Drugs,
the Brain, and Behavior
THIRD EDITION
Jerrold S. Meyer University of Massachusetts
Linda F. Quenzer University of Hartford
Chapter 20, Neurodegenerative Diseases
By Jennifer R. Yates, University of Alabama
SINAUER ASSOCIATES
NEW YORK OXFORD
OXFORD UNIVERSITY PRESS
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Psychopharmacology Drugs, the Brain, and Behavior, Third Edition
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Library of Congress Cataloging-in-Publication Data
Names: Meyer, Jerrold S., 1947- author. Title: Psychopharmacology : drugs, the brain, and behavior / Jerrold S. Meyer, Linda F. Quenzer.
Description: Third edition. | Sunderland, Massachusetts, USA : Oxford University Press, [2019] | Includes bibliographical references and index. Identifiers: LCCN 2017049700 | ISBN 9781605355559
Subjects: LCSH: Psychotropic drugs--Pharmacokinetics. | Psychotropic drugs--Therapeutic use.
Classification: LCC RM315 .M478 2019 | DDC 615.7/88--dc23 LC record available at https://lccn.loc.gov/2017049700
The Diagnostic and Statistical Manual of Mental Disorders, DSM, DSM-IV, DSM-IV-TR , and DSM-5 are registered trademarks of the American Psychiatric Association. Oxford University Press is not associated with the American Psychiatric Association or with any of its products or publications, nor do the views expressed herein represent the policies and opinions of the American Psychiatric Association.
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Brief Contents
CHAPTER 1 Principles of Phar macology 3
CHAPTER 2 Structure and Function of the Nervous System 45
CHAPTER 3 Chemical Signaling by Neurotransmitters and Hormones 83
CHAPTER 4 Methods of Research in Psychopharmacology 117
CHAPTER 5 Catecholamines 159
CHAPTER 6 Serotonin 189
CHAPTER 7 Acetylcholine 213
CHAPTER 8 Glutamate and GABA 231
CHAPTER 9 Drug Abuse and Addiction 265
CHAPTER 10 Alcohol 307
CHAPTER 11 The Opioids 351
CHAPTER 12 Psychomotor Stimulants: Cocaine, Amphetamine, and Related Drugs 391
CHAPTER 13 Nicotine and Caffeine 429
CHAPTER 14 Marijuana and the Cannabinoids 467
CHAPTER 15 Hallucinogens, PCP, and Ketamine 501
CHAPTER 16 Inhalants, GHB, and Anabolic–Androgenic Steroids 527
CHAPTER 17 Disorders of Anxiety and Impulsivity and the Drugs Used to Treat These Disorders 559
CHAPTER 18 Affective Disorders: Antidepressants and Mood Stabilizers 601
CHAPTER 19 Schizophrenia: Antipsychotic Drugs 633
CHAPTER 20 Neurodegenerative Diseases 671
Contents
Preface xvii
1
Principles of Pharmacology 3
Pharmacology: The Science of Drug Action 4
Placebo effect 5
Box 1.1 Pharmacology in Action Naming Drugs 6
Pharmacokinetic Factors Determining Drug Action 7
Methods of drug administration influence the onset of drug action 8
Multiple factors modify drug absorption 12
Drug distribution is limited by selective barriers 15
Depot binding alters the magnitude and duration of drug action 18
Biotransfor mation and elimination of drugs contribute to bioavailability 19
Therapeutic Drug Monitoring 25
Box 1.2 Pharmacology in Action Interspecies Drug Dose Extrapolation 25
2
Pharmacodynamics: Drug–Receptor Interactions 27
Box 1.3 Pharmacology in Action Drug Categories 28
Extracellular and intracellular receptors have several common features 30
Dose–response curves describe receptor activity 31
The therapeutic index calculates drug safety 32
Receptor antagonists compete with agonists for binding sites 33
Biobehavioral Effects of Chronic Drug Use 34
Repeated drug exposure can cause tolerance 35
Chronic drug use can cause sensitization 38
Pharmacogenetics and Personalized Medicine in Psychiatry 39
Structure and Function of the Nervous System 45
Cells of the Nervous System 46
Neurons have three major external features 46
Box 2.1 The Cutting Edge Embryonic Stem Cells 47
Characteristics of the cell membrane are critical for neuron function 54
Glial cells provide vital support for neurons 55
Box 2.2 Of Special Interest Astrocytes 56
Electrical Transmission within a Neuron 58
Ion distribution is responsible for the cell’s resting potential 58
Local potentials are small, transient changes in membrane potential 60
Sufficient depolarization at the axon hillock opens voltagegated Na+ channels, producing an action potential 61
Drugs and poisons alter axon conduction 63
Organization of the Nervous System 65
Box 2.3 The Cutting Edge Finding Your Way in the Nervous System 65
The nervous system comprises the central and peripheral divisions 66
CNS functioning is dependent on structural features 68
The CNS has six distinct regions reflecting embryological development 70
Box 2.4 Of Special Interest Neuroendocrine Response to Stress 76
3
The cerebral cortex is divided into four lobes, each having primary, secondary, and tertiary areas 76
