulation of Phospholipase C;150
10.4.2;6.4.2 D2-Like Receptor Regulation of PLC;151
10.4.3;6.4.3 Regulation of PLC Through D1 and D2 Receptor Heteromerization ;152
10.4.4;6.4.4 PLC and Behavior;153
10.5;6.5 Arrestin-Dependent Signaling;153
10.5.1;6.5.1 Overview;153
10.5.2;6.5.2 Regulation of MAP Kinases;154
10.5.2.1;6.5.2.1 Overview of MAP Kinases;154
10.5.2.2;6.5.2.2 D1-Like Receptor Regulation of MAP Kinases;155
10.5.2.3;6.5.2.3 D2-Like Receptor Regulation of MAP Kinases;156
10.5.3;6.5.3 Regulation of the Akt/GSK-3 Pathway;158
10.5.3.1;6.5.3.1 Akt/GSK-3 Pathway Overview;158
10.5.3.2;6.5.3.2 D1-Like Receptor Regulation of the Akt/GSK-3 Pathway;159
10.5.3.3;6.5.3.3 D2-Like Receptor Regulation of the Akt/GSK-3 Pathway;159
10.6;6.6 D1-/D2-Like Receptor Cooperativity;160
10.6.1;6.6.1 Overview;160
10.6.2;6.6.2 Heterologous Sensitization;161
10.7;6.7 Autoreceptors;162
10.8;6.8 Summary;165
10.9;References;166
11;7 Dopaminergic Modulation of Glutamatergic Signalingin Striatal Medium Spiny Neurons;181
11.1;7.1 Introduction;181
11.2;7.2 The Classical View of DA Modulation;182
11.2.1;7.2.1 Modulation of Intrinsic Excitability and Glutamatergic Signaling by D 1 Receptors;183
11.2.2;7.2.2 Modulation of Intrinsic Excitability and Glutamatergic Signaling by D 2 Receptors;185
11.3;7.3 Long-Term Depression of Glutamatergic Synaptic Transmission;186
11.4;7.4 Long-Term Potentiation of Glutamatergic Synaptic Transmission;187
11.5;7.5 A Reconciliation of Models of Striatal Synaptic Plasticity;187
11.6;7.6 What Might This Mean for Behavior?;192
11.7;References;193
12;8 Regulation of Dopamine Receptor Traffickingand Responsiveness;198
12.1;8.1 Introduction;198
12.1.1;8.1.1 GPCRs Traffic as Oligomers;199
12.2;8.2 Biosynthesis, Export, and Cell-Surface Stabilization;200
12.2.1;8.2.1 Biosynthesis and Cell-Surface Trafficking of Dopamine Receptors;201
12.2.1.1;8.2.1.1 Calnexin;201
12.2.1.2;8.2.1.2 The Triple Phenylalanine Export Motif and DRiP78;202
12.2.1.3;8.2.1.3 Role of Glycosylation in Receptor Cell-Surface Targeting;203
12.2.2;8.2.2 Stabilization of Dopamine Receptors at the Cell Surface;204
12.2.2.1;8.2.2.1 The NMDA-D1 Receptor Trap ;204
12.2.2.2;8.2.2.2 Role of Scaffolding Proteins in Dopamine Receptor Cell-Surface Stability;205
12.3;8.3 Desensitization;205
12.3.1;8.3.1 D1-Like Receptors;205
12.3.2;8.3.2 D2-Like Receptors;207
12.3.3;8.3.3 The D1--D2 Heteromer;208
12.4;8.4 Internalization;209
12.4.1;8.4.1 D1-Like Receptors;209
12.4.2;8.4.2 D2-Like Receptors;211
12.4.3;8.4.3 The D1-D2 Heteromer;212
12.5;8.5 Resensitization;212
12.5.1;8.5.1 D1-Like Receptors;212
12.5.2;8.5.2 D2-Like Receptors;213
12.6;8.6 Dysregulation of Receptor Trafficking in Health and Disease;214
