Principles of

Neuropsychopharmacology

Robert S. Feldman
University of Massachusetts

Jerrold S. Meyer
University of Massachusetts

Linda F. Quenzer
University of Hartford

Sinauer Associates, Inc., Publishers

Sunderland, Massachusetts

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or disseminated in any form without express written permission from the publisher.
Brief Contents

Basic Concepts xxi

1. Principles of Pharmacology 1
2. Methods in Neuropsychopharmacology 27
3. Neurons and Glial Cells 75
4. Functional Neuroanatomy 111
5. Neurophysiological Mechanisms 155
6. Synaptic Structure and Function 185

Neurotransmitter Systems 233

7. Acetylcholine 235
8. Catecholamines 277
9. Serotonin 345
10. The Amino Acid Neurotransmitters and Histamine 391
11. Peptide Neurotransmitters 455

Major Drug Classes 493

12. The Opiates 495
13. Stimulants: Amphetamine and Cocaine 549
14. Stimulants: Nicotine and Caffeine 591
15. Alcohol 625
16. Sedative–Hypnotic and Anxiolytic Drugs 673
17. Mind-Altering Drugs 731

Clinical Applications 781

18. Schizophrenia 783
19. Affective Disorders 819
20. Parkinson’s Disease and Alzheimer’s Disease 861

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Contents
BASIC CONCEPTS xxi Part II Techniques in Behavioral Pharmacology 57
Animal Care Guidelines 57
1. Principles of Pharmacology 1 New Drug Evaluation 58
Determinants of Drug Action 1 Primary Evaluation 59
Route of Administration 2 Measures of Motor Activity 59
Drug Absorption and Distribution 5 Interactions with Other Drugs 60
Effects of Age, Sex, and Body Size 6 Secondary Evaluation 60
Drug Transport across Membranes 6 Measures of Analgesia 60
Drug Binding 12 Tests of Learning and Memory 61
Depot Binding 12 Measures of Spatial Learning 63
Receptor Binding 13 Tests of Delayed Reaction 64
Law of Mass Action 13 Measures of Anxiety 65
Dose–Response Relationships 14 Schedule-Controlled Behavior 66
Side Effects and the Therapeutic Index 15 Positive Reinforcement Schedules 67
Receptor Antagonists 16 Drug Effects and Baseline Response Rate 69
Drug Inactivation and Elimination 17 Negative Reinforcement and Punishment 69
Drug Clearance 17 Drugs Used as Discriminative Stimuli 71
Drug Metabolism 17 Part II Summary 73
Renal Excretion 19
Tolerance and Sensitization 20 3. Neurons and Glial Cells 75
Cross Tolerance 21 Neuron Function 75
Drug Disposition Tolerance 21 Neuron Morphology 76
Pharmacodynamic Tolerance 22 Microanatomy of Neurons 77
Behavioral Tolerance 22 The Cell Body 77
Tolerance by Indirect Mechanisms 23 The Nucleus and Nucleolus 78
Sensitization or Reverse Tolerance 24 Mitochondria 80
Placebo Effects 24 Peroxisomes 80
Summary 25 Lysosomes and Endosomes 81
The Neuronal Cytoskeleton: Microtubules,
2. Methods in Neuropsychopharmacology 27 Neurofilaments, and Actin Filaments 81
Part I Neurochemical Techniques 28 Genetic Activity within Neurons 82
Neurotransmitter Measurement and Localization 28 DNA Strucutre 82
Histofluorescent Techniques 28 The Permanence of the Genetic Code 83
Immunocytochemistry 29 Gene Transcription 83
Autoradiography 31 Gene Translation 85
In Situ Hybridization 31 Protein Destination 87
Immunoassay Techniques 35 The Role of the Endoplasmic Reticulum 87
Colunm Chromatography 36 The Smooth Endoplasmic Reticulum and the Golgi
In Vivo Microdialysis 39 Apparatus 87
Electrochemistry 41 Dendrites 88
Receptor Measurement and Localization 43 Learning and Dendritic Changes 90
Radioligand Binding 43 Axons 90
Interpretation of Ligand–Receptor Binding 43 Axon Dimensions 91
Ligand–Receptor Kinetics 46 Axonal Collaterals 92
Mathematical Transformations and Data Plotting 48 Axonal Transport 92
Receptor Autoradiography 49 The Nerve Cell Membrane 95
Receptor Isolation and Labeling 50 Membrane Structure 95
Brain Metabolism and Imaging Methods 51 Transport across Membranes 99
Enzyme Kinetics 51 Neuroglia 103
Autoradiography of Dynamic Cell Processes 52 Myelin and Myelination 104
In Vivo Imaging 54 Myelin Formation 105
Part I Summary 56 Chemical Factors in Myelination 106
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x Contents

