Molecular Neuropharmacology : A Foundation for Clinical Neuroscience

by Nestler, Eric J.; Hyman, Steven E.; Malenka, Robert C.

• ISBN13: 9780071120654
• ISBN10: 0071120653
• Edition: Large
• Format: Hardcover
• Copyright: 2001-06-01
• Publisher: McGraw Hill (Tx)

Summary

This innovative book presents a molecular and cellular approach to drugs that affect the central nervous system, brain function, and disease states within the nervous system. Filled with superb illustrations, it integrates molecular, cellular, and physiological concepts with pharmacology, and explores the relevance of this model to disese and therapeutics

Author Biography

Eric J. Nestler is Lou and Ellen McGinley Distinguished Professor and Chairman, Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas, Texas.

Table of Contents

Contributing Authors	xiii
Preface	xv
PART 1. FUNDAMENTALS OF NEUROPHARMACOLOGY	1	(138)
Basic Principles of Neuropharmacology	3	(14)
How Drugs Work	4	(1)
Drugs As Tools to Probe Brain Function	4	(1)
Principles of General Pharmacology	5	(7)
Drug Binding	6	(3)
Drug Efficacy	9	(2)
Dose-Dependent Drug Response	11	(1)
Drug Interaction With Nonreceptor Proteins	11	(1)
Neuropharmacology in the Molecular Era	12	(5)
Molecular Diversity of the Brain	15	(2)
Neurons and Glia	17	(17)
The Neuron	20	(7)
The Cell Body	20	(2)
The Axon	22	(1)
Dendrites	23	(1)
The Cytoskeleton and the Transport of Proteins	23	(2)
The Synapse	25	(2)
Glia	27	(2)
Astrocytes	27	(1)
Oligodendrocytes and Schwann Cells	28	(1)
Microglia	28	(1)
Cerebral Blood flow	29	(1)
Blood-Brain Barrier	29	(5)
Electrical Excitability of Neurons	34	(25)
Electrical Potential in Cells	35	(9)
How Neurons Maintain Electrical Potential	35	(1)
A Simple Cell Model	36	(1)
A More Complicated Cell Model	37	(1)
Maintenance of Resting Potential by ATP-Dependent Pumps	38	(1)
Biophysical Properties of the Cell Membrane	39	(1)
Sensory, Synaptic, and Action Potentials	40	(4)
Molecular Properties of Ion Channels	44	(4)
The Prototypic Voltage-Gated Channel	44	(2)
Voltage-Activated Opening of Ion Channels	46	(1)
Voltage-Activated Closing of Ion Channels	47	(1)
Types of Ion Channels	48	(11)
Sodium Channels	48	(2)
Potassium Channels	50	(3)
Calcium Channels	53	(2)
Chloride Channels	55	(4)
Synaptic Transmission	59	(26)
Neuronal Morphology	60	(5)
Dendrites and Axons	60	(1)
The Synapse	61	(1)
Chemical Synaptic Transmission	61	(1)
Storage and Release of Neurotransmitters	61	(1)
Postsynaptic Signaling	62	(2)
Fast Synaptic Transmission	64	(2)
Slow Synaptic Transmission	66
Reception Subtypes	65	(1)
Neurotransmitter Storage, Reuptake, and Release	65	(5)
The Role of Calcium Ions	65	(1)
Quantal Release	66	(1)
Packaging and Transport of Neurotransmitters	67	(1)
Termination of Neurotransmitter Action	68	(1)
Synaptic Vesicles and Large Dense Core-Vesicles	69	(1)
Vesicle Biosynthesis and Transport	70	(1)
Segregation of Vesicles	70	(1)
Biochemistry of Neurotransmitter Release: The Exocytotic Cycle	70	(15)
Proteins Involved in the Exocytotic Cycle	72	(8)
Endocytosis and Recycling	80	(2)
Complexity and Specialization	82	(3)
Signal Transduction Pathways in the Brain	85	(30)