12.7;8.7 Concluding Remarks;215
12.8;References;216
13;9 Dopamine Receptor-Interacting Proteins;223
13.1;9.1 Introduction to the Signalplex;223
13.1.1;9.1.1 Constituents of the Signalplex -- DRIPs and DRAPs;225
13.1.2;9.1.2 Points of Interaction for DRIPs;225
13.1.3;9.1.3 The Signalplex as the Most Efficient Unit for Transmission;226
13.2;9.2 Discovery Mechanisms;226
13.2.1;9.2.1 Membrane-Based Two-Hybrid and Split-Ubiquitin Systems;227
13.2.2;9.2.2 Biochemical Approaches: GST-Fusion Protein Pull Downs;228
13.2.3;9.2.3 Protein Microarrays;229
13.2.4;9.2.4 Mass Spectroscopy-Coupled Co-immunoprecipitation Proteomics;229
13.3;9.3 Experimental Manipulations;230
13.3.1;9.3.1 Verification and Significance of the Interaction;231
13.3.2;9.3.2 Location of the Interaction -- Tissues and Protein Domains;232
13.3.3;9.3.3 Model Systems and Disease Relevance;233
13.4;9.4 Protein Members of the Dopamine Receptor Signalplex;233
13.4.1;9.4.1 Targeting and Trafficking Proteins;233
13.4.1.1;9.4.1.1 Calnexin;234
13.4.1.2;9.4.1.2 Dopamine Receptor-Interacting Protein-78;235
13.4.1.3;9.4.1.3 ALG-2-Interacting Protein 1;235
13.4.1.4;9.4.1.4 Neurofilament-M;236
13.4.1.5;9.4.1.5 Dynamin-2;236
13.4.1.6;9.4.1.6 GAIP-Interacting Protein, C Terminus;237
13.4.1.7;9.4.1.7 N -Ethylmaleimide-Sensitive Factor;237
13.4.1.8;9.4.1.8 Sorting Nexin-1;238
13.4.1.9;9.4.1.9 G Protein-Coupled Receptor-Associated Sorting Protein;238
13.4.2;9.4.2 Anchoring, Scaffolding, and Adaptor Proteins;239
13.4.2.1;9.4.2.1 Filamin-A;239
13.4.2.2;9.4.2.2 Protein 4.1 N;239
13.4.2.3;9.4.2.3 Spinophilin;240
13.4.2.4;9.4.2.4 Radixin;240
13.4.2.5;9.4.2.5 Multi-PDZ-Domain-Containing Protein 1;240
13.4.2.6;9.4.2.6 Heart-Type Fatty Acid Binding Protein;241
13.4.2.7;9.4.2.7 Caveolin-1;241
13.4.2.8;9.4.2.8 Arrestin;242
13.4.3;9.4.3 Signaling Proteins;242
13.4.3.1;9.4.3.1 Calcium-Dependent Activator Protein for Secretion 1;243
13.4.3.2;9.4.3.2 Neuronal Calcium Sensor-1;243
13.4.3.3;9.4.3.3 S100B;244
13.4.3.4;9.4.3.4 Calcineurin;244
13.4.3.5;9.4.3.5 Calmodulin;244
13.4.3.6;9.4.3.6 Prostate Apoptosis Response 4;245
13.4.3.7;9.4.3.7 Post-synaptic Density 95;245
13.4.3.8;9.4.3.8 Protein Kinases;246
13.4.3.9;9.4.3.9 Protein Kinase C--Interacting Protein 1;246
13.4.3.10;9.4.3.10 Regulator of G Protein Signaling 19;246
13.4.4;9.4.4 Ion Channels and Pumps;247
13.4.4.1;9.4.4.1 Chloride Intracellular Channel 6;247
13.4.4.2;9.4.4.2 Transient Receptor Potential Channel 1;248
13.4.4.3;9.4.4.3 G Protein-Activated Inwardly Rectifying Potassium Channels;248
13.4.4.4;9.4.4.4 Na+,K+-ATPase;248
13.4.4.5;9.4.4.5 AMPA Receptors;249
13.4.4.6;9.4.4.6 NMDA Receptors;249
13.4.4.7;9.4.4.7 GABA Receptors;250
13.4.5;9.4.5 Neurotransmitter Transporters and Other GPCRs;251