Nodes of Ranvier 108 Determinants and Effects of Nerve Impulse

Myelin Function 108 Frequency 180
Myelin Pathology 109 Information Transmission 180
Summary 109 Refractory Periods 181
Impulse Transmission between Neurons 182
4. Functional Neuroanatomy 111 Part II Summary 184
Organization of the CNS 112
Part I The Spinal Cord, Brain Stem, Diencephalon, 6. Synaptic Structure and Function 185
Limbic System, and Basal Ganglia 113 Psychotropic Drugs and Synapses 185
Morphology of Synapses 186
The Spinal Cord 113
Synaptic Ultrastructure 187
The Brain Stem 116
Quantitative Considerations 190
The Cranial Nerves 116
Qualitative Considerations 191
The Cerebellum 119
Axoaxonic Synapses and Presynaptic Inhibition 192
The Reticular Formation 121
Neuroeffector Junctions 194
The Midbrain 122
Gap Junctions 196
The Diencephalon 125
Neurochemistry of Synaptic Transmission 197
The Thalamus 125
The Identification of Neurotransmitters 198
The Hypothalamus and Limbic System 126
The Chemical Structure of Neurotransmitters 200
The Basal Ganglia 130
Neurotransmitter Release 201
Part I Summary 132
Neurotransmitter Receptors and Signal Transduction
Part II The Cerebral Cortex 132 Mechanisms 208
The Telencephalon 132 The Concept of Receptor Subtypes 208
The Cerebral Cortex 133 Receptor Superfamilies 208
Function of the Corpus Callosum 133 Structure and Mechanism of G Proteins 209
Cortical Cell Morphology 134 Direct Interactions of G Proteins with Ion Channels
Organization of the Cortex 135 211
Functional Localization in the Neocortex 136 Receptor Tyrosine Kinases 212
Cortical Control of Movement 139 Second Messenger Systems 212
Language Functions of the Cerebral Cortex 142 Cyclic AMP 213
Part II Summary 144 Cyclic GMP 215
Part III The Autonomic Nervous System 144 Calcium and Calmodulin 217
The Enteric System 146 Phosphoinositide-Derived Second Messengers 219
The Parasympathetic System 146 Messenger Substances Related to Arachidonic Acid
The Sympathetic System 149 221
Part III Summary 152 Divergence and Convergence of Transmitter
Action 222
5. Neurophysiological Mechanisms 155 Neurotransmitters and Gene Regulation in the
Part I Bioelectric Properties of Neurons 155 Nervous System 222
Neuron Excitability 155 Termination of Transmitter Action 224
The Membrane Resting Potential 156 Autoreceptors and Heteroreceptors 225
Measurement of the Resting Potential 158 Synaptic Plasticity 227
Establishment of the Resting Potential 159 Reflexive and Instinctive Behaviors 227
The Nernst Equation 161 Learning 228
Ion Involvement during Changes in Membrane Mechanisms of Synaptic Plasticity 228
Potentials 161 Summary 231
The Sodium–Potassium Pump 162
Part I Summary 163 NEUROTRANSMITTER SYSTEMS 233
Part II Action Potentials: Development, 7. Acetylcholine 235
Propagation, and Behavior 163 Part I Acetylcholine Neurochemistry: Synthesis,
Determinants of Ion Permeability 163 Storage, Release, and Inactivation 235
Carrier Proteins 163
Acetylcholine Synthesis 237
Membrane Channels 164
Choline Acetyltransferase 237
Channel Gating Mechanisms 165
The Sources of Acetylcholine Precursors 237
Voltage-Gated Channels 168
Regulation of Acetylcholine Synthesis 238
The Generation and Propagation of Action
Acetylcholine Storage and Release 239
Potentials 171
Miniature End-Plate Potentials 239
Passive Electrical Conduction by Neurons 171
The Source of Quantally Released Acetylcholine 240
The Generation of Electrotonic Potentials 172
Cholinergic Vesicles and Biochemical Pools of
The Mechanics of Action Potentials 175
Acetylcholine 249
Propagation of the Action Potential 178
Acetylcholine Inactivation 242
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Cholinesterases 242
Properties of Acetylcholinesterase 242
Noncholinergic Functions of Acetylcholinesterase 244
Drugs That Affect Acetylcholine Synthesis, Storage,
Release, and Inactivation 244
Drugs That Block Acetylcholine Synthesis 244
Drugs That Affect Acetylcholine Storage and Release
245
Drugs That Affect Acetylcholine Inactivation 246