Rat and human brains have many similarities and some differences 79
Chemical Signaling by Neurotransmitters and Hormones 83
Chemical Signaling between Nerve Cells 84
Neurotransmitter Synthesis, Release, and Inactivation 86
Neurotransmitters encompass several different kinds of chemical substances 86
Box 3.1 Clinical Applications Orexin-Based
Medications: New Approaches to the Treatment of Sleep Disorders 87
Neuropeptides are synthesized by a different mechanism than other transmitters 90
Neuromodulators are chemicals that don’t act like typical neurotransmitters 91
Classical transmitter release involves exocytosis and recycling of synaptic vesicles 91
Lipid and gaseous transmitters are not released from synaptic vesicles 95
Several mechanisms control the rate of neurotransmitter release by nerve cells 96
Neurotransmitters are inactivated by reuptake and by enzymatic breakdown 97
4
Neurotransmitter Receptors and Second-Messenger Systems 98
There are two major families of neurotransmitter receptors 99
Second messengers work by activating specific protein kinases within a cell 102
Tyrosine kinase receptors mediate the effects of neurotrophic factors 104
Pharmacology of Synaptic Transmission 104
Synaptic Plasticity 105
The Endocrine System 107
Endocrine glands can secrete multiple hormones 107
Mechanisms of hor mone action vary 109
Why is the endocrine system important to pharmacologists? 111
Box 3.2 Phar macology in Action Sex Hormones and Drug Abuse 112
Methods of Research in Psychopharmacology 117
Research Methods for Evaluating the Brain and Behavior 118
Techniques in Behavioral Pharmacology 118
Evaluating Animal Behavior 118
Animal testing needs to be valid and reliable to produce useful information 118
A wide variety of behaviors are evaluated by psychopharmacologists 120
Box 4.1 Pharmacology in Action Using the ThreeChamber Social Interaction Test 125
Box 4.2 Clinical Applications Drug Testing for FDA Approval 131
Techniques in Neuropharmacology 134
Multiple Neurobiological Techniques for Assessing the CNS 134
Stereotaxic surgery is needed for accurate in vivo measures of brain function 134
Neurotransmitters, receptors, and other proteins can be quantified and visually located in the CNS 138
New tools are used for imaging the structure and function of the brain 145
Genetic engineering helps neuroscientists to ask and answer new questions 150
Box 4.3 Pharmacology in Action Transgenic Model of Huntington’s Disease 153
Behavioral and neuropharmacological methods complement one another 155
Catecholamines 159
Catecholamine Synthesis, Release, and Inactivation 160
Tyrosine hydroxylase catalyzes the rate-limiting step in catecholamine synthesis 160
Catecholamines are stored in and released from synaptic vesicles 161
Catecholamine inactivation occurs through the combination of reuptake and metabolism 164
Organization and Function of the Dopaminergic System 166
Two important dopaminergic cell groups are found in the midbrain 166
Ascending dopamine pathways have been implicated in several important behavioral functions 167
Box 5.1 Clinical Applications Mutations That Affect Dopamine Neurotransmission 168
Serotonin 189
Serotonin Synthesis, Release, and Inactivation 190
Serotonin synthesis is regulated by enzymatic activity and precursor availability 190
Similar processes regulate storage, release, and inactivation of serotonin and the catecholamines 192
Box 6.1 History of Psychopharmacology “Ecstasy”— Har mless Feel-Good Drug, Dangerous Neurotoxin, or Miracle Medication? 193
Organization and Function of the Serotonergic System 196
Acetylcholine 213
Acetylcholine Synthesis, Release, and Inactivation 214
Acetylcholine synthesis is catalyzed by the enzyme choline acetyltransferase 214
Many different drugs and toxins can alter acetylcholine storage and release 214
Acetylcholinesterase is responsible for acetylcholine breakdown 215
Box 7.1 Pharmacology In Action Botulinum Toxin— Deadly Poison, Therapeutic Remedy, and Cosmetic Aid 216
There are five main subtypes of dopamine receptors organized into D1- and D2-like families 171
Dopamine receptor agonists and antagonists affect locomotor activity and other behavioral functions 172
Box 5.2 The Cutting Edge Using Molecular Genetics to Study the Dopaminergic System 174
Organization and Function of the Noradrenergic System 177
Norepinephrine is an important transmitter in both the central and peripheral nervous systems 177
Norepinephrine and epinephrine act through α- and β-adrenergic receptors 178
The central noradrenergic system plays a significant role in arousal, cognition, and the consolidation of emotional memories 179
Several medications work by stimulating or inhibiting peripheral adrenergic receptors 183
The serotonergic system originates in the brainstem and projects to all forebrain areas 196
