Psychopharmacology Drugs, the Brain, and Behavior

Unique in its breadth of coverage ranging from historical accounts of drug use to clinical and preclinical behavioral studies, Psychopharmacology is appropriate for undergraduates studying the relationships between the behavioral effects of psychoactive drugs and their mechanisms of action.

Preface

Chapter 1. Principles of Pharmacology
Pharmacology: The Science of Drug Action
Placebo effect
Box 1.1. Pharmacology in Action: Naming Drugs
Pharmacokinetic Factors Determining Drug Action
Methods of drug administration influence the onset of drug action
Multiple factors modify drug absorption
Drug distribution is limited by selective barriers
Depot binding alters the magnitude and duration of drug action
Biotransformation and elimination of drugs contribute to bioavailability
Therapeutic Drug Monitoring
Box 1.2. Pharmacology in Action: Interspecies Drug Dose Extrapolation
Pharmacodynamics: Drug-Receptor Interactions
Box 1.3. Pharmacology in Action: Drug Categories
Extracellular and intracellular receptors have several common features
Dose-response curves describe receptor activity
The therapeutic index calculates drug safety
Receptor antagonists compete with agonists for binding sites
Biobehavioral Effects of Chronic Drug Use
Repeated drug exposure can cause tolerance
Chronic drug use can cause sensitization
Pharmacogenetics and Personalized Medicine in Psychiatry

Chapter 2. Structure and Function of the Nervous System
Cells of the Nervous System
Neurons have three major external features
Box 2.1. The Cutting Edge: Embryonic Stem Cells
Characteristics of the cell membrane are critical for neuron function
Glial cells provide vital support for neurons
Box 2.2. Of Special Interest: Astrocytes
Electrical Transmission within a Neuron
Ion distribution is responsible for the cell's resting potential
Local potentials are small, transient changes in membrane potential
Sufficient depolarization at the axon hillock opens voltage-gated Na+ channels, producing an action potential
Drugs and poisons alter axon conduction
Organization of the Nervous System
Box 2.3. The Cutting Edge: Finding Your Way in the Nervous System
The nervous system comprises the central and peripheral divisions
CNS functioning is dependent on structural features
The CNS has six distinct regions reflecting embryological development
Box 2.4. Of Special Interest: Neuroendocrine Response to Stress
The cerebral cortex is divided into four lobes, each having primary, secondary, and tertiary areas
Rat and human brains have many similarities and some differences

Chapter 3. Chemical Signaling by Neurotransmitters and Hormones
Chemical Signaling between Nerve Cells
Neurotransmitter Synthesis, Release, and Inactivation
Neurotransmitters encompass several different kinds of chemical substances
Box 3.1. Clinical Applications: Orexin-Based Medications: New Approaches to the Treatment of Sleep Disorders
Neuropeptides are synthesized by a different mechanism than other transmitters
Neuromodulators are chemicals that don't act like typical neurotransmitters
Classical transmitter release involves exocytosis and recycling of synaptic vesicles
Lipid and gaseous transmitters are not released from synaptic vesicles
Several mechanisms control the rate of neurotransmitter release by nerve cells
Neurotransmitters are inactivated by reuptake and by enzymatic breakdown
Neurotransmitter Receptors and Second-Messenger Systems
There are two major families of neurotransmitter receptors
Second messengers work by activating specific protein kinases within a cell
Tyrosine kinase receptors mediate the effects of neurotrophic factors
Pharmacology of Synaptic Transmission
Synaptic Plasticity
The Endocrine System
Endocrine glands can secrete multiple hormones
Mechanisms of hormone action vary
Why is the endocrine system important to pharmacologists?
Box 3.2. Pharmacology in Action: Sex Hormones and Drug Abuse