Part I Summary 248
Part II Anatomy and Physiology of Cholinergic
Systems 249
Distribution of Cholinergic Neurons and Their
Connections 249
Cholinergic Systems within the CNS 249
Location of Cholinergic Cell Groups and Pathways in
the Brain 249
Peripheral Cholinergic Systems 251
Acetylcholine Receptors 251
Acetylcholine Receptor Subtypes 251
Nicotinic Receptors 252
Muscarinic Receptors 256
Localization and Physiological Effects of Nicotinic and
Muscarinic Receptors 259
Regulation of Neurotransmitter Release by Cholinergic
Autoreceptors and Heteroreceptors 262
Drugs That Affect Cholinergic Receptors 263
General Cholinergic Agonists 263
Nicotinic Agonists and Antagonists 263
Muscarinic Agonists and Antagonists 265
Part II Summary 267
Part III Behavioral Functions of Acetylcholine
268
The Role of Acetylcholine in Sleep and Arousal 268
Acetylcholine and Ascending Arousal Systems 268
Acetylcholine and Sleep 269
Cognitive Functions of Acetylcholine 271
Effects of Cholinergic Drugs on Learning, Memory, and
Attention 271
Acetylcholine, Aging, and Memory 273
Role of the Basal Forebrain Cholinergic System 273
Part III Summary 275
8. Catecholamines 277
Part I Catecholamine Neurochemistry: Synthesis,
Storage, Release, and Inactivation 278
Basic Aspects of Catecholamine Synthesis 278
Tyrosine Hydroxylase 278
Aromatic Amino Acid Decarboxylase 281
Dopamine -Hydroxylase 282
Phyenylethanolamine N-Methyltransferase 283
Regulation of Catecholamine Synthesis 283
Acute Regulation of Tyrosine Hydroxylase 283
Long-Term Regulation of Tyrosine Hydroxylase:
Trans-Synaptic Induction 286
Regulation of Dopamine -Hydroxylase and
Phenylethanolamine N-Methyltransferase 288
Summary of Catecholamine Synthesis Regulation 289
Catecholamine Storage and Release 290
Catecholamine Storage Mechanisms 290
Catecholamine Release 292
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Contents xi
Catecholamine Inactivation 294
Catecholamine Uptake 294
Catecholamine Uptake Inhibitors 294
Catabolism of Catecholamines 296
Measurement of Catecholamine Turnover 301
Catecholamine Neurotoxins 301
Part I Summary 302
Part II Dopamine Systems: Anatomy, Physiology,
and Behavior 303
Distribution of Dopamine Neurons in the Nervous
System 303
Methods Used to Map Dopaminergic Pathways 303
Anatomy of Central Dopaminergic Systems 304
Peripheral Dopaminergic Systems 307
Fine Structure of Dopamine Synapses: Implications for
Dopaminergic Neurotransmission 307
Coexistence of Dopamine with Other Transmitters 307
Electrophysiology of Dopaminergic Neurons 308
Dopamine Receptors 308
The D1-Like Receptor Subfamily 309
The D2-Like Receptor Subfamily 310
Dopamine Receptor Mechanisms 313
Dopamine Autoreceptors 315
The D2 Receptor and Dopaminergic Behavioral
Supersensitivity 316
Behavioral Effects of Selective Dopamine Receptor
Agonists and Antagonists 318
The Role of Dopamine in Motivational Processes
319
Basic Concepts of Motivation: Reward and
Reinforcement 319
Dopamine and Brain Self-Stimulation 320
Self-Administration of and Place Conditioning with
Dopaminergic Drugs 321
Dopamine in Learning and Motivation: Theoretical
Formulations 321
Part II Summary 323
Part III Norepinephrine and Epinephrine Systems:
Anatomy, Physiology, and Behavior 324
Distribution of Noradrenergic and Adrenergic
Neurons in the Nervous System 324
Methods Used to Map Noradrenergic and Adrenergic
Pathways 324
Anatomy of Central Noradrenergic Systems 324
Anatomy of Central Adrenergic Systems 326
Norepinephrine and Epinephrine in the Peripheral
Nervous System 326
Coexistence of Norepinephrine with Other
Transmitters 327
Electrophysiology of Noradrenergic Neurons 327
Adrenergic Receptors 327
-Adrenergic Receptors 328
-Adrenergic Receptors 330
Adrenergic Receptor Mechanisms 334
Adrenergic Autoreceptors 336
Adrenergic Receptors in Nonneural Cells 336
-Receptor Regulation 337
Therapeutic Use of Adrenergic Drugs 338
Use of Catecholamines as Drugs 339
Adrenergic Agonists 339
Adrenergic Antagonists 340
xii Contents