The firing of dorsal raphe serotonergic neurons varies with behavioral state and in response to rewards and punishments 197
There is a large family of serotonin receptors, most of which are metabotropic 198
Multiple approaches have identified several behavioral and physiological functions of serotonin 200
Box 6.2 The Cutting Edge Serotonin and Aggression 203
Organization and Function of the Cholinergic System 219
Cholinergic neurons play a key role in the functioning of both the peripheral and central nervous systems 219
Box 7.2 The Cutting Edge Acetylcholine and Cognitive Function 220
There are two acetylcholine receptor subtypes: nicotinic and muscarinic 222
Glutamate 232
Glutamate Synthesis, Release, and Inactivation 232
Neurons generate glutamate from the precursor glutamine 232
Glutamate packaging into vesicles and uptake after release are mediated by multiple transport systems 232
Organization and Function of the Glutamatergic System 235
Glutamate is the neurotransmitter used in many excitatory pathways in the brain 235
Both ionotropic and metabotropic receptors mediate the synaptic effects of glutamate 236
Box 8.1 Clinical Applications Fragile X Syndrome and Metabotropic Glutamate Receptor Antagonists:
A Contemporary Saga of Translational Medicine 239
AMPA and NMDA receptors play a key role in learning and memory 239
High levels of glutamate can be toxic to nerve cells 245
9
Drug Abuse and Addiction 265 8
Introduction to Drug Abuse and Addiction 266
Drugs of abuse are widely consumed in our society 266
Drug use in our society has increased and has become more heavily regulated over time 267
Features of Drug Abuse and Addiction 270
Drug addiction is considered to be a chronic, relapsing behavioral disorder 270
There are two types of progression in drug use 272
Box 9.1 Of Special Interest Should the Term Addiction Be Applied to Compulsive Behavioral Disorders That Don’t Involve Substance Use? 273
Which drugs are the most addictive? 275
Factors That Influence the Development and Maintenance of Drug Abuse and Addiction 276
The addiction potential of a substance is influenced by its route of administration 277
Most abused drugs exert rewarding and reinforcing effects 277
GABA 251
GABA Synthesis, Release, and Inactivation 251
GABA is synthesized by the enzyme glutamic acid decarboxylase 251
GABA packaging into vesicles and uptake after release are mediated by specific transporter proteins 251
GABA is coreleased with several other classical neurotransmitters 253
Organization and Function of the GABAergic System 254
Some GABAergic neurons are interneurons, while others are projection neurons 254
The actions of GABA are primarily mediated by ionotropic GABAA receptors 254
Box 8.2 Clinical Applications GABA and Epilepsy 255
GABA also signals using metabotropic GABAB receptors 260
Drug dependence leads to withdrawal symptoms when abstinence is attempted 280
Discriminative stimulus effects contribute to drug-seeking behavior 282
Genetic factors contribute to the risk for addiction 283
Psychosocial variables also contribute to addiction risk 285
The factors contributing to drug addiction can be combined into a biopsychosocial model 287
The Neurobiology of Drug Addiction 289
Drug reward and incentive salience drive the binge–intoxication stage of drug use 289
The withdrawal/negative affect stage is characterized by stress and by the recruitment of an antireward circuit 292
The preoccupation/anticipation stage involves dysregulation of prefrontal cortical function and corticostriatal circuitry 294
Molecular neuroadaptations play a key role in the transition to an addicted state 296
Is addiction a disease? 299
10
Alcohol 307
Psychopharmacology of Alcohol 308
Alcohol has a long history of use 308
What is an alcohol and where does it come from? 309
The phar macokinetics of alcohol determines its bioavailability 310
Chronic alcohol use leads to both tolerance and physical dependence 313
Alcohol affects many organ systems 315
Box 10.1 Pharmacology in Action The Role of Expectation in Alcohol-Enhanced Human Sexual Response 315
11
The Opioids 351
Narcotic Analgesics 352
The opium poppy has a long history of use 352
Minor differences in molecular structure determine behavioral effects 353
Bioavailability predicts both physiological and behavioral effects 354
Opioids have their most important effects on the CNS and on the gastrointestinal tract 354
Box 11.1 Clinical Applications Saving a Life: Naloxone for Opioid Overdoses 355
Opioid Receptors and Endogenous Neuropeptides 357
Receptor binding studies identified and localized opioid receptors 357
Four opioid receptor subtypes exist 358
Several families of naturally occurring opioid peptides bind to these receptors 360