Chapter 4. Methods of Research in Psychopharmacology
Research Methods for Evaluating the Brain and Behavior
TECHNIQUES IN BEHAVIORAL PHARMACOLOGY
Evaluating Animal Behavior
Animal testing needs to be valid and reliable to produce useful information
A wide variety of behaviors are evaluated by psychopharmacologists
Box 4.1. Pharmacology in Action: Using the Three-Chamber Social Interaction Test
Box 4.2. Clinical Applications: Drug Testing for FDA Approval
TECHNIQUES IN NEUROPHARMACOLOGY
Multiple Neurobiological Techniques for Assessing the CNS
Stereotaxic surgery is needed for accurate in vivo measures of brain function
Neurotransmitters, receptors, and other proteins can be quantified and visually located in the CNS
New tools are used for imaging the structure and function of the brain
Genetic engineering helps neuroscientists to ask and answer new questions
Box 4.3. Pharmacology in Action: Transgenic Model of Huntington's Disease
Behavioral and neuropharmacological methods complement one another

Chapter 5. Catecholamines
Catecholamine Synthesis, Release, and Inactivation
Tyrosine hydroxylase catalyzes the rate-limiting stepin catecholamine synthesis
Catecholamines are stored in and released from synaptic vesicles
Catecholamine inactivation occurs through the combination of reuptake and metabolism
Organization and Function of the Dopaminergic System
Two important dopaminergic cell groups are found in the midbrain
Ascending dopamine pathways have been implicated in several important behavioral functions
Box 5.1. Clinical Applications: Mutations That Affect Dopamine Neurotransmission
There are five main subtypes of dopamine receptors organized into D1- and D2-like families
Dopamine receptor agonists and antagonists affect locomotor activity and other behavioral functions
Box 5.2. The Cutting Edge: Using Molecular Genetics to Study the Dopaminergic System
Organization and Function of the Noradrenergic System
Norepinephrine is an important transmitter in both the central and peripheral nervous systems
Norepinephrine and epinephrine act through alpha- and beta-adrenergic receptors
The central noradrenergic system plays a significant role in arousal, cognition, and the consolidation of emotional memories
Several medications work by stimulating or inhibiting peripheral adrenergic receptors

Chapter 6. Serotonin
Serotonin Synthesis, Release, and Inactivation
Serotonin synthesis is regulated by enzymatic activity and precursor availability
Similar processes regulate storage, release, and inactivation of serotonin and the catecholamines
Box 6.1. History of Psychopharmacology: "Ecstasy"--Harmless Feel-Good Drug, Dangerous Neurotoxin, or Miracle Medication?
Organization and Function of the Serotonergic System
The serotonergic system originates in the brainstem and projects to all forebrain areas
The firing of dorsal raphe serotonergic neurons varies with behavioral state and in response to rewards and punishments
There is a large family of serotonin receptors, most of which are metabotropic
Multiple approaches have identified several behavioral and physiological functions of serotonin
Box 6.2. The Cutting Edge: Serotonin and Aggression

Chapter 7. Acetylcholine
Acetylcholine Synthesis, Release, and Inactivation
Acetylcholine synthesis is catalyzed by the enzyme choline acetyltransferase
Many different drugs and toxins can alter acetylcholine storage and release
Acetylcholinesterase is responsible for acetylcholine breakdown
Box 7.1. Pharmacology In Action: Botulinum Toxin--Deadly Poison, Therapeutic Remedy, and Cosmetic Aid
Organization and Function of the Cholinergic System
Cholinergic neurons play a key role in the functioning of both the peripheral and central nervous systems
Box 7.2. The Cutting Edge: Acetylcholine and Cognitive Function
There are two acetylcholine receptor subtypes: nicotinic and muscarinic

Chapter 8. Glutamate and GABA
GLUTAMATE
Glutamate Synthesis, Release, and Inactivation
Neurons generate glutamate from the precursor glutamine
Glutamate packaging into vesicles and uptake after release are mediated by multiple transport systems
Organization and Function of the Glutamatergic System
Glutamate is the neurotransmitter used in many excitatory pathways in the brain
Both ionotropic and metabotropic receptors mediate the synaptic effects of glutamate
Box 8.1. Clinical Applications: Fragile X Syndrome and Metabotropic Glutamate Receptor Antagonists: A Contemporary Saga of Translational Medicine
AMPA and NMDA receptors play a key role in learning and memory
High levels of glutamate can be toxic to nerve cells
GABA
GABA Synthesis, Release, and Inactivation
GABA is synthesized by the enzyme glutamic acid decarboxylase
GABA packaging into vesicles and uptake after release are mediated by specific transporter proteins
GABA is coreleased with several other classical neurotransmitters
Organization and Function of the GABAergic System
Some GABAergic neurons are interneurons, while others are projection neurons
The actions of GABA are primarily mediated by ionotropic GABAA receptors
Box 8.2. Clinical Applications: GABA and Epilepsy
GABA also signals using metabotropic GABAB receptors