13.4.5.1;9.4.5.1 Dopamine Transporter;251
13.5;9.5 Conclusions;251
13.6;References;252
14;10 Dopamine Receptor Oligomerization;259
14.1;10.1 Introduction;260
14.2;10.2 ReceptorReceptor Interactions;260
14.3;10.3 The Concept of Receptor Mosaics;262
14.4;10.4 On the Existence of Different Types of DA Receptor Mosaics;264
14.4.1;10.4.1 DA Type 1 Receptor Mosaics;264
14.4.1.1;10.4.1.1 The D2/D3 Heteromer ;264
14.4.1.2;10.4.1.2 The D1/D2 Heteromer ;264
14.4.1.3;10.4.1.3 The D1/D3 Heteromer ;265
14.4.2;10.4.2 DA Type 2 Receptor Mosaics;266
14.4.2.1;10.4.2.1 The Somatostatin SSTR5/D 2 Receptor Heteromer ;266
14.4.2.2;10.4.2.2 Putative Neuropeptide Receptor/D 2 Heteromers ;266
14.4.2.3;10.4.2.3 The D2-non-7 nAChR Heteromer ;268
14.4.2.4;10.4.2.4 The A2A /D2 Heteromer ;268
14.4.2.5;10.4.2.5 The Putative mGluR5/A2A /D2 Heteromer (High-Order RM2) ;269
14.4.2.6;10.4.2.6 The A2A /D3 Heteromer ;271
14.4.2.7;10.4.2.7 The CB1/D2 Heteromer and the Putative A 2A /D 2/CB High-Order RM2 ;271
14.4.2.8;10.4.2.8 The A1/D1 Heteromer ;272
14.4.2.9;10.4.2.9 The -Opioid Receptor/D1 Heteromer ;273
14.4.2.10;10.4.2.10 The D1/NMDA Receptor Mosaic ;273
14.4.2.11;10.4.2.11 The D2/NMDA Receptor Mosaic ;274
14.4.2.12;10.4.2.12 The D5/GABA-A Receptor Mosaic ;275
14.4.2.13;10.4.2.13 Putative D2-Receptor Tyrosine Kinase Receptor Mosaics ;275
14.5;10.5 General Comments on Receptor Mosaics;275
14.6;10.6 Conclusions;276
14.7;References;277
15;11 Dopamine Receptor Modulation of GlutamatergicNeurotransmission;285
15.1;11.1 Introduction;285
15.2;11.2 Classification of DA and Glutamate Receptors;286
15.3;11.3 Morphological Basis for DA and Glutamate Receptor Interactions in Striatum;286
15.4;11.4 DA Receptors Modulate Neuronal Excitability by Altering Voltage-Gated Conductances;287
15.5;11.5 DA Modulation of Glutamate Release;288
15.6;11.6 DA Modulation of Glutamate Receptor-Mediated Responses;289
15.6.1;11.6.1 DA and D2-like Receptors Decrease AMPA Receptor-Mediated Responses ;289
15.6.2;11.6.2 D1-Like Receptors Can Increase AMPA Receptor-Mediated Responses ;292
15.6.3;11.6.3 DA and D1-Like Receptor Activation Enhances NMDA Receptor-Mediated Responses ;292
15.6.4;11.6.4 D1-Like Receptor Activation Can Depress NMDA Responses by Physical Receptor Interactions;293
15.6.5;11.6.5 The NMDA0D1 Receptor Trap ;294
15.6.6;11.6.6 DA, via D2-Like Receptors, Reduces NMDA Receptor-Mediated Responses ;294
15.7;11.7 Genetic Manipulations of DAGlutamate Receptor Interactions;295
15.8;11.8 A Model of Striatal DAGlutamate Receptor Interactions;296
15.9;11.9 Functional Relevance of DAGlutamate Receptor Interactions;297
15.10;11.10 Conclusions;298
15.11;References;299