Box 11.2 The Cutting Edge Science in Action 361
Opioid receptor–mediated cellular changes are inhibitory 365
Opioids and Pain 366
The two components of pain have distinct features 367
Opioids inhibit pain transmission at spinal and supraspinal levels 369
Other for ms of pain control depend on opioids 371
Neurochemical Effects of Alcohol 325
Animal models are vital for alcohol research 325
Alcohol acts on multiple neurotransmitters 327
Alcohol Use Disorder (AUD) 335
Defining alcohol use disorder and estimating its incidence have proved difficult 335
The causes of alcohol use disorder are multimodal 338
Multiple treatment options provide hope for rehabilitation 342
Opioid Reinforcement, Tolerance, and Dependence 374
Animal testing shows significant reinforcing properties 376
Dopaminergic and nondopaminergic components contribute to opioid reinforcement 376
Long-ter m opioid use produces tolerance, sensitization, and dependence 377
Box 11.3 Of Special Interest The Opioid Epidemic 379
Several brain areas contribute to the opioid abstinence syndrome 381
Neurobiological adaptation and rebound constitute tolerance and withdrawal 381
Environmental cues have a role in tolerance, drug abuse, and relapse 382
Treatment Programs for Opioid Use Disorder 383
Detoxification is the first step in the therapeutic process 383
Treatment goals and programs rely on pharmacological support and counseling 384
Psychomotor Stimulants: Cocaine, Amphetamine, and Related Drugs 391
Cocaine 392
Background and History 392
Basic Phar macology of Cocaine 393
Mechanisms of Cocaine Action 395
Acute Behavioral and Physiological Effects of Cocaine 397
Cocaine stimulates mood and behavior 398
Cocaine’s physiological effects are mediated by the sympathetic nervous system 399
Dopamine is important for many effects of cocaine and other psychostimulants 399
Brain imaging has revealed the neural mechanisms of psychostimulant action in humans 401
Several DA receptor subtypes mediate the functional effects of psychostimulants 402
Cocaine Abuse and the Effects of Chronic Cocaine Exposure 403
Experimental cocaine use may escalate over time to a pattern of cocaine abuse and dependence 403
Chronic cocaine exposure leads to significant behavioral and neurobiological changes 405
Box 12.1 The Cutting Edge Neurochemical Mechanisms of Cocaine Tolerance and Sensitization 406
Nicotine and Caffeine 429
Nicotine 430
Background and History 430
Basic Phar macology of Nicotine and Its Relationship to Smoking 431
Features of tobacco smoking and nicotine pharmacokinetics 431
Features of e-cigarette vaping and nicotine pharmacokinetics 431
Nicotine metabolism 432
Mechanisms of Action 432
Behavioral and Physiological Effects 433
Nicotine elicits different mood changes in smokers compared with nonsmokers 434
Nicotine enhances cognitive function 434
Repeated or high-dose cocaine use can produce serious health consequences 409
Phar macological, behavioral, and psychosocial methods are used to treat cocaine abuse and dependence 409
The Amphetamines 412
Background and History 412
Basic Phar macology of the Amphetamines 413
Mechanisms of Amphetamine and Methamphetamine Action 414
Behavioral and Neural Effects of Amphetamines 415
Amphetamine and methamphetamine have therapeutic uses 415
High doses or chronic use of amphetamines can cause a variety of adverse effects 415
Methylphenidate, Modafinil, and Synthetic Cathinones 418
Methylphenidate 418
Box 12.2 Clinical Applications Psychostimulants and ADHD 420
Modafinil 422
Synthetic Cathinones 423
Nicotine exerts both reinforcing and aversive effects 436
Nicotine produces a wide range of physiological effects 438
Nicotine is a toxic substance that can be fatal at high doses 439
Chronic exposure to nicotine induces tolerance and dependence 440
Cigarette Smoking and Vaping 443
What percentage of the population are current users of tobacco and/or e-cigarettes? 443
Nicotine users progress through a series of stages in their pattern and frequency of use 444
Box 13.1 The Cutting Edge How Safe Are E-cigarettes? 446
Why do smokers smoke and vapers vape? 447
Smoking is a major health hazard and a cause of premature death 450
Behavioral and phar macological strategies are used to treat tobacco dependence 451
Caffeine 455
Background 455
Basic Phar macology of Caffeine 456
Behavioral and Physiological Effects 456
Acute subjective and behavioral effects of caffeine depend on dose and prior exposure 456
Caffeine consumption can enhance sports performance 457
Regular caffeine use leads to tolerance and dependence 458
Caffeine and caffeine-containing beverages pose health risks but also exert therapeutic benefits 459
Mechanisms of Action 460
Marijuana and the Cannabinoids 467
Background and History of Cannabis and Marijuana 468