Behavioral Functions of Norepinephrine 340 Glutamate and Aspartate as Neurotransmitters 392

The Role of Norepinephrine in Attention, Arousal, and Synthesis and Metabolism of Glutamate and
Vigilance 340 Aspartate 392
Regulation of Hunger and Feeding Behavior 341 Synthesis 392
Part III Summary 343 Catabolism 395
Storage, Release, and Uptake of Glutamate and
9. Serotonin 345 Aspartate 396
Part I Serotonin Neurochemistry: Synthesis, Vesicular Storage and Release 396
Storage, Release, and Inactivation 346 Synaptic Uptake 396
Serotonin Synthesis 346 Localization of Glutamatergic and Aspartatergic
Tryptophan Hydroxylase 346 Pathways 396
Tryptophan Hydroxylase Inhibitors 346 Excitatory Amino Acid Receptors 398
5-Hydroxytryptophan Decarboxylation 348 Ionotropic Receptors 398
Regulation of Serotonin Synthesis 348 Metabotropic Receptors 404
Serotonin Storage and Release 352 Distribution of Excitatory Amino Acid Receptors 404
Mechanisms of Storage and Release 352 The Role of Excitatory Amino Acids in Neural and
Serotonin-Releasing Drugs 352 Behavioral Functions 405
Regulation of Serotonin Release by Autoreceptors 353 Amino Acid Excitotoxicity 405
Serotonin Inactivation 355 Excitatory Amino Acids, Synaptic Plasticity, and
Serotonin Uptake 355 Learning 410
Serotonin Uptake Inhibitors 356 Part I Summary 416
Metabolism of Serotonin 356 Part II Inhibitory Amino Acids: GABA 417
Measurement of Serotonin Turnover 357
The Discovery of GABA and Its Identification as a
Serotonin Neurotoxins 358
Neurotransmitter 417
Blood Platelets as a Model for Serotonergic
Synthesis and Metabolism of GABA 417
Neurons 360
Regulation of GABA Synthesis 418
Part I Summary 361
Drugs That Affect GABA Synthesis and Metabolism 420
Part II Anatomy and Physiology of Serotonergic Storage, Release, and Uptake of GABA 421
Systems 361 Vesicular Storage and Release 421
Distribution of Serotonin Neurons in the Nervous Synaptic Uptake 421
System 361 GABA Distribution 422
Serotonergic Pathways in the Brain 362 Anatomy of GABA Pathways 422
Location of Other Serotonergic Cells 365 GABAA Receptors 423
Electrophysiology of Serotonergic Neurons 366 Pharmacology of the GABAA Receptor Complex 423
Serotonin Receptors 367 Benzodiazepines and the GABAA Receptor 425
Serotonin Receptor Subtypes 367 Barbiturates and the GABAA Receptor 429
5-HT1 Receptors 369 Steroid Hormones and the GABAA Receptor 429
5-HT2 Receptors 373 Ethanol and the GABAA Receptor 430
5-HT3 Receptors 376 Structure of the GABAA Receptor Complex 431
5-HT4 Receptors 377 Regulation of GABAA Receptors 433
Serotonin Receptor Mechanisms 378 GABAB Receptors 434
Part II Summary 379 Pharmacology of GABAB Receptors 434
Part III Behavioral Functions of Serotonin 380 GABAB Receptor Mechanisms 435
GABAC Receptors 435
Feeding Behavior and Body Weight Reulation 380
The Role of GABA in Physiological and Behavioral
Changes in Serotonergic Acticity Associated with
Functions 435
Feeding 380
Presynaptic Inhibition 436
Effects of Serotonergic Drugs on Food Intake 380
GABA and Epilepsy 436
Serotonin and Obesity 382
Part II Summary 439
Serotonin and Aggression 383
The Role of Serotonin in Animal Aggression 383 Part III Inhibitory Amino Acids: Glycine 441
Serotonin and Human Aggression 386 Synthesis and Metabolism of Glycine 441
Is There a Link between Animal and Human Research? Storage, Release, and Uptake of Glycine 441
387 Anatomy of Glycine Pathways 442
Serotonin and Obsessive–Compulsive Disorder 388 The Glycine Receptor 442
Part III Summary 389 Glycine Pharmacology and Behavioral Functions 442
Part III Summary 444
10. The Amino Acid Neurotransmitters and
Histamine 391 Part IV Histamine 445
Histamine Synthesis, Release, and Inactivation 445
Part I Excitatory Amino Acids: Glutamate and
Synthesis and Release 445
Aspartate 391
Sources and Distribution of Histamine in the Brain
Amino Acids 391
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 Contents xiii

