Drugs, Addiction, and the Brain -  Michael A. Arends,  George F. Koob,  Michel Le Moal

Drugs, Addiction, and the Brain (eBook)

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2014 | 1. Auflage
350 Seiten
Elsevier Science (Verlag)
978-0-12-386959-3 (ISBN)
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Drugs, Addiction, and the Brain explores the molecular, cellular, and neurocircuitry systems in the brain that are responsible for drug addiction. Common neurobiological elements are emphasized that provide novel insights into how the brain mediates the acute rewarding effects of drugs of abuse and how it changes during the transition from initial drug use to compulsive drug use and addiction. The book provides a detailed overview of the pathophysiology of the disease. The information provided will be useful for neuroscientists in the field of addiction, drug abuse treatment providers, and undergraduate and postgraduate students who are interested in learning the diverse effects of drugs of abuse on the brain.


  • Full-color circuitry diagrams of brain regions implicated in each stage of the addiction cycle
  • Actual data figures from original sources illustrating key concepts and findings
  • Introduction to basic neuropharmacology terms and concepts
  • Introduction to numerous animal models used to study diverse aspects of drug use.
  • Thorough review of extant work on the neurobiology of addiction


George F. Koob, Ph.D., received his Bachelor of Science degree from Pennsylvania State University and his Ph.D. in Behavioral Physiology from The Johns Hopkins University. He was recently appointed (in 2014) as Director of the National Institute on Alcohol Abuse and Alcoholism (currently on a leave of absence as Professor at The Scripps Research Institute, Adjunct Professor in the Departments of Psychology and Psychiatry at the University of California San Diego, and Adjunct Professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California San Diego). As an authority on drug addiction and stress, he has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and the neuroadaptations of the reward and stress circuits associated with the transition to dependence. Dr. Koob has published over 780 scientific papers. In collaboration with Dr. Michel Le Moal, he wrote the renowned book Neurobiology of Addiction (Elsevier, 2006). He was previously Director of the NIAAA Alcohol Research Center at The Scripps Research Institute, Consortium Coordinator for NIAAA's multi-center Integrative Neuroscience Initiative on Alcoholism, and Co-Director of the Pearson Center for Alcoholism and Addiction Research. He has trained 75 postdoctoral fellows and 11 predoctoral fellows. He is currently Editor-in-Chief of the journal Pharmacology Biochemistry and Behavior and Senior Editor for Journal of Addiction Medicine. Dr. Koob taught for 35 years in the Psychology Department at the University of California San Diego, including courses such as Drugs Addiction and Mental Disorders and Impulse Control Disorders, courses that regularly matriculated 400-500 students each. He also taught Contemporary Topics in Central Nervous System Pharmacology at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD for 9 years.
Dr. Koob's research interests have been directed at the neurobiology of emotion, with a focus on the theoretical constructs of reward and stress. He has made contributions to our understanding of the anatomical connections of the emotional systems and the neurochemistry of emotional function. Dr. Koob has identified afferent and efferent connections of the basal forebrain (extended amygdala) in the region of the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala in motor activation, reinforcement mechanisms, behavioral responses to stress, drug self-administration, and the neuroadaptation associated with drug dependence.
Dr. Koob also is one of the world's authorities on the neurobiology of drug addiction. He has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and more recently on the neuroadaptations of these reward circuits associated with the transition to dependence. He has validated key animal models for dependence associated with drugs of abuse and has begun to explore a key role of anti-reward systems in the development of dependence.
Dr. Koob's work with the neurobiology of stress includes the characterization of behavioral functions in the central nervous system for catecholamines, opioid peptides, and corticotropin-releasing factor. Corticotropin-releasing factor, in addition to its classical hormonal functions in the hypothalamic-pituitary-adrenal axis, is also located in extrahypothalamic brain structures and may have an important role in brain emotional function. Recent use of specific corticotropin-releasing factor antagonists suggests that endogenous brain corticotropin-releasing factor may be involved in specific behavioral responses to stress, the psychopathology of anxiety and affective disorders, and drug addiction.
Drugs, Addiction, and the Brain explores the molecular, cellular, and neurocircuitry systems in the brain that are responsible for drug addiction. Common neurobiological elements are emphasized that provide novel insights into how the brain mediates the acute rewarding effects of drugs of abuse and how it changes during the transition from initial drug use to compulsive drug use and addiction. The book provides a detailed overview of the pathophysiology of the disease. The information provided will be useful for neuroscientists in the field of addiction, drug abuse treatment providers, and undergraduate and postgraduate students who are interested in learning the diverse effects of drugs of abuse on the brain. Full-color circuitry diagrams of brain regions implicated in each stage of the addiction cycle Actual data figures from original sources illustrating key concepts and findings Introduction to basic neuropharmacology terms and concepts Introduction to numerous animal models used to study diverse aspects of drug use. Thorough review of extant work on the neurobiology of addiction

Front Cover 1
Drugs, Addiction, and the Brain 4
Copyright 5
Contents 6
Preface 8
Chapter 1 - What is Addiction? 10
DEFINITIONS OF ADDICTION 10
NEUROADAPTATIONAL VIEWS OF ADDICTION 
29 
SUMMARY 35
Suggested Reading 36
Chapter 2 - Introduction to the Neuropsychopharmacology of Drug Addiction 38
THE CENTRAL NERVOUS SYSTEM 39
PHARMACOLOGY FOR ADDICTION 42
PHARMACOKINETICS 44
BASIC NEUROBIOLOGY OF ADDICTION 51
BRAIN STRUCTURES AND FUNCTIONS RELEVANT TO THE THREE STAGES OF THE ADDICTION CYCLE 61
NEUROADAPTATIONAL SUMMARY 71
Suggested Reading 72
Chapter 3 - Animal Models of Addiction 74
VALIDATION OF ANIMAL MODELS OF DRUG ADDICTION 76
ANIMAL MODELS OF THE BINGE/INTOXICATION STAGE OF THE ADDICTION CYCLE 77
ANIMAL MODELS OF THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE ADDICTION CYCLE 87
ANIMAL MODELS OF THE PREOCCUPATION/ANTICIPATION STAGE OF THE ADDICTION CYCLE 92
ANIMAL MODELS OF VULNERABILITY TO ADDICTION 97
SUMMARY OF ANIMAL MODELS OF ADDICTION 98
Suggested Reading 99
Chapter 4 - Psychostimulants 102