Forms of cannabis and their chemical constituents 468
History of cannabis 468
Basic Pharmacology of Marijuana 470
THC 470
Cannabidiol 471
Mechanisms of Action 472
Cannabinoid effects are mediated by cannabinoid receptors 472
Phar macological and genetic studies reveal the functional roles of cannabinoid receptors 473
Endocannabinoids are cannabinoid receptor agonists synthesized by the body 474
Acute Behavioral and Physiological Effects of Cannabinoids 480
Cannabis consumption produces a dose-dependent state of intoxication 480
Marijuana use can lead to deficits in memory and other cognitive processes 481
Rewarding and reinforcing effects of cannabinoids have been studied in both humans and animals 482
Cannabis Abuse and the Effects of Chronic Cannabis Exposure 484
Chronic use of cannabis can lead to the development of a cannabis use disorder 485
Chronic cannabis use can lead to adverse behavioral, neurobiological, and health effects 489
Box 14.1 Of Special Interest Beyond Cannabis: The Rise of Synthetic Cannabinoids 495
Hallucinogens, PCP, and Ketamine 501
Hallucinogenic Drugs 502
Mescaline 502
Psilocybin 502
Dimethyltryptamine and Related Tryptamines 504
LSD 504
Box 15.1 History of Phar macology
The Discovery of LSD 505
NBOMes 506
Salvinorin A 507
Phar macology of Hallucinogenic Drugs 507
Different hallucinogenic drugs vary in potency and in their time course of action 507
Hallucinogens produce a complex set of psychological and physiological responses 508
Most hallucinogenic drugs share a common indoleamine or phenethylamine structure 509
Indoleamine and phenethylamine hallucinogens are 5-HT2A receptor agonists 510
Salvinorin A is a κ-opioid receptor agonist 511
The neural mechanisms underlying hallucinogenesis are not yet fully understood 511
Hallucinogenic drug use leads to adverse effects in some users 511
Can hallucinogenic drugs be used therapeutically? 513
PCP and Ketamine 515
Background and History 515
Phar macology of PCP and Ketamine 516
PCP and ketamine produce a state of dissociation 516
PCP and ketamine are noncompetitive antagonists of NMDA receptors 517
PCP and ketamine have significant abuse potential 517
Use of PCP, ketamine, or related drugs can cause a variety of adverse consequences 519
Box 15.2 Phar macology In Action Getting High on Cough Syrup 520
Novel therapeutic applications have been proposed for ketamine 522
Inhalants, GHB, and Anabolic–Androgenic Steroids 527 16
Inhalants 528
Background 528
Inhalants comprise a range of substances including volatile solvents, fuels, halogenated hydrocarbons, anesthetics, and nitrites 528
Abused inhalants are rapidly absorbed and readily enter the brain 528
These substances are particularly favored by children and adolescents 529
Behavioral and Neural Effects 530
Many inhalant effects are similar to alcohol intoxication 530
Chronic inhalant use can lead to tolerance and dependence 530
Rewarding and reinforcing effects have been demonstrated in animals 530
Inhalants have complex effects on central nervous system (CNS) function and behavioral activity 531
Health risks have been associated with inhalant abuse 532
Gamma-Hydroxybutyrate 534
Background 534
Behavioral and Neural Effects 535
GHB produces behavioral sedation, intoxication, and learning deficits 535
GHB and its precursors have reinforcing properties 535
Effects of GHB are mediated by multiple mechanisms 536
Medical and Recreational Uses of GHB 538
GHB is used therapeutically for the treatment of narcolepsy and alcoholism 538
GHB has significant abuse potential when used recreationally 539
Anabolic–Androgenic Steroids
Background and History 541
540
Anabolic–androgenic steroids are structurally related to testosterone 541
Anabolic–androgenic steroids were developed to help build muscle mass and enhance athletic performance 542
Anabolic–androgenic steroids are currently taken by many adolescent and adult men 543
Anabolic–androgenic steroids are taken in specific patterns and combinations 543
Pharmacology of Anabolic–Androgenic Steroids 545
Research is beginning to unravel the mechanism of action of anabolic–androgenic steroids on muscle 545
Many adverse side effects are associated with anabolic–androgenic steroid use 546
Regular anabolic–androgenic steroid use causes dependence in some individuals 548
Box 16.1 Of Special Interest Anabolic–Androgenic Steroids and “Roid Rage” 549
Testosterone has an important role in treating hypogonadism 552
Disorders of Anxiety and Impulsivity and the Drugs Used to Treat These Disorders 559
Neurobiology of Anxiety 560
What is anxiety? 560
The amygdala is important to emotion-processing circuits 561
Multiple neurotransmitters mediate anxiety 564
Box 17.1 The Cutting Edge Neural Mechanism
Responsible for High Tonic Cell Firing Mediating Anxiety 566
