The Dopamine Receptors (eBook)

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