Overview of Signal Transduction Pathways	86	(2)
G Proteins and Second Messengers	88	(11)
G Proteins	88	(3)
G Protein Regulation of Ion Channels	91	(1)
Second Messengers	92	(7)
Protein Phosphorylation: A Final Common Pathway in the Regulation of Neuronal Function	99	(13)
Second Messenger-Dependent Protein Phosphorylation Cascades	99	(6)
Neurotrophic Factor-Regulated Protein Phosphorylation Cascades	105	(4)
Other Protein Phosphorylation Cascades	109	(2)
Centrality of Protein Phosphorylation	111	(1)
Neuromodulators	112	(1)
Heterogeneity in Brain Signal Transduction Pathways	112	(3)
Signaling to the Nucleus	115	(24)
Control of Gene Expression	116	(5)
DNA Replication and Transcription	116	(1)
Regulation of Gene Expression by Chromatin	117	(1)
Genes and the Genome	117	(1)
Regulated Steps of Transcription	117	(1)
Alternative Splicing of Primary RNA Transcripts	118	(2)
Regulation of mRNA Stability and Translatability	120	(1)
Translation of Mature mRNA in the Cytoplasm	120	(1)
Posttranslational Processing of Proteins	121	(1)
Regulation of Transcription	121	(3)
Transcription Initiation: A Critical Biologic Control Point	121	(1)
Core Promoters	121	(1)
Transcription Factors: Key Regulators of Gene Expression	122	(2)
Regulation of Gene Expression by Extracellular Signals	124	(15)
Transcription Factors: Targets of Signaling Pathways	125	(1)
CREB Family of Transcription Factors	126	(3)
AP-1 Family of Transcription Factors	129	(5)
Steroid Hormone Receptor Superfamily	134	(1)
Other Transcription Factors	135	(4)
PART 2. NEURAL SUBSTRATES OF DRUG ACTION	139	(114)
Excitatory and Inhibitory Amino Acids	141	(26)
Glutamate	142	(12)
The Major Excitatory Neurotransmitter	142	(1)
Synthetic and Degradative Pathways	142	(1)
Release and Reuptake	142	(2)
Glutamate Receptors	144	(9)
Role of Glutamate in Neural Plasticity	153	(1)
Role of Glutamate in Neuronal Toxicity	153	(1)
GABA	154	(8)
Major Inhibitory Neurotransmitter in the Brain	154	(1)
Synthetic and Degradative Pathways	155	(1)
Release and Reuptake	156	(1)
GABA Receptors	157	(5)
Glycine	162	(5)
Synthetic and Degradative Pathways	162	(1)
Glycine Release and Reuptake	163	(1)
Glycine Receptors	164	(3)
Catecholamines	167	(24)
Synthetic Pathways	168	(5)
Tyrosine Hydroxylase	170	(3)
Degradative Pathways	173	(1)
Monoamine Oxidase	173	(1)
Catechol-O-Methyl Transferase	173	(1)
Functional Anatomy	173	(4)
Norepinephrine	173	(2)
Dopamine	175	(2)
Storage, Release, and Reuptake	177	(3)
Plasma Membrane Transporters	177	(1)
Norepinephrine Transporter	178	(1)
Dopamine Transporter	179	(1)
Receptors	180	(11)
Physiology of Catecholamine Receptors	183	(1)
Autoreceptors	183	(1)
Structural Features of G Protein-Coupled Receptors	184	(3)
Receptor Trafficking	187	(1)
Receptor Distribution in the Brain	187	(4)
Serotonin, Acetylcholine, and Histamine	191	(22)
Serotonin	192	(8)
Synthetic and Degradative Pathways	192	(3)
Functional Anatomy	195	(1)
Storage, Release, and Reuptake	196	(2)
Serotonin Receptors	198	(2)
Acetylcholine	200	(8)
Synthetic and Degradative Pathways	201	(1)
Functional Anatomy	202	(1)
Storage, Release, and Reuptake	203	(1)
Acetylcholine Receptors	204	(4)