16;12 Unraveling the Role of Dopamine Receptors In Vivo:Lessons from Knockout Mice;307
16.1;12.1 Introduction;307
16.2;12.2 Advantages and Drawbacks of the Knockout Technology;308
16.3;12.3 Lessons from KO Mice;309
16.4;12.4 Dopamine Receptors in the Control of Motor Behavior;310
16.4.1;12.4.1 Motor Behavior: D 1 R KO;312
16.4.2;12.4.2 Motor Behavior: D 2 R KO;312
16.4.3;12.4.3 Motor Behavior: D 3 R KO;313
16.4.4;12.4.4 Motor Behavior: D 4 R KO;313
16.4.5;12.4.5 Motor Behavior: D 5 R KO;314
16.5;12.5 Dopamine Receptors and Drugs of Abuse;314
16.5.1;12.5.1 The D 1 R and Drugs of Abuse;315
16.5.2;12.5.2 The D 2 R and Drugs of Abuse;316
16.5.3;12.5.3 The D 3 R and Drugs of Abuse;317
16.5.4;12.5.4 The D 4 R and Drugs of Abuse;318
16.5.5;12.5.5 The D 5 R and Drugs of Abuse;318
16.6;12.6 Dopamine and Growth;319
16.7;12.7 Future Challenges;320
16.8;References;320
17;13 Dopamine Receptors and Behavior: From Psychopharmacology to Mutant Models;327
17.1;13.1 Introduction;327
17.2;13.2 Psychopharmacological Studies;328
17.2.1;13.2.1 D1-Like Receptors and Behavior;329
17.2.2;13.2.2 D2-Like Receptors and Behavior;330
17.3;13.3 D1-like Receptor Family;331
17.3.1;13.3.1 D1 Knockout: Spontaneous Behavior;331
17.3.2;13.3.2 D1 Knockout: Drug-Induced Behavior;333
17.3.3;13.3.3 Interpretation of D1 Knockout Phenotype;335
17.3.4;13.3.4 D5 Knockout: Spontaneous Behavior;340
17.3.5;13.3.5 D5 Knockout: Drug-Induced Behavior;341
17.3.6;13.3.6 Interpretation of D5 Knockout Phenotype;342
17.4;13.4 D2-Like Receptor Family;344
17.4.1;13.4.1 D2 Knockout: Spontaneous Behavior;344
17.4.2;13.4.2 D2 Knockout: Drug-Induced Behavior;346
17.4.3;13.4.3 D2L Knockout;348
17.4.4;13.4.4 Interpretation of D2 and D2L Knockout Phenotypes;349
17.4.5;13.4.5 D3 Knockout: Spontaneous Behavior;352
17.4.6;13.4.6 D3 Knockout: Drug-Induced Behavior;354
17.4.7;13.4.7 Interpretation of D3 Knockout Phenotype;356
17.4.8;13.4.8 D4 Knockout: Spontaneous Behavior;359
17.4.9;13.4.9 D4 Knockout: Drug-Induced Behavior;360
17.4.10;13.4.10 Interpretation of D4 Knockout Phenotype;361
17.5;13.5 Double Knockouts Involving Dopamine Receptors;363
17.5.1;13.5.1 D1/D2 Double Knockout;363
17.5.2;13.5.2 D1/D3 Double Knockout;363
17.5.3;13.5.3 D2/D3 Double Knockout;364
17.6;13.6 Challenges;365
17.7;References;366
18;14 Dopamine Modulation of the Prefrontal Cortexand Cognitive Function;376
18.1;14.1 Introduction;376
18.2;14.2 Basic Anatomy of DA Release;377
18.3;14.3 Behavioral Activation of the Mesocortical DA System;378
18.3.1;14.3.1 Aversive Events;378
18.3.2;14.3.2 Appetitive Events;379
18.3.3;14.3.3 Cognitive Processing;379
18.3.4;14.3.4 Release Conclusions;380
18.4;14.4 DA Receptors in PFC;381
18.5;14.5 Contribution of PFC DA Receptors to Stress;382
