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 © 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 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 © 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 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 © Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 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 © 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 Neurotoxins 301 Drugs That Affect Acetylcholine Storage and Release Part I Summary 302 245 Part II Dopamine Systems: Anatomy, Physiology, 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 Neurotransmission 307 the Brain 249 Coexistence of Dopamine with Other Transmitters 307 Peripheral Cholinergic Systems 251 Electrophysiology 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