Histamine	208	(5)
Synthetic and Degradative Pathways	208	(1)
Functional Anatomy	208	(1)
Histamine Receptors	209	(4)
Neuropeptides and Purines	213	(22)
Characteristics of Neuropeptides	214	(11)
Precursor Proteins	215	(1)
Proteolytic Processing	215	(2)
Generation of Diversity	217	(1)
Storage and Release	217	(2)
Long-Distance Signaling by Neuropeptides	219	(3)
Receptor Types and Subtypes	222	(2)
Neuropeptide Functions	224	(1)
Neuropeptide Systems	225	(4)
Opioid Peptides	225	(2)
Corticotropin-Releasing Factor	227	(1)
Substance P	227	(1)
Neurotensin	228	(1)
Neuropeptide Y	228	(1)
Purines	229	(6)
Biochemistry	229	(1)
Storage and Release	229	(1)
Transporters	229	(1)
Receptors	230	(2)
Purine Functions	232	(3)
Neurotrophic Factors	235	(18)
Functional Characteristics of Neurotrophic Factors	236	(2)
Families of Neurotrophic Factors	237	(1)
Neurotrophins	238	(4)
Trk Receptors	239	(1)
The p75 Receptor	240	(1)
Neurotrophin and Trk Receptor Knockout Mice	240	(1)
Neurotrophins and Synaptic Plasticity	241	(1)
GDNF Family	242	(1)
CNTF Family	243	(2)
CNTF Signaling Pathways	244	(1)
Immune-Response Cytokines and the CNS	245	(1)
Chemokines	245	(2)
Neuronal Injury and Death	247	(6)
Oxidative Stress	250	(3)
PART 3. NEUROPHARMACOLOGY OF SPECIFIC NEURAL FUNCTIONS AND RELATED DISORDERS	253	(252)
Autonomic Nervous System	255	(22)
Anatomy of the Autonomic Nervous System	259	(1)
Sympathetic Nervous System	259	(1)
Parasympathetic Nervous System	260	(1)
Neurotransmitters of the Autonomic Nervous System	260	(1)
Principal Neurotransmitters	260	(1)
Neuropeptides	260	(1)
Pharmacology of the Autonomic Nervous System	261	(6)
Ganglionic Stimulating and Blocking Agents	261	(2)
Adrenergic Receptor Agonists and Antagonists	263	(3)
Muscarinic Cholinergic Receptor Agonists and Antagonists	266	(1)
Central Control of the Autonomic Nervous System	267	(2)
Nucleus Tractus Solitarius	267	(1)
Hypothalamus	268	(1)
Other Control Centers	269	(1)
Disorders of the Autonomic Nervous System	269	(8)
Genetic Causes of Dysautonomia	269	(4)
Systemic Diseases Associated With Autonomic Dysfunction	273	(2)
Other Autonomic Syndromes	275	(1)
Experimental Models of Autonomic Neuropathy	275	(2)
Neuroendocrine Control of the Internal Milieu	277	(26)
Neuroendocrine Hypothalamus	278	(2)
Afferent Signals	278	(1)
Efferent Signals	279	(1)
Organization of the Hypothalamic-Pituitary Unit	279	(1)
Hypothalamic-Neurohypophyseal System	280	(1)
Arginine Vasopressin	280	(1)
Oxytocin	280	(1)
Hypothalamic-Pituitary-Adrenal Axis	281	(5)
Corticotropin-Releasing Factor and Its Receptors	282	(1)
ACTH and Glucocorticoids	282	(1)
Glucocorticoid Synthesis	282	(1)
Glucocorticoid Physiology	282	(4)
Hypothalamic-Pituitary-Thyroid Axis	286	(2)
Function of the HPT Axis in Stress and Depression	288	(1)
Hypothalamic-Pituitary-Gonadal Axis	288	(4)
Prolactin	292	(2)
Growth Hormone	294	(1)
Control of Energy Balance and Appetite	295	(4)
Potential Pathways of Leptin Action	297	(1)
Disorders of Appetite Control	298	(1)
Hypothalamic Response to Infection and Inflammation	299	(4)
Control of Movement	303	(24)
Normal Control of Movement	304	(5)