Chapter 9. Drug Abuse and Addiction
Introduction to Drug Abuse and Addiction
Drugs of abuse are widely consumed in our society
Drug use in our society has increased and has become more heavily regulated over time
Features of Drug Abuse and Addiction
Drug addiction is considered to be a chronic, relapsing behavioral disorder
There are two types of progression in drug use
Box 9.1. Of Special Interest: Should the Term Addiction Be Applied to Compulsive Behavioral Disorders That Don't Involve Substance Use?
Which drugs are the most addictive?
Factors That Influence the Development and Maintenance of Drug Abuse and Addiction
The addiction potential of a substance is influenced by its route of administration
Most abused drugs exert rewarding and reinforcing effects
Drug dependence leads to withdrawal symptoms when abstinence is attempted
Discriminative stimulus effects contribute to drug-seeking behavior
Genetic factors contribute to the risk for addiction
Psychosocial variables also contribute to addiction risk
The factors contributing to drug addiction can be combined into a biopsychosocial model
The Neurobiology of Drug Addiction
Drug reward and incentive salience drive the binge-intoxication stage of drug use
The withdrawal/negative affect stage is characterized by stress and by the recruitment of an antireward circuit
The preoccupation/anticipation stage involves dysregulation of prefrontal cortical function and corticostriatal circuitry
Molecular neuroadaptations play a key role in the transition to an addicted state
Is addiction a disease?

Chapter 10. Alcohol
Psychopharmacology of Alcohol
Alcohol has a long history of use
What is an alcohol and where does it come from?
The pharmacokinetics of alcohol determines its bioavailability
Chronic alcohol use leads to both tolerance and physical dependence
Alcohol affects many organ systems
Box 10.1. Pharmacology in Action:The Role of Expectation in Alcohol-Enhanced Human Sexual Response
Neurochemical Effects of Alcohol
Animal models are vital for alcohol research
Alcohol acts on multiple neurotransmitters
Alcohol Use Disorder (AUD)
Defining alcohol use disorder and estimating its incidence have proved difficult
The causes of alcohol use disorder are multimodal
Multiple treatment options provide hope for rehabilitation

Chapter 11. The Opioids
Narcotic Analgesics
The opium poppy has a long history of use
Minor differences in molecular structure determine behavioral effects
Bioavailability predicts both physiological and behavioral effects
Opioids have their most important effects on the CNS and on the gastrointestinal tract
Box 11.1. Clinical Applications: Saving a Life: Naloxone for Opioid Overdoses
Opioid Receptors and Endogenous Neuropeptides
Receptor binding studies identified and localized opioid receptors
Four opioid receptor subtypes exist
Several families of naturally occurring opioid peptides bind to these receptors
Box 11.2. The Cutting Edge: Science in Action
Opioid receptor-mediated cellular changes are inhibitory
Opioids and Pain
The two components of pain have distinct features
Opioids inhibit pain transmission at spinal and supraspinal levels
Other forms of pain control depend on opioids
Opioid Reinforcement, Tolerance, and Dependence
Animal testing shows significant reinforcing properties
Dopaminergic and nondopaminergic components contribute to opioid reinforcement
Long-term opioid use produces tolerance, sensitization, and dependence
Box 11.3. Of Special Interest: The Opioid Epidemic
Several brain areas contribute to the opioid abstinence syndrome
Neurobiological adaptation and rebound constitute tolerance and withdrawal
Environmental cues have a role in tolerance, drug abuse, and relapse
Treatment Programs for Opioid Use Disorder
Detoxification is the first step in the therapeutic process
Treatment goals and programs rely on pharmacological support and counseling