18.6;14.6 Contribution of PFC DA Receptors to Cognition;383
18.6.1;14.6.1 DA Modulation of Working Memory;383
18.6.2;14.6.2 How Is DA Improving Working Memory?;385
18.7;14.7 DA Modulation of Working Memory or Working Attention?;386
18.8;14.8 DA Modulation of Response Flexibility;387
18.8.1;14.8.1 D2 Receptors and Response Flexibility;387
18.8.2;14.8.2 How Is DA Modulating Response Flexibility?;390
18.9;14.9 Summary and Conclusions;391
18.10;References;392
19;15 In Vivo Imaging of Dopamine Receptors;402
19.1;15.1 Introduction;402
19.2;15.2 Imaging Dopamine Receptors in Schizophrenia;403
19.2.1;15.2.1 Striatal DA Transmission and Receptors;404
19.2.1.1;15.2.1.1 Dopamine Receptors;404
19.2.1.2;15.2.1.2 Dopamine Transporter;406
19.2.1.3;15.2.1.3 Vesicular Monoamine Transporter;406
19.2.1.4;15.2.1.4 Striatal Amphetamine-Induced DA Release;406
19.2.1.5;15.2.1.5 Baseline Occupancy of Striatal D 2 Receptors by DA;407
19.2.1.6;15.2.1.6 Striatal Aromatic Amino Acid Decarboxylase Activity;407
19.2.2;15.2.2 Extrastriatal D2 Receptors;408
19.2.3;15.2.3 Prefrontal DA Receptors;409
19.2.4;15.2.4 Antipsychotic Drug Occupancy Studies;409
19.3;15.3 Dopamine Receptors in Affective Disorders;411
19.3.1;15.3.1 Major Depressive Disorder;411
19.3.2;15.3.2 Bipolar Disorder;411
19.4;15.4 Social Phobia (Social Anxiety Disorder);412
19.5;15.5 Personality Disorders and Traits;412
19.6;15.6 Attention Deficit Hyperactivity Disorder;413
19.7;15.7 Substance Abuse;413
19.7.1;15.7.1 Cocaine;414
19.7.1.1;15.7.1.1 D2 Receptors;414
19.7.1.2;15.7.1.2 Stimulant-Induced DA Release;414
19.7.1.3;15.7.1.3 DOPA Decarboxylase;415
19.7.1.4;15.7.1.4 DAT;415
19.7.2;15.7.2 Methamphetamine;416
19.7.3;15.7.3 Nicotine;417
19.7.4;15.7.4 Alcohol;418
19.8;15.8 Conclusions;419
19.9;References;421
20;16 Dopamine Receptors and the Treatment of Schizophrenia;434
20.1;16.1 Schizophrenia;435
20.1.1;16.1.1 The Dopamine Hypothesis;435
20.1.2;16.1.2 The Glutamate Hypothesis;437
20.1.3;16.1.3 Integration of the Dopamine and Glutamate Hypotheses;438
20.2;16.2 Classification of Antipsychotic Drugs;438
20.2.1;16.2.1 Typical Antipsychotics;438
20.2.2;16.2.2 Atypical Antipsychotics;439
20.3;16.3 Neuropharmacology of Antipsychotics;440
20.4;16.4 Dopamine Receptors Involved in Antipsychotic Drug Action;441
20.4.1;16.4.1 Role of D2 Receptor Blockade;442
20.4.1.1;16.4.1.1 In Vitro Evidence for an Antipsychotic Action at the D 2 Receptors;442
20.4.1.2;16.4.1.2 Preclinical Evidence for an Antipsychotic Action at the D 2 Receptors;442
20.4.1.3;16.4.1.3 Clinical Evidence for an Antipsychotic Action at the D 2 Receptors;445
20.4.2;16.4.2 Role of D2 Receptor Partial Agonism;446
20.4.3;16.4.3 Role of D1 Receptor Blockade;448
20.4.4;16.4.4 Role of D3 Receptor Blockade;449