446 Structure–Activity Relationships 496

Neurons 446 Pharmacodynamics: Absorption and Excretion 497
Nonneuronal Cells 447 Physiological and Behavioral Effects 497
Histamine Receptors 448 CNS Effects 497
H1 Receptors 448 Gastrointestinal Effects 498
H2 Receptors 449 Part I Summary 498
H3 Receptors 450 Part II Opiate Receptors 498
Distribution of Histamine Receptors 450 Receptor Characteristics 498
The Role of Histamine in Neural and Behavioral Receptor Binding Studies 499
Functions 451 Biochemical Characterization of Opiate Binding 499
Electrophysiological Effects 451 Ionic Requirements 499
Behavioral Functions 451 Opiate Bioassay 500
Part IV Summary 453 Opiate Receptor Subtypes 500
11. Peptide Neurotransmitters 455 Opiate Receptor Pharmacology and Localization within
The Discovery of Peptides in the Nervous System 455 the CNS 501
Vasopressin, Oxytocin, and the Concept of Molecular Cloning of Opiate Receptor Subtypes 503
Neurosecretion 455 Cellular Mechanisms of Action 505
Hypothalamic Releasing Hormones 455 G Protein Mediation 505
The Biochemistry of Peptides 456 Opiate Receptors Regulate Ion Channels 506
Peptide Structure and Synthesis 456 Inhibition of Adenylyl Cyclase 506
Features of Peptidergic Transmission 458 Part II Summary 507
Peptides versus Classical Transmitters 458 Part III Endogenous Opioid Peptides 508
Coexistence of Peptides with Classical Transmitters 459 Three Families of Peptides 508
The Organizational Framework of Neuropeptide Opioid Peptide Processing 508
Systems 462 Localization and Regulation 510
Vasopressin and Oxytocin 463 Inactivation 512
Structure and Synthesis 463 Relationship to Receptor Subtypes 513
Localization 464 Functional Effects of Opiates and Opioid Peptides
Vasopressin Receptors 465 514
Physiological Effects of Vasopressin 465 Methodology 514
The Role of Vasopressin in Learning and Memory 467 Effects on Synaptic Processes 515
Physiological Effects of Oxytocin 469 Analgesia 518
The Role of Oxytocin in Social Behaviors 469 Pain Pathways 519
Thyrotropin-Releasing Hormone (TRH) 470 Analgesic Effects of Opioids 522
Structure and Localization 470 Localization of Opioid Analgesia 523
Physiological and Behavioral Effects 471 Opiate Effects on Gastrointestinal Function 524
Corticotropin-Releasing Factor (CRF) 472 Opiates and Development 525
Structure and Localization 472 Learning and Memory 525
Physiological and Behavioral Effects 473 Opioid Effects on Food Consumption 526
Substance P and the Tachykinins 476 Endogenous Opiates in Social Behavior 527
Structure and Localization of the Tachykinins 476 Endogenous Opiates and Psychiatric Disorders 528
Regulation of Substance P Synthesis 478 Affective Disorders 528
Tachykinin Receptors 479 Schizophrenia 529
Behavioral Effects of Substance P 480 Endorphins and Autism 530
The Role of Substance P in Pain Transmission 480 Part III Summary 530
Substance P and Inflammation 483 Part IV Opiate Dependence and Abuse 530
The Role of Substance P in the Gastrointestinal
General Features of Drug Abuse 530
System 484
Diagnostic Criteria 530
Cholecystokinin 484
Biopsychosocial Model of Substance Dependence and
Structure and Localization 484
Abuse 531
Cholecystokinin Receptors 486
Consequences of Opiate Use 532
Physiological and Behavioral Effects 486
Tolerance 532
Interactions between CCK and Dopamine 487
Physical Dependence 532
The Role of CCK in Food Intake and Metabolism 488
Psychological Dependence 534
Summary 491
Opiates as Reinforcers 534
Methods of Assessing Drug Reinforcement 534
MAJOR DRUG CLASSES 493 Mechanisms of Opiate Reward 536
12. The Opiates 495 Neurochemical Mechanisms of Opiate Tolerance and
Dependence 538
Part I General Pharmacology: History, Identity,
Down-Regulation of Opioid Peptide Synthesis 538
and Use 495
Role of Receptor Changes 539
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xiv Contents

Role of Adenylyl Cyclase 540 Cocaine Toxicity 584

Behavioral Mechanisms of Tolerance and Effects of Prenatal Cocaine Exposure 585
Dependence 543 Treatment of Cocaine Abuse 586
Modes of Treatment for Opiate Dependence 545 Part II Summary 589
Detoxification 545
Treatment Goals 545
14. Stimulants: Nicotine and Caffeine 591
Drug Abuse Treatment Programs 545 Part I Nicotine 591
Part IV Summary 548 Basic Pharmacology of Nicotine 592
Tobacco: A Vehicle for Delivering Nicotine 592
13. Stimulants: Amphetamine and Metabolism of Nicotine 592
Cocaine 549 Acute Behavioral and Physiological Effects of Nico-
Part I Amphetamine 549 tine 593
Basic Pharmacology of Amphetamine 550 Reinforcing Effects 593
Mechanisms of Amphetamine Action 552 Psychomotor Performance 594
Neurochemical Effects on Catecholamine Systems 552 Peripheral Physiological Effects 596
Other Neurochemical Effects 555 Physiological Effects on the CNS 597
Electrophysiological Effects 555 Toxic Effects of Nicotine 597
Acute Behavioral and Physiological Effects of Carbon Monoxide Toxicity 597
Amphetamine in Humans 556 Mechanisms of Nicotine Action 598
Effects on Mood and Behavior 556 Nicotinic Receptors 598
Physiological Effects 556 Neural Mechanisms of Nicotine-Induced Behavioral
Therapeutic Uses of Amphetamine 557 Effects 598
Acute Behavioral Effects of Amphetamine in Who Are the Smokers and Why Do They Smoke?
Animals 558 599
Locomotor and Stereotyped Behaviors 558 Characteristics of Smokers 599
Schedule-Controlled Behavior 559 Determinants of Smoking Behavior 600
Discriminative Stimulus Properties of Amphetamine Commercial Promotion of Smoking and Tobacco Prod-
559 ucts 601
Reinforcing Effects of Amphetamine 560 Effects of Chronic Tobacco Use 603
Mechanisms Underlying Behavioral Effects of Nicotine Tolerance 603
Amphetamine 561 Nicotine Abstinence and Withdrawal Symptoms 604
Amphetamine Abuse and the Effects of Chronic Health Effects of Smoking 605
Amphetamine Exposure 564 Treatment Strategies for Nicotine Dependence 606
Initiation and Progression of Amphetamine Abuse 564 Characteristics of Nicotine Dependence 606
Amphetamine Tolerance and Sensitization 564 Treatment Goals 606
Amphetamine Dependence 565 Behavioral Interventions 606
Amphetamine Psychosis 566 Pharmacological Interventions 607
Neurotoxic Effects of Amphetamine 566 Part I Summary 611
Part I Summary 567 Part II Caffeine 611
Part II Cocaine 568 Basic Pharmacology of Caffeine 612
Basic Pharmacology of Cocaine 569 Acute Behavioral and Physiological Effects of Caf-
Mechanisms of Cocaine Action 570 feine 612
Neurochemical Effects on Monoamine Systems 570 Therapeutic Uses of Caffeine 614
Other Neurochemical Effects 571 Effects of Chronic Caffeine Exposure 614
Electrophysiological Effects 572 Caffeine Tolerance and Sensitization 614
Acute Behavioral and Physiological Effects of Caffeine Dependence 614
Cocaine in Humans 573 Adverse Physiological Effects of Chronic Caffeine Con-
Effects on Mood and Behavior 573 sumption 615
Physiological Effects 574 Mechanisms of Caffeine Action 615
Acute Behavioral Effects of Cocaine in Animals 574 Adenosine 616
Reinforcing Effects of Cocaine 574 Adenosine Antagonism as the Mechanism of Caffeine
Mechanisms Underlying the Behavioral Effects of Action 620
Cocaine 576 Part II Summary 623
Is There a Common Neural Mechanism Underlying
the Reinforcing Effects of All Abused Drugs? 579
15. Alcohol 625
Cocaine Abuse and the Effects of Chronic Cocaine Alcohol Pharmacokinetics 626
Exposure 580 Alcohol Absorption and Distribution 626
Initiation and Progression of Cocaine Abuse 580 Alcohol Metabolism 627
Cocaine Tolerance and Sensitization 581 Alcohol Use and Abuse 629
Cocaine Dependence 582 The Prevalence and Cost of Alcoholism 629
Cocaine Psychosis 584 Anxiety and Alcoholism 630
Alcohol-Related Fatalities 630
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 Contents xv