Chapter 12. Psychomotor Stimulants: Cocaine and the Amphetamines
COCAINE
Background and History
Basic Pharmacology of Cocaine
Mechanisms of Cocaine Action
Acute Behavioral and Physiological Effects of Cocaine
Cocaine stimulates mood and behavior
Cocaine's physiological effects are mediated by the sympathetic nervous system
Dopamine is important for many effects of cocaine and other psychostimulants
Brain imaging has revealed the neural mechanisms of psychostimulant action in humans
Several DA receptor subtypes mediate the functional effects of psychostimulants
Cocaine Abuse and the Effects of Chronic Cocaine Exposure
Experimental cocaine use may escalate over time to a pattern of cocaine abuse and dependence
Chronic cocaine exposure leads to significant behavioral and neurobiological changes
Box 12.1. The Cutting Edge: Neurochemical Mechanisms of Cocaine Tolerance and Sensitization
Repeated or high-dose cocaine use can produce serious health consequences
Pharmacological, behavioral, and psychosocial methods are used to treat cocaine abuse and dependence
THE AMPHETAMINES
Background and History
Basic Pharmacology of the Amphetamines
Mechanisms of Amphetamine and Methamphetamine Action
Behavioral and Neural Effects of Amphetamines
Amphetamine and methamphetamine have therapeutic uses
High doses or chronic use of amphetamines can cause a variety of adverse effects
METHYLPHENIDATE, MODAFINIL, AND SYNTHETIC CATHINONES
Methylphenidate
Box 12.2. Clinical Applications: Psychostimulants and ADHD
Modafinil
Synthetic Cathinones

Chapter 13. Nicotine and Caffeine
NICOTINE
Background and History
Basic Pharmacology of Nicotine and Its Relationship to Smoking
Features of tobacco smoking and nicotine pharmacokinetics
Features of e-cigarette vaping and nicotine pharmacokinetics
Nicotine metabolism
Mechanisms of Action
Behavioral and Physiological Effects
Nicotine elicits different mood changes in smokers compared with nonsmokers
Nicotine enhances cognitive function
Nicotine exerts both reinforcing and aversive effects
Nicotine produces a wide range of physiological effects
Nicotine is a toxic substance that can be fatal at high doses
Chronic exposure to nicotine induces tolerance and dependence
Cigarette Smoking and Vaping
What percentage of the population are current users of tobacco and/or e-cigarettes?
Nicotine users progress through a series of stages in their pattern and frequency of use
Box 13.1. The Cutting Edge: How Safe Are E-cigarettes?
Why do smokers smoke and vapers vape?
Smoking is a major health hazard and a cause of premature death
Behavioral and pharmacological strategies are used to treat tobacco dependence
CAFFEINE
Background
Basic Pharmacology of Caffeine
Behavioral and Physiological Effects
Acute subjective and behavioral effects of caffeine depend on dose and prior exposure
Caffeine consumption can enhance sports performance
Regular caffeine use leads to tolerance and dependence
Caffeine and caffeine-containing beverages pose health risks but also exert therapeutic benefits
Mechanisms of Action

Chapter 14. Marijuana and the Cannabinoids
Background and History of Cannabis and Marijuana
Forms of cannabis and their chemical constituents
History of cannabis
Basic Pharmacology of Marijuana
THC
Cannabidiol
Mechanisms of Action
Cannabinoid effects are mediated by cannabinoid receptors
Pharmacological and genetic studies reveal the functional roles of cannabinoid receptors
Endocannabinoids are cannabinoid receptor agonists synthesized by the body
Acute Behavioral and Physiological Effects of Cannabinoids
Cannabis consumption produces a dose-dependent state of intoxication
Marijuana use can lead to deficits in memory and other cognitive processes
Rewarding and reinforcing effects of cannabinoids have been studied in both humans and animals
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Chronic use of cannabis can lead to the development of a cannabis use disorder
Chronic cannabis use can lead to adverse behavioral, neurobiological, and health effects
Box 14.1. Of Special Interest: Beyond Cannabis: The Rise of Synthetic Cannabinoids