20.4.5;16.4.5 Role of D4 Receptor Blockade;450
20.5;16.5 Considerations Critical for Understanding Receptor Involvement in Antipsychotic Action;450
20.5.1;16.5.1 Speed of Onset and Implications for Mechanism;450
20.5.2;16.5.2 Relapse on Withdrawal and Supersensitivity;451
20.5.3;16.5.3 Antagonist vs. Inverse Agonist;453
20.5.4;16.5.4 Fast Dissociation and Transient Occupancy of D 2 Receptors;454
20.5.5;16.5.5 Preferential Limbic D2 Receptor Blockade;455
20.6;16.6 Other Receptors Involved in Antipsychotic Drug Action;455
20.6.1;16.6.1 Role of 5HT 2A Receptor Blockade and 5HT 1A Receptor Activation;456
20.6.2;16.6.2 Role of Drugs Acting on the Glutamate System;457
20.6.3;16.6.3 Role of CB1 Receptor Blockade;458
20.6.4;6.6.4 Role of 1and 2 Adrenergic Receptor Blockade;459
20.6.5;16.6.5 Role of NK3 Receptor Blockade;459
20.7;16.7 Conclusion and Future directions;460
20.8;References;460
21;17 Dopamine Receptor Subtypes in Reward and Relapse;481
21.1;17.1 Introduction;481
21.2;17.2 Dopamine Receptor Subtypes that Mediate Primary Reward;483
21.2.1;17.2.1 Self-Administration of D 1 -Like and D 2 -Like Receptor Agonists;484
21.2.2;17.2.2 Conditioned Place Preference with D 1 -Like and D 2 -Like Receptor Agonists;487
21.3;17.3 Modulation of Natural and Endogenous Reward by Dopamine Receptor Subtypes;488
21.3.1;17.3.1 Modulation of Food, Water, and Sexual Reward by Dopamine Receptor Subtypes ;488
21.3.2;17.3.2 Modulation of Brain Stimulation Reward by Dopamine Receptor Subtypes;490
21.3.3;17.3.3 Modulation of Conditioned Reward by Dopamine Receptor Subtypes;492
21.4;17.4 Modulation of Drug Self-Administration by Dopamine Receptor Subtypes;493
21.4.1;17.4.1 Modulation of Psychostimulant Self-Administration by Dopamine Receptor Subtypes;494
21.4.2;17.4.2 Modulation of Opiate and Nicotine Self-Administration by Dopamine Receptor Subtypes;498
21.4.3;17.4.3 Modulation of Alcohol Self-Administration by Dopamine Receptor Subtypes;500
21.5;17.5 Dopamine Receptor Subtypes in Relapse to Drug-Seeking Behavior;501
21.5.1;17.5.1 Modulation of Cocaine Seeking by Dopamine Receptor Subtypes: Systemic Administration;503
21.5.2;17.5.2 Modulation of Cocaine Seeking by Dopamine Receptor Subtypes: IntraCranial Administration;505
21.5.3;17.5.3 Modulation of Heroin, Nicotine, and Alcohol Seeking by Dopamine Receptor Subtypes;508
21.6;17.6 Future Directions;509
21.7;References;512
22;18 Dopamine Receptors and the Treatment of Parkinson'sDisease;527
22.1;18.1 Dopamine Receptors in the Pathology of Parkinsons Disease;528
22.1.1;18.1.1 Expression Pattern of DA Receptors in the Forebrain of Rodents and Primates;529
22.1.2;18.1.2 Changes in Dopamine Receptor Expression in Parkinson's Disease;532