Adverse Systemic Effects of Alcoholism 630 The Site of Barbiturate Action 680
Effects on the Gastrointestinal System 631 The Role of GABA in Barbiturate Effects 681
Effects on the Cardiovascular System 632 Barbiturate Effects on the GABAA Receptor Complex
Effects on Reproductive Functions 633 681
Effects on the CNS 633 Barbiturate Effects on the CNS 682
Gender and Alcohol-Related Pathology 634 Barbiturate Abuse and Toxicology 682
Neuromolecular Effects of Alcohol 634 Barbiturate Abuse 682
Alcohol–GABA Interactions 637 Assessment Methods 682
Interactions between Alcohol and Other Neurotransmit- Barbiturate Toxicity 683
ters 637 Parameters of Barbiturate Dependence 683
Alcohol Tolerance 643 Barbiturate Tolerance 683
Acute Tolerance 643 Barbiturate Tolerance and Dependence in Animals 683
Chronic Tolerance 645 Barbiturate Tolerance and Dependence in Humans 685
Alcohol Interactions with Other Drugs 647 Diagnosis and Treatment of Barbiturate Abuse 685
Acute Alcohol–Drug Interactions 648 Part II Summary 685
Chronic Alcohol–Drug Interactions 648 Part III The Benzodiazepines and Other
Acute Alcohol–Chronic Drug Interactions 648 Nonbarbiturate Anxiolytics 686
Alcohol Withdrawal Syndrome 649
Early Nonbarbiturate Anxiolytics 686
Alcohol Abuse and Alcoholism 650
The Development of the Benzodiazepines 686
Models of Alcoholism 650
Molecular Studies 688
Genetic and Environmental Factors in Alcoholism 651
Chemistry of the Benzodiazepines 688
Is There a Gene for Alcoholism? 653
Benzodiazepine Binding Characteristics 688
Serotonin, Personality Disorders, and Alcohol Abuse
Mechanisms of Action 689
654
Neurophysiological Studies 689
Gender-Specific Drinking Styles 655
Biochemical Studies: The Interaction with GABA 689
Treatment of Alcoholism 656
Pharmacological Studies 689
Pharmacotherapy for Alcoholism 656
Benzodiazepine Receptors and Their Ligands 691
Nondrug Approaches to the Treatment of Alcoholism
The -Carbolines and Other BDZ Receptor Ligands
660
691
The Effectiveness of Different Treatment Approaches
Endogenous Benzodiazepines in Mammalian Brains
661
692
The Relapse Prevention Approach 662
Anxiety and the Inverse Agonists 694
Fetal Alcohol Syndrome 663
What Is the Natural Role of BDZ Receptors? 694
Frequency and Antecedents of Fetal Alcohol
The -Carbolines: Pharmacological Assessment 695
Syndrome 663
Binding Potency 695
Alcohol Effects on Fetal Development and Postnatal
Comparative Anxiolysis 696
Behavior 663
Drug Discrimination Tests 696
Factors Contributing to FAS 666
Corticosterone Reactions 697
Is There a No-Risk Level of Alcohol Use for Pregnant
Effects of Stress on GABA and BDZ Receptors 697
Women? 668
Stress-Induced Proconflict and Proconvulsant Effects
Summary 669
698
16. Sedative–Hypnotic and Anxiolytic Benzodiazepine Effects on Transmitter Systems 698
Drugs 673 The Limited Role of GABA 698
Part I The History and the Study of Anxiolytic Benzodiazepine–Catecholamine Interactions 699
Benzodiazepine–Acetylcholine Interactions 700
Drugs 673
Benzodiazepine–Serotonin Interactions 700
Early Sedative–Anxiolytic Drugs 673 Effects of Serotonin Agonists and Antagonists in the
Bromides 673 Geller–Seifter Paradigm 701
Belladonna Alkaloids 674 Alternative Testing Procedures 702
Narcotic Analgesics (Opiates) 674 Serotonergic Drugs and Anxiety 703
The Development of Modern Anxiolytics 674 5-HT1A Receptor Ligands 704
Experimental Methods for the Assessment of 5-HT3 Receptor Ligands 706
Anxiolytic Drugs 674 Part III Summary 708
Classical Paradigms for Assessing Anxiolytic Effects
Part IV Benzodiazepine Therapeutics 709
675
Alternative Testing Procedures 677 Pharmacological Considerations 709
Part I Summary 678 The Efficacy of Benzodiazepines 709
The Safety of Benzodiazepines 710
Part II The Barbiturates 678 Tolerance and Dependence 710
The History of Barbiturates 678 Alcohol–Benzodiazapine Interactions 713
Barbiturate Pharmacology 680 Benzodiazepine Treatment of the Anxiety
Synaptic Effects of Barbiturates 680 Disorders 713
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xvi Contents