Genes and environment interact to determine the tendency to express anxiety 574
The effects of early stress are dependent on timing 576
The effects of early stress vary with gender 577
Characteristics of Anxiety Disorders 579
Drugs for Treating Anxiety, OCD, and PTSD 587
Barbiturates are the oldest sedative–hypnotics 588
Benzodiazepines are highly effective for anxiety reduction 590
Second-generation anxiolytics produce distinctive clinical effects 595
Antidepressants relieve anxiety and depression 596
Many novel approaches to treating anxiety are being developed 597
Affective Disorders: Antidepressants and Mood Stabilizers 601
Characteristics of Affective Disorders 602
Major depression damages the quality of life 602
In bipolar disorder moods alternate from mania to depression 602
Risk factors for mood disorders are biological and environmental 604
Animal Models of Affective Disorders 608
Models of bipolar disorder 608
Neurochemical Basis of Mood Disorders 610
Serotonin dysfunction contributes to mood disorders 611
Norepinephrine activity is altered by antidepressants 614
Norepinephrine and serotonin modulate one another 615
Neurobiological Models of Depression 615
Box 18.1 The Cutting Edge Epigenetic Modifications in Psychopathology and Treatment 618
Therapies for Affective Disorders 621
Monoamine oxidase inhibitors are the oldest antidepressant drugs 621
Tricyclic antidepressants block the reuptake of norepinephrine and serotonin 623
Second-generation antidepressants have different side effects 624
Third-generation antidepressants have distinctive mechanisms of action 625
Drugs for treating bipolar disorder stabilize the highs and the lows 628
Schizophrenia: Antipsychotic Drugs 633
Characteristics of Schizophrenia 634
There is no defining cluster of schizophrenic symptoms 634
Etiology of Schizophrenia 636
Abnormalities of brain structure and function occur in individuals with schizophrenia 636
Genetic, environmental, and developmental factors interact 639
Box 19.1 The Cutting Edge Epigenetic Modifications and Risk for Schizophrenia 642
Preclinical Models of Schizophrenia 646
Box 19.2 Phar macology In Action
The Prenatal Inflammation Model of Schizophrenia 648
Neurochemical Models of Schizophrenia 650
Abnormal dopamine function contributes to schizophrenic symptoms 650
The neurodevelopmental model integrates anatomical and neurochemical evidence 651
Glutamate and other neurotransmitters contribute to symptoms 652
Classic Neuroleptics and Atypical Antipsychotics 650
Phenothiazines and butyrophenones are classic neuroleptics 654
Neurodegenerative Diseases 671
Parkinson’s Disease and Alzheimer’s Disease 672
Parkinson’s Disease 672
The clinical features of PD are primarily motor related 672
Patients with Parkinson’s may also develop dementia 673
The primary pathology of PD is a loss of dopaminergic neurons in the substantia nigra 673
Animal models of PD have strengths and limitations 676
Phar macological treatments for PD are primarily symptomatic, not disease altering 676
There are several unmet needs in PD diagnosis and treatment 677
Alzheimer’s Disease 678
AD is defined by several pathological cellular disturbances 679
There are several behavioral, health, and genetic risk factors for AD 681
Alzheimer’s disease cannot be definitively diagnosed until postmortem analysis 682
Several different animal models contribute to our understanding of AD 683
Symptomatic treatments are available, and several others are under study for slowing disease progression 683
Glossary G-1
References R-1
Author Index AI-1
Subject Index SI-1
Dopamine receptor antagonism is responsible for antipsychotic action 655
Side effects are directly related to neurochemical action 657
Atypical antipsychotics are distinctive in several ways 660
Practical clinical trials help clinicians make decisions about drugs 663
There are renewed efforts to treat the cognitive symptoms 664
Box 20.1 The Cutting Edge Alzheimer’s Disease: It’s all in your gut??? 684
Other Major Neurodegenerative Diseases 685
Huntington’s Disease 685
Symptoms 686
Only symptomatic treatments are available for HD; none alter disease progression 686
Amyotrophic Lateral Sclerosis 687
The symptoms and disease progression in ALS are devastating 687
The loss of motor neurons in ALS is complicated and poorly understood 687
Two medications exist that are approved for ALS treatment 688
Multiple Sclerosis 688
The symptoms of MS are variable and unpredictable 689
Diagnosis 689
Causes of MS 690
Treatments fall into several categories for MS and can be very effective 691
Box 20.2 Phar macology in Action Can We Repair or Replace Myelin? 693
Preface