Anatomy of the Corticospinal Pathway	304	(1)
Anatomy of the Extrapyramidal System	304	(4)
Cerebellar Control of Movement	308	(1)
Disorders of Movement	309	(18)
Disorders of the Pyramidal Tract and Cerebellum	310	(2)
Parkinson Disease	312	(2)
Drug-Induced Parkinsonism	314	(3)
Treatment of Parkinson Disease	317	(2)
Essential Tremor	319	(1)
Huntington Disease	320	(2)
Dystonia	322	(1)
Tourette Syndrome	323	(1)
Sydenham Chorea	324	(1)
Obsessive-Compulsive Disorder	324	(1)
Wilson Disease	325	(2)
Mood and Emotion	327	(28)
Representation of Emotion in the Brain	328	(4)
Fear	329	(1)
Anxiety	330	(1)
Anxiety and Emotional Memory	330	(2)
Mood Regulation	332	(1)
Pharmacology of Anxiety and Anxiety Disorders	332	(6)
Molecular Pharmacology of the GABAA Receptor	333	(1)
Effects of GABAergic Drugs on Anxiety	334	(2)
Tolerance and Dependence Associated With Benzodiazepines	336	(1)
Nonbenzodiazepine Anxiolylics	337	(1)
Treatment of Anxiety Disorders	337	(1)
Obsessive-Compulsive Disorder	338	(1)
Pharmacology of Mood Disorders	338	(17)
Genetics of Mood Disorders	341	(1)
Neuroendocrine Abnormalities Associated With Depression	341	(1)
Anxiety Disorders and Depression	342	(1)
Antidepressant Drugs	342	(8)
Lithium and Other Mood-Stabilizing Drugs	350	(5)
Reinforcement and Addictive Disorders	355	(28)
Brain Reward Pathways	356	(4)
A Comparison Between Addictive Drugs and Natural Reinforcers	357	(1)
Functional Consequences of Long-Term Drug Exposure	357	(1)
Reward Pathways: Anatomy and Neurochemistry	358	(2)
Initial Actions of Drugs of Abuse and Natural Reinforcers	360	(9)
Psychostimulants	360	(2)
Opiates	362	(2)
Ethanol	364	(1)
Nicotine	365	(1)
Cannabinoids	365	(1)
Phencyclidine	366	(1)
Other Drugs of Abuse	366	(1)
Activation of Reward Circuitry by Natural Reinforcers	367	(1)
Dopaminergic Neurons and Reward-Dependent Learning	368	(1)
Extended Reward Circuitry	368	(1)
Molecular and Cellular Mechanisms of Addiction	369	(10)
Adaptations That Produce Tolerance and Physical Dependence	370	(1)
Opiate Tolerance and Dependence	370	(2)
Emotional and Motivational Aspects of Dependence	372	(1)
Adaptations Implicated in Emotional-Motivational Dependence	372	(2)
Other Mechanisms Related to Tolerance	374	(1)
Specificity of Neural Substrates That Underlie Dependence	374	(1)
Link Between Drug Craving and Relapse of Addiction	374	(1)
Sensitization of Neural Processes May Underline Drug Craving	375	(1)
Mechanisms of Sensitization	375	(1)
Impact of Gene Expression on Long-Lasting Adaptations	376	(1)
Adaptations in Neuronal Morphology and Survival	377	(1)
Adaptations Relevant to Conditioned Craving and Relapse of Addiction	378	(1)
Treatment of Addiction	379	(4)
Psychostimulants	379	(1)
Opiates	379	(2)
Alcohol	381	(2)
Higher Cognitive Function and Psychosis	383	(26)
Neuroanatomy of Higher Cognition	384	(1)
Working Memory and Cognitive Abstraction	385	(1)
Psychosis and Schizophrenia	386	(6)
Pathophysiology of Schizophrenia	388	(4)
Pharmacology of Perception and Integration	392	(17)
Drugs That Induce Psychosis	392	(6)
Drugs That Reduce Psychosis	398	(11)
Sleep, Arousal, and Attention	409	(24)
Historical Overview	410	(1)