Parameters of Anxiety Disorders 713 Excitatory and Depressant Effects 753

Panic Disorder 713 Effects on Learning and Memory 753
Generalized Anxiety Disorder 715 Discriminative Stimulus Properties of PCP 754
Paradoxical Benzodiazepine Effects 715 Reinforcing Effects of PCP 755
Abuse Liability of Benzodiazepines 716 PCP Abuse and the Effects of Chronic PCP
The Parameters of BDZ Abuse 717 Exposure 756
Serotonergic Anxiolytics 717 Why Is PCP Abused? 756
Buspirone Characterization and Therapeutics 717 Tolerance and Dependence 757
Buspirone Side Effects and Overdoses 718 Psychological and Neurological Effects of Chronic PCP
Buspirone versus BDZ Treatment 718 Use 758
The Treatment of Insomnia 718 Mechanisms of PCP Action 758
The Nature of Sleep 719 The PCP Receptor 758
The Nature of Insomnia 720 Other Neurochemical Actions of PCP 760
The Assessment and Diagnosis of Insomnia 722 Role of the NMDA Receptor and Other Neurochemical
Pharmacological Treatment of Insomnia 722 Systems in the Behavioral Effects of PCP 762
Adverse Effects of Triazolam 726 Part II Summary 764
BDZ Hypnotics: Management of Treatment 728 Part III LSD 765
Part IV Summary 729
Synthesis and Characteristic Effects of LSD 765
17. Mind-Altering Drugs 731 Basic Pharmacology of LSD 766
Part I Marijuana and the Cannabinoids 731 Psychological and Physiological Efects 766
Does LSD Cause Hallucinations? 767
The History of Cannabis Use 732
LSD and Schizophrenia 767
Cannabinoid Pharmacology: Chemical Structures,
Psychedelic Properties of LSD 767
Pharmacokinetics, and Metabolism 732
LSD–5-HT Interactions 770
Cannabinoid Structure and Activity 732
Receptor Binding of LSD 770
Cannabinoid Absorption, Metabolism, and Clearance
Single-Cell Studies 771
734
LSD-Induced Raphe Activity and Behavior 772
Acute Behavioral and Physiological Effects in
The Role of the 5-HT Receptor in Hallucinogenesis
Humans 734
773
Cannabis Intoxication 735
LSD and 5-HT in Review 775
Learning, Memory, and Other Cognitive Functions
Isoergine (Lysergic Acid Amide) 775
736
Therapeutic Use of Hallucinogens 776
Psychomotor Performance 736
Assessment of LSD Therapies 777
Acute Physiological Effects of Cannabis 737
Misuse and Abuse of LSD 778
Therapeutic Uses of Cannabinoids 737
Part III Summary 779
Acute Behavioral Effects in Animals 738
Unconditioned Behavior 738 CLINICAL APPLICATIONS 781
Operant Behavior 738
Discriminative Stimulus Properties of THC 738 18. Schizophrenia 783
Reinforcing Effects of Cannabinoids 739 Diagnosis, Etiology, and Pathology 783
Cannabis Abuse and the Effects of Chronic Cannabis Symptoms 784
Exposure 739 Diagnosis 784
Initiation and Progression of Cannabis Use 739 Prognosis 787
Tolerance 739 Etiology 787
Dependence and Withdrawal 741 Neuropathology 791
Psychological and Neurological Effects of Long-Term Models of Schizophrenia 795
Exposure 742 Pharmacotherapy: Phenothiazines and Butyrophe-
Physiological Effects of Long-Term Exposure 743 nones 795
Mechanisms of Action of Cannabinoids 744 Structure–Activity Relationships of Neuroleptics 795
Cannabinoid Receptors 744 Effectiveness 797
Electrophysiological Effects 747 Side Effects of Neuroleptics 798
Effects on Neurotransmitter Systems 748 Parkinsonism 798
Part I Summary 749 Tardive Dyskinesias 798
Part II Phencyclidine 750 Other Effects of Neuroleptics 800
Basic Pharmacology of PCP 750 Tolerance and Dependence 801
Acute Behavioral Effects of PCP in Humans 751 Effects on Conditioned Avoidance in Animals 801
Results From Controlled Studies 751 Mechanisms of Neuroleptic Action 802
PCP Intoxication in Drug Abusers 752 Atypical Neuroleptics 807
PCP and Psychopathology 752 Neurochemical Hypotheses of Schizophrenia 811
Acute Behavioral Effects of PCP in Animals 753