Chapter 15. Hallucinogens, PCP, and Ketamine
HALLUCINOGENIC DRUGS
Mescaline
Psilocybin
Dimethyltryptamine and Related Tryptamines
LSD
Box 15.1. History of Pharmacology: The Discovery of LSD
NBOMes
Salvinorin A
Pharmacology of Hallucinogenic Drugs
Different hallucinogenic drugs vary in potency and in their time course of action
Hallucinogens produce a complex set of psychological and physiological responses
Most hallucinogenic drugs share a common indoleamine or phenethylamine structure
Indoleamine and phenethylamine hallucinogens are 5-HT2A receptor agonists
Salvinorin A is a kappa-opioid receptor agonist
The neural mechanisms underlying hallucinogenesis are not yet fully understood
Hallucinogenic drug use leads to adverse effects in some users
Can hallucinogenic drugs be used therapeutically?
PCP AND KETAMINE
Background and History
Pharmacology of PCP and Ketamine
PCP and ketamine produce a state of dissociation
PCP and ketamine are noncompetitive antagonists of NMDA receptors
PCP and ketamine have significant abuse potential
Use of PCP, ketamine, or related drugs can cause a variety of adverse consequences
Box 15.2. Pharmacology In Action: Getting High on Cough Syrup
Novel therapeutic applications have been proposed for ketamine

Chapter 16. Inhalants, GHB, and Anabolic-Androgenic Steroids
INHALANTS
Background
Inhalants comprise a range of substances including volatile solvents, fuels, halogenated hydrocarbons, anesthetics, and nitrites
Abused inhalants are rapidly absorbed and readily enter the brain
These substances are particularly favored by children and adolescents
Behavioral and Neural Effects
Many inhalant effects are similar to alcohol intoxication
Chronic inhalant use can lead to tolerance and dependence
Rewarding and reinforcing effects have been demonstrated in animals
Inhalants have complex effects on central nervous system (CNS) function and behavioral activity
Health risks have been associated with inhalant abuse
GAMMA-HYDROXYBUTYRATE
Background?
Behavioral and Neural Effects
GHB produces behavioral sedation, intoxication, and learning deficits
GHB and its precursors have reinforcing properties
Effects of GHB are mediated by multiple mechanisms
Medical and Recreational Uses of GHB
GHB is used therapeutically for the treatment of narcolepsy and alcoholism
GHB has significant abuse potential when used recreationally
ANABOLIC-ANDROGENIC STEROIDS
Background and History
Anabolic-androgenic steroids are structurally related to testosterone
Anabolic-androgenic steroids were developed to help build muscle mass and enhance athletic performance
Anabolic-androgenic steroids are currently taken by many adolescent and adult men
Anabolic-androgenic steroids are taken in specific patterns and combinations
Pharmacology of Anabolic-Androgenic Steroids
Research is beginning to unravel the mechanism of action of anabolic-androgenic steroids on muscle
Many adverse side effects are associated with anabolic-androgenic steroid use
Regular anabolic-androgenic steroid use causes dependence in some individuals
Box 16.1. Of Special Interest: Anabolic-Androgenic Steroids and "Roid Rage"
Testosterone has an important role in treating hypogonadism

Chapter 17. Disorders of Anxiety and Impulsivity and the Drugs Used to Treat These Disorders
Neurobiology of Anxiety
What is anxiety?
The amygdala is important to emotion-processing circuits
Multiple neurotransmitters mediate anxiety
Box 17.1. The Cutting Edge: Neural Mechanism Responsible for High Tonic Cell Firing Mediating Anxiety
Genes and environment interact to determine the tendency to express anxiety
The effects of early stress are dependent on timing
The effects of early stress vary with gender
Characteristics of Anxiety Disorders
Drugs for Treating Anxiety, OCD, and PTSD
Barbiturates are the oldest sedative-hypnotics
Benzodiazepines are highly effective for anxiety reduction
Second-generation anxiolytics produce distinctive clinical effects
Antidepressants relieve anxiety and depression
Many novel approaches to treating anxiety are being developed

