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Home , Mechanism of action, Neuropsychopharmacology, Therapeutic index

Principles of

Robert S. Feldman University of Massachusetts

Jerrold S. Meyer University of Massachusetts

Linda F. Quenzer University of Hartford

Sinauer Associates, Inc., Publishers Sunderland, Massachusetts

© Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Brief Contents

Basic Concepts xxi 1. Principles of 1 2. Methods in Neuropsychopharmacology 27 3. and Glial Cells 75 4. Functional Neuroanatomy 111 5. Neurophysiological Mechanisms 155 6. Synaptic Structure and Function 185 Systems 233 7. Acetylcholine 235 8. Catecholamines 277 9. Serotonin 345 10. The Amino Acid and Histamine 391 11. Peptide Neurotransmitters 455 Major Classes 493 12. The 495 13. : Amphetamine and 549 14. Stimulants: Nicotine and 591 15. 625 16. – and 673 17. -Altering Drugs 731 Clinical Applications 781 18. Schizophrenia 783 19. Affective Disorders 819 20. Parkinson’s Disease and Alzheimer’s Disease 861

© Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 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 Binding 13 Tests of Delayed Reaction 64 Law of Mass Action 13 Measures of Anxiety 65 –Response Relationships 14 Schedule-Controlled Behavior 66 Side Effects and the 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 17 Drugs Used as Discriminative Stimuli 71 17 Part II Summary 73 Renal 19 Tolerance and Sensitization 20 3. Neurons and Glial Cells 75 Cross Tolerance 21 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 83 Autoradiography 31 Gene Translation 85 In Situ Hybridization 31 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 90 Interpretation of –Receptor Binding 43 Dimensions 91 Ligand–Receptor Kinetics 46 Axonal Collaterals 92 Mathematical Transformations and Data Plotting 48 Axonal Transport 92 Receptor Autoradiography 49 The Nerve 95 Receptor Isolation and Labeling 50 Membrane Structure 95 Brain Metabolism and Imaging Methods 51 Transport across Membranes 99 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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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 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 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 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 209 Cortical Cell Morphology 134 Direct Interactions of G Proteins with 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 144 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 – 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 178 Acetylcholine Inactivation 242 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Contents xi