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 Contents xvii

The Dopamine Hypothesis 811 Part III Summary 859

The Neurodevelopmental Model 813
The Role of Norepinephrine 814
20. Parkinson’s Disease and Alzheimer’s
The Serotonin Hypothesis 815 Disease 861
Other Neurotransmitter Systems 815 Part I Parkinson’s Disease 861
The Supersensitivity–Subsensitivity Hypothesis 816 Behavioral and Psychological Characteristics of
Summary 817 Parkinson’s Disease 862
Motor Disturbances 862
19. Affective Disorders 819 Cognitive Dysfunction 863
Part I Affective Disorders and Antidepressant Depression 863
Drugs 819 Neuropathological Characteristics of Parkinson’s
Clinical Profile 819 Disease 864
Description 819 Histopathological Findings 864
Demography 820 Abnormalities in Neurotransmitter Systems 865
Relationship to Stress 820 Relationships between Symptomatology and Specific
Genetics 820 Neurotransmitter Systems 867
Physiological Correlates of Depression 821 Models of Parkinson’s Disease 871
Biological Rhythms: Cortisol Secretion 822 Early Animal Models 871
Biological Rhythms: Sleep and REM 823 The MPTP Model 872
Seasonal Affective Disorder (SAD) 825 Pathogenesis of Parkinson’s Disease 877
Biogenic Amine Hypothesis 825 The Oxidative Stress Hypothesis 877
Antidepressant Screening with Animal Models 826 Mitochondrial Dysfunction 878
Reserpine-Induced Sedation 826 The Environmental Toxin Hypothesis 879
Behavioral Despair Syndrome 827 Conclusions 879
Learned Helplessness 827 Treatment of Parkinson’s Disease 880
Olfactory Bulbectomy Model 827 Pharmacotherapies 880
Effectiveness of Pharmacotherapy 828 Pallidotomy 884
Depression Subtypes 829 Tissue Grafting 884
Monoamine Oxidase Inhibitors 830 Part I Summary 886
Structure and Pharmacokinetics 831 Part II Alzheimer’s Disease 887
Interaction with Monoamine Oxidase 831 Introduction 887
Mechanism of Antidepressant Effects 832 Behavioral and Psychological Characteristics 888
Side Effects 832 Dementia 888
Tricyclic and Second Generation Antidepressants Other Behavioral and Psychiatric Symptoms 888
833 Neuropathology 888
Pharmacodynamics 835 Histological Features 888
Pharmacological Side Effects 835 Neuron and Synapse Loss in the Cortex and
Effects on Behavior 835 Hippocampus 890
Newer Antidepressant Drugs 836 Abnormalities in Neurotransmitter Systems 891
Part I Summary 837 Relationships between Alzheimer’s Neuropathology and
Part II Neurochemistry of Depression and Symptomatology 891
Antidepressant Action 838 Diagnosis of Alzheimer’s Disease 892
Norepinephrine 838 Pathogenesis of Alzheimer’s Disease 892
Postsynaptic 1-Receptors 841 -Amyloid Protein 892
Changes in -Receptors and cAMP 841 Tau Protein 894
Serotonin 842 Genetics of Alzheimer’s Disease 895
NE–5-HT Interactions 846 Theories of Alzheimer’s Disease Pathogenesis 898
Other Neurotransmitters 847 Treatment of Alzheimer’s Disease 901
Part II Summary 849 Early Treatment Concepts 902
Part III Other Therapies for Affective Disorders 849 Nootropics 902
Electroconvulsive Therapy 849 Pharmacological Treatment of Cholinergic Deficits 903
Mechanism of Action 851 Neurotrophic Therapy 905
Lithium Carbonate 852 Tissue Grafting 907
Pharmacokinetics 853 Part II Summary 907
Biological Effects of Lithium 853
Effects on Second Messenger Systems 855 References R–1
Lithium Effects on Gene Expression 858
Alternative Drug Therapies for Bipolar Disorder 858
Illustration Credits IC–1

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or disseminated in any form without express written permission from the publisher.