Chapter 18. Affective Disorders: Antidepressants and Mood Stabilizers
Characteristics of Affective Disorders
Major depression damages the quality of life
In bipolar disorder moods alternate from mania to depression
Risk factors for mood disorders are biological and environmental
Animal Models of Affective Disorders
Models of bipolar disorder
Neurochemical Basis of Mood Disorders
Serotonin dysfunction contributes to mood disorders
Norepinephrine activity is altered by antidepressants
Norepinephrine and serotonin modulate one another
Neurobiological Models of Depression
Box 18.1.The Cutting Edge: Epigenetic Modifications in Psychopathology and Treatment
Therapies for Affective Disorders
Monoamine oxidase inhibitors are the oldest antidepressant drugs
Tricyclic antidepressants block the reuptake of norepinephrine and serotonin
Second-generation antidepressants have different side effects
Third-generation antidepressants have distinctive mechanisms of action
Drugs for treating bipolar disorder stabilize the highs and the lows

Chapter 19. Schizophrenia: Antipsychotic Drugs
Characteristics of Schizophrenia
There is no defining cluster of schizophrenic symptoms
Etiology of Schizophrenia
Abnormalities of brain structure and function occur in individuals with schizophrenia
Genetic, environmental, and developmental factors interact
Box 19.1. The Cutting Edge: Epigenetic Modifications and Risk for Schizophrenia
Preclinical Models of Schizophrenia
Box 19.2. Pharmacology In Action: The Prenatal Inflammation Model of Schizophrenia
Neurochemical Models of Schizophrenia
Abnormal dopamine function contributes to schizophrenic symptoms
The neurodevelopmental model integrates anatomical and neurochemical evidence
Glutamate and other neurotransmitters contribute to symptoms
Classic Neuroleptics and Atypical Antipsychotics
Phenothiazines and butyrophenones are classic neuroleptics
Dopamine receptor antagonism is responsible for antipsychotic action
Side effects are directly related to neurochemical action
Atypical antipsychotics are distinctive in several ways
Practical clinical trials help clinicians make decisions about drugs
There are renewed efforts to treat the cognitive symptoms

Chapter 20. Neurodegenerative Diseases, by Jennifer R. Yates, Ohio Wesleyan University
PARKINSON'S DISEASE AND ALZHEIMER'S DISEASE
Parkinson's Disease
The clinical features of PD are primarily motor related
Patients with Parkinson's may also develop dementia
The primary pathology of PD is a loss of dopaminergic neurons in the substantia nigra
Animal models of PD have strengths and limitations
Pharmacological treatments for PD are primarily symptomatic, not disease altering
There are several unmet needs in PD diagnosis and treatment
Alzheimer's Disease
AD is defined by several pathological cellular disturbances
There are several behavioral, health, and genetic risk factors for AD?
Alzheimer's disease cannot be definitively diagnosed until postmortem analysis
Several different animal models contribute to our understanding of AD
Symptomatic treatments are available, and several others are under study for slowing disease progression
Box 20.1. The Cutting Edge: Alzheimer's Disease: It's all in your gut???
OTHER MAJOR NEURODEGENERATIVE DISEASES
Huntington's Disease
Symptoms
Only symptomatic treatments are available for HD; none alter disease progression
Amyotrophic Lateral Sclerosis
The symptoms and disease progression in ALS are devastating
The loss of motor neurons in ALS is complicated and poorly understood
Two medications exist that are approved for ALS treatment
Multiple Sclerosis
The symptoms of MS are variable and unpredictable
Diagnosis
Causes of MS
Treatments fall into several categories for MS and can be very effective
Box 20.2. Pharmacology in Action: Can We Repair or Replace Myelin?

Glossary
References
Author Index
Subject Index

Note: Environmental Neurotoxicants and Endocrine Disruptors, by Susan A. Rice, Susan A. Rice and Associates, Inc.-Chapter 17 in the Second Edition-has moved to the Web.