When we wrote the preface to the Second Edition of Psychopharmacology: Drugs, the Brain, and Behavior, we were struck by the many exciting developments in the field and the remarkable rate of progress elucidating the underlying neurobiological mechanisms of psychoactive drug action. This has not changed over the 5 years since the publication of that edition. The entire field of neuroscience, including neuropsychopharmacology, continues to be driven by technical advances. Using optogenetics, neurobiologists can activate or suppress anatomically and molecularly defined populations of nerve cells with amazing temporal precision. Neuropharmacologists can visualize the 3-dimensional structure of neurotransmitter receptors, enabling synthetic chemists to design novel agonist or antagonist drugs with much greater selectivity than could have been possible before. And huge projects like the Human Connectome Project (www.humanconnectomeproject. org) are using the most advanced neuroimaging techniques to map the detailed circuitry of the living human brain. Because of these technical innovations, we continue to add new information to Chapter 4, on Methods of Research in Psychopharmacology. Readers may choose to go through the chapter in its entirety to familiarize themselves with all of the neuropharmacological and behavioral methods reviewed, or they may choose to use the chapter as a reference source when they encounter an unfamiliar method in one of the book’s later chapters.
Development and introduction of new pharmaceutical compounds continues as well, although the emphasis has somewhat shifted away from the large pharmaceutical companies to a greater reliance on drug discovery efforts by researchers at universities and medical centers. Statistics show that development of new drugs for CNS disorders (e.g., schizophrenia, depression, and Alzheimer’s disease) costs more than for other kinds of disorders, and the failure rate is significantly higher. These data have caused many of the large companies to downsize their CNS drug discovery programs. As you read the chapters on drug addiction, mental disorders, and neurodegenerative disorders, it
will become apparent that new medications for these disorders are being introduced at a slower rate than expected, despite ongoing research that continues to identify potential new molecular targets for pharmacotherapy. For this reason, we must admit that exciting advances in understanding the basic structure and function of the nervous system have not yet led to similar progress in treating, much less “curing,” disorders of this system. We came to the same conclusion when writing the preface to the Second Edition, so it’s disappointing that the hoped-for surge in medication development failed to occur during the intervening period.
As before, this new edition of the text is completely updated to incorporate the latest research findings, methodological advances, and novel drugs of abuse. Regarding the latter, illicit drug labs in the United States and abroad are working hard to turn out massive amounts of recreational drugs, whether already known compounds such as cocaine or fentanyl, or novel synthetic compounds that can only be identified by submitting drug seizures to advanced forensic laboratories for chemical analysis. The national drug epidemic involving fentanyl, heroin, and other opioid compounds is discussed in Chapter 11. New and, in some cases, highly dangerous stimulant and cannabinoid drugs are introduced in Chapters 12, 14, and 15 respectively. Most chapters have new opening vignettes and breakout boxes, and new photographs, drawings, and graphs have been added to bring attention both to updated material and to completely new topic areas for discussion.
Importantly, in preparing this next edition of the book we have maintained our conviction that a deep understanding of the relationship between drugs and behavior requires basic knowledge of how the nervous system works and how different types of drugs interact with nervous system function (i.e., mechanisms of drug action). We have also continued to present the methods and findings from behavioral pharmacological studies using animal models alongside key studies from the human clinical research literature. Pharmacologists must depend on in vitro preparations and laboratory
animal studies for determining mechanisms of drug action, for screening new compounds for potential therapeutic activity, and, of course, for basic toxicology and safety testing. In cases in which clinical trials have already been performed based on promising preclinical results, both sets of findings are presented. In other instances in which clinical trials had not yet been undertaken at the time of our writing, we have striven to point you toward new directions of drug development so that you can seek out the latest information using your own research efforts.