Cholinesterases 242 Catecholamine Inactivation 294 Properties of Acetylcholinesterase 242 Catecholamine Uptake 294 Noncholinergic Functions of Acetylcholinesterase 244 Catecholamine Uptake Inhibitors 294 Drugs That Affect Acetylcholine Synthesis, Storage, Catabolism of Catecholamines 296 Release, and Inactivation 244 Measurement of Catecholamine Turnover 301 Drugs That Block Acetylcholine Synthesis 244 Catecholamine 301 Drugs That Affect Acetylcholine Storage and Release Part I Summary 302 245 Part II Systems: Anatomy, , Drugs That Affect Acetylcholine Inactivation 246 and Behavior 303 Part I Summary 248 Distribution of Dopamine Neurons in the Nervous Part II Anatomy and Physiology of Cholinergic System 303 Systems 249 Methods Used to Map Dopaminergic Pathways 303 Distribution of Cholinergic Neurons and Their Anatomy of Central Dopaminergic Systems 304 Connections 249 Peripheral Dopaminergic Systems 307 Cholinergic Systems within the CNS 249 Fine Structure of Dopamine Synapses: Implications for Location of Cholinergic Cell Groups and Pathways in Dopaminergic 307 the Brain 249 Coexistence of Dopamine with Other Transmitters 307 Peripheral Cholinergic Systems 251 of Dopaminergic Neurons 308 Acetylcholine Receptors 251 Dopamine Receptors 308 Acetylcholine Receptor Subtypes 251 The D1-Like Receptor Subfamily 309 Nicotinic Receptors 252 The D2-Like Receptor Subfamily 310 Muscarinic Receptors 256 Dopamine Receptor Mechanisms 313 Localization and Physiological Effects of Nicotinic and Dopamine Autoreceptors 315 Muscarinic Receptors 259 The D2 Receptor and Dopaminergic Behavioral Regulation of Neurotransmitter Release by Cholinergic Supersensitivity 316 Autoreceptors and Heteroreceptors 262 Behavioral Effects of Selective Dopamine Receptor Drugs That Affect Cholinergic Receptors 263 and Antagonists 318 General Cholinergic Agonists 263 The Role of Dopamine in Motivational Processes Nicotinic Agonists and Antagonists 263 319 Muscarinic Agonists and Antagonists 265 Basic Concepts of Motivation: Reward and Part II Summary 267 Reinforcement 319 Part III Behavioral Functions of Acetylcholine Dopamine and Brain Self-Stimulation 320 268 Self-Administration of and Place Conditioning with Dopaminergic Drugs 321 The Role of Acetylcholine in and Arousal 268 Dopamine in Learning and Motivation: Theoretical Acetylcholine and Ascending Arousal Systems 268 Formulations 321 Acetylcholine and Sleep 269 Part II Summary 323 Cognitive Functions of Acetylcholine 271 Effects of Cholinergic Drugs on Learning, Memory, and Part III and Epinephrine Systems: Attention 271 Anatomy, Physiology, and Behavior 324 Acetylcholine, Aging, and Memory 273 Distribution of Noradrenergic and Adrenergic Role of the Basal Forebrain Cholinergic System 273 Neurons in the Nervous System 324 Part III Summary 275 Methods Used to Map Noradrenergic and Adrenergic Pathways 324 8. Catecholamines 277 Anatomy of Central Noradrenergic Systems 324 Part I Catecholamine Neurochemistry: Synthesis, Anatomy of Central Adrenergic Systems 326 Storage, Release, and Inactivation 278 Norepinephrine and Epinephrine in the Peripheral Basic Aspects of Catecholamine Synthesis 278 Nervous System 326 Tyrosine Hydroxylase 278 Coexistence of Norepinephrine with Other Aromatic Amino Acid Decarboxylase 281 Transmitters 327 Dopamine -Hydroxylase 282 Electrophysiology of Noradrenergic Neurons 327 Phyenylethanolamine N-Methyltransferase 283 Adrenergic Receptors 327 Regulation of Catecholamine Synthesis 283 -Adrenergic Receptors 328 Acute Regulation of Tyrosine Hydroxylase 283 -Adrenergic Receptors 330 Long-Term Regulation of Tyrosine Hydroxylase: Mechanisms 334 Trans-Synaptic Induction 286 Adrenergic Autoreceptors 336 Regulation of Dopamine -Hydroxylase and Adrenergic Receptors in Nonneural Cells 336 Phenylethanolamine N-Methyltransferase 288 -Receptor Regulation 337 Summary of Catecholamine Synthesis Regulation 289 Therapeutic Use of Adrenergic Drugs 338 Catecholamine Storage and Release 290 Use of Catecholamines as Drugs 339 Catecholamine Storage Mechanisms 290 Adrenergic Agonists 339 Catecholamine Release 292 Adrenergic Antagonists 340 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 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 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 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 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 GABA Receptors 435 Feeding Behavior and Body Weight Reulation 380 C 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 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. Contents xiii

446 Structure–Activity Relationships 496 Neurons 446 : 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 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 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 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 Effects of 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 Part I General Pharmacology: History, Identity, Dependence 538 Down-Regulation of Opioid Peptide Synthesis 538 and Use 495 Role of Receptor Changes 539 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. xiv Contents

Role of Adenylyl Cyclase 540 Cocaine 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 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 574 616 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 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 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 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 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 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 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 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 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 Drugs 673 Benzodiazepine–Acetylcholine Interactions 700 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 (Opiates) 674 Serotonergic Drugs and Anxiety 703 The Development of Modern Anxiolytics 674 5-HT Receptor Ligands 704 Experimental Methods for the Assessment of 1A 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 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. xvi Contents

Parameters of Anxiety Disorders 713 Excitatory and Depressant Effects 753 Panic Disorder 713 Effects on Learning and Memory 753 Generalized 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 : 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 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 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 741 791 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 798 Part II 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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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 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 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 Other Behavioral and Psychiatric Symptoms 888 833 Neuropathology 888 Pharmacodynamics 835 Histological Features 888 Pharmacological Side Effects 835 Neuron and Loss in the Cortex and Effects on Behavior 835 890 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 849 902 Electroconvulsive Therapy 849 Pharmacological Treatment of Cholinergic Deficits 903 851 Neurotrophic Therapy 905 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 858 Alternative Drug Therapies for Bipolar Disorder 858 Illustration Credits IC–1

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