Normal Human Sleep	411	(1)
Ontogeny of Sleep	411	(2)
Functions of Sleep	413	(1)
Neural Substrates of Sleep	414	(2)
NREM Sleep	414	(1)
REM Sleep	414	(2)
Association of Adenosine With Sleep	416	(1)
Circadian and Homeostatic Control of the Sleep-Wake Cycle	416	(2)
Molecular Control of Circadian Rhythms	417	(1)
Neurobiology of Arousal	418	(1)
Sleep Disorders	419	(2)
Dysomnias	419	(2)
Parasomnias	421	(1)
Pharmacology of Sleep-Wake Disorders	421	(5)
Benzodiazepines	421	(2)
Nonbenzodiazepine Sedative-Hypnotic Agents	423	(2)
Drugs That Increase Alertness	425	(1)
Attention	426	(1)
Cortical Responsiveness to Stimuli	426	(1)
Orchestration of Attentional Processes	427	(2)
Attention Deficit and Hyperactivity Disorder	429	(1)
Neurobiologic Mechanisms of ADHD	429	(1)
Treatment of ADHD	430	(3)
Pain	433	(20)
Processing of Pain-Related Information by the Peripheral Nervous System	434	(5)
Primary Afferent Nociceptors	434	(3)
Sensitization	437	(2)
Neurogenic Inflammation	439	(1)
Processing of Pain-Related Information by the CNS	439	(5)
Dorsal Horn of the Spinal Cord	439	(2)
Neurotransmitters and Receptors in the Dorsal Horn	441	(2)
Multiple Pathways to the Brain	443	(1)
Endogenous Mechanisms of Analgesia	444	(2)
Endogenous Opioids and Related Peptides	444	(1)
Descending Analgesic Pathways	445	(1)
Analgesic Medications	446	(3)
Opiates	446	(2)
Nonsteroidal Antiinflammatory Drugs	448	(1)
Nonopioid, Non-NSAID Analgesics	449	(1)
Clinical Pain Syndromes	449	(4)
Neuropathic Pain	450	(1)
Migraine	450	(3)
Memory and Dementias	453	(26)
Memory	454	(3)
Declarative and Nondeclarative Memory	454	(1)
The Medial Temporal Lobe System	455	(2)
Synaptic Plasticity: How Do Neurons Remember?	457	(8)
LTP and Memory Formation	458	(4)
Other Forms of Synaptic Plasticity	462	(1)
Beyond LTP: Why We Remember What We Remember	463	(2)
Pharmacologic Regulation of Memory	465	(1)
Disorders of Memory	465	(3)
Alzheimer Disease and Related Dementias	468	(11)
Pathology	469	(1)
Genetic and Molecular Mechanisms	470	(1)
Role of APP and Aβ	470	(2)
Role of Presenilins	472	(1)
Role of ApoE	472	(1)
Role of Other Genes	473	(1)
Treatment	474	(5)
Seizures and Stroke	479	(26)
Stroke	480	(1)
Basic Mechanisms of Excitotoxicity	480	(6)
Depletion of Energy Stores	482	(1)
Failure of Ion Pumps	482	(1)
Depolarization and Firing	482	(1)
Increases in Intracellular Ca2+	482	(1)
Activation of Enzymes by Ca2+	482	(2)
Acidosis	484	(1)
Formation of Free Radicals	484	(1)
Apoptosis	485	(1)
Treatment of Stroke	486	(4)
The Peri-infarct Area: An Important Treatment Target	486	(1)
Restoring Blood Supply	486	(4)
Minimizing Ca2+ Influx into Cells	490	(1)
Reducing Free Radical Damage	490	(1)
Promoting Neural Recovery	490	(1)
Seizures and Epilepsy	490	(9)
Generation of a Seizure	492	(1)
Classification of Seizures	493	(4)
What Causes Epilepsy?	497	(1)
Genetic Influences	497	(1)
Neural Death, Neurogenesis, and Neural Sprouting: Keys to Epileptogenesis?	498	(1)
Treatment of Epilepsy	499	(6)
Drugs That Enhance Na+ Channel Inactivation	500	(1)
Drugs That Enhance Inhibitory GABAergic Transmission	501	(1)
Rhyme and Reason: Determining the Appropriate Drug	502	(3)
Index	505