22.1.3;18.1.3 Modifications of Dopamine Receptor Signaling in Parkinson's Disease;533
22.1.3.1;18.1.3.1 Changes in the Responsiveness of Signaling Pathways Caused by DA Depletion;533
22.1.3.2;18.1.3.2 The Effects of Dopamine Depletion on Transcription Factors;536
22.1.3.3;18.1.3.3 Changes in the Basal Activity or Expression of Signaling Proteins;537
22.1.3.4;18.1.3.4 Changes in D2 Receptor-Mediated Signaling;538
22.1.3.5;18.1.3.5 Possible Role of the Synergism Between D 1 and D 2 Receptors in Parkinson's Disease;541
22.1.4;18.1.4 Molecular Mechanisms of the Dopamine Receptor Supersensitivity Induced by Dopaminergic Denervation;542
22.2;18.2 DA Receptors and Treatment of the Motor Symptoms of Parkinsons Disease;546
22.2.1;18.2.1 Dopamine Replacement Therapy and the Pathophysiology of l -DOPA-Induced Dyskinesia;546
22.2.2;18.2.2 The Effects of l-DOPA Treatment on Dopaminergic Signaling;548
22.2.2.1;18.2.2.1 Signaling Consequences of Dopamine Depletion Normalized by l -DOPA;548
22.2.2.2;18.2.2.2 Molecular Consequences of Dopamine Depletion Unchanged or Augmented by l -DOPA;550
22.2.2.3;18.2.2.3 Effects of l-DOPA in ''Dyskinetic'' Versus ''Non-dyskinetic'' Animal;551
22.2.2.4;18.2.2.4 Effects of l-DOPA on Immediate Early Genes and Transcription Factors;553
22.2.3;18.2.3 Dopamine Agonists in the Treatment of Parkinson's Disease;556
22.2.3.1;18.2.3.1 Dyskinesia-Inducing Properties of DA Agonists;556
22.2.3.2;18.2.3.2 Why Are Clinically Used DA Agonists Less Efficacious than l -DOPA?;557
22.2.3.3;18.2.3.3 Continuous Versus Pulsatile Stimulation of DA Receptors;559
22.2.4;18.2.4 Molecular Mechanisms of l-DOPA-Induced Dyskinesia;560
22.2.4.1;18.2.4.1 Critical Elements in the Development of l -DOPA-Induced Dyskinesia;560
22.2.4.2;18.2.4.2 DA Receptor Supersensitivity and l -DOPA-Induced Dyskinesia;561
22.2.4.3;18.2.4.3 Molecular Mechanisms of the Dopaminergic Supersensitivity in l -DOPA-Induced Dyskinesia;562
22.2.5;18.2.5 Mechanisms of l-DOPA-Induced Motor Fluctuations;565
22.3;18.3 Dopamine Receptors and Neuroprotection in Parkinsons Disease;567
22.4;18.4 Conclusions;569
22.5;References;570
23;19 Dopamine Receptor Genetics in Neuropsychiatric Disorders;587
23.1;19.1 Introduction;587
23.2;19.2 Characteristics of Dopamine Receptors;588
23.2.1;19.2.1 Structural Characteristics of Dopamine Receptors;590
23.2.2;19.2.2 Pharmacological Characteristics of Dopamine Receptors;590
23.3;19.3 Dopamine Receptor Function and Neuropsychiatric Disease;591
23.3.1;19.3.1 D1 Receptors;592
23.3.2;19.3.2 D2 Receptors;595
23.3.3;19.3.3 D3 Receptors;602
23.3.4;19.3.4 D4 Receptors;607
23.3.5;19.3.5 D5 Receptors;616
23.4;19.4 Conclusion;620
23.5;References;621
24;Index;635