A new point of emphasis in the text concerns neural circuits as mediators of behavior and as targets of drug action. As implied above in referring to the Human Connectome Project, focusing on circuits instead of cells as the nervous system’s functional units is the contemporary way to think about how our brains control our actions, and how drugs, whether recreational or medicinal, alter our subjective awareness and behavior.
The Third Edition of Psychopharmacology: Drugs, the Brain, and Behavior retains the same four-section organization as the previous editions. Chapters 1 through 4 provide extensive foundation materials, including the basic principles of pharmacology, neurophysiology and neuroanatomy, cell signaling (primarily synaptic transmission), and current methods in behavioral assessment and neuropharmacology. An increased use of clinical examples demonstrates the relevance of the material to real-life issues. Chapters 5 through 8 describe key features of major neurotransmitter systems, including the catecholamines, serotonin, acetylcholine, glutamate, and GABA. These are the neurotransmitter
systems most often associated with psychoactive drug effects, and presentation of their neurochemistry, anatomy, and function lays the groundwork for the chapters that follow. Chapters 9 through 16 cover theories and mechanisms of drug addiction and all the major substances of abuse. Finally, Chapters 17 through 20 consider the neurobiology of neuropsychiatric and neurodegenerative disorders and the drugs used to treat these disorders. Among the neuropsychiatric disorders, special emphasis is placed on affective disorders such as major depression and bipolar disorder, various anxiety disorders, and schizophrenia. Bulleted interim summaries highlight the key points made in each part of the chapter. New to this edition, study questions are provided at the end of each chapter to assist students in reviewing the most important material. Finally, a dedicated website for the book (oup-arc.com/access/ meyer-3e) is available that offers Web Boxes (advanced topics for interested readers), study resources such as flashcards, web links, and animations that visually illustrate key neurophysiological and neurochemical processes important for psychopharmacology.
It has been our privilege in the first two editions of Psychopharmacology: Drugs, the Brain, and Behavior to introduce so many students to the study of drugs and behavior. With this new and updated edition, we hope to continue this tradition and perhaps inspire some of you to continue your studies in graduate school and join the thousands of researchers worldwide who are working to better understand and ultimately defeat illnesses like addiction, depression, schizophrenia, and Alzheimer’s disease.
Acknowledgments
This book is the culmination of the efforts of many dedicated people who contributed their ideas and hard work to the project. We’d like to thank and acknowledge the outstanding editorial team at Sinauer Associates: Sydney Carroll, Martha Lorantos, and Danna Lockwood, thank you all for your suggestions for improving the Third Edition, your help and guidance throughout the process of writing and revising, and not least for your patience (textbook writing is a slow process when one is simultaneously teaching, conducting research, and meeting administrative responsibilities). You were unwavering in your vision to produce the best possible psychopharmacology textbook. Mark Siddall did a superb job of seeking out just the right photographs for the book. We are indebted to other key staff members of Sinauer Associates who worked on this project, including Chris Small, Ann Chiara, and Joan Gemme. And we must acknowledge Dragonfly Media Group for the beautiful job rendering the illustrations.
The following reviewers contributed many excellent suggestions for improving the book:
Joel Alexander, Western Oregon University
Sage Andrew, University of Missouri
Susan Barron, University of Kentucky
Ethan Block, University of Pittsburgh
Kirstein Cheryl, University of South Florida
Matt Clasen, American University
Patricia DiCiano, The Centre for Addiction and Mental Health and Seneca College
Henry Gorman, Austin College
Bill Griesar, Portland State University
Joshua Gulley, University of Illinois at UrbanaChampaign
Matt Holahan, Carleton University
Phillip Holmes, University of Georgia
Michael Kane, University of Pennsylvania
Thomas Lanthorn, Sam Houston State University
Lauren Liets, University of California, Davis
Ilyssa Loiacono, Queens College
Margaret Martinetti, The College of New Jersey
Janice McMurray, University of Nevada, Las Vegas
M. Foster, Olive Arizona State University
Robert Patrick, Brown University
Anna Rissanen, Memorial University, Newfoundland
Margaret Ruddy, The College of New Jersey
Jeffrey Rudski Muhlenberg College
Lawrence Ryan Oregon State University
Fred Shaffer Truman State University
Evan Zucker Loyola University
Most of all, we are indebted to our spouses, Melinda Novak and Ray Rosati, who supported and encouraged us and who willingly sacrificed so much of our time together during this lengthy project. Linda gives special thanks to her husband Ray for providing extensive editorial advice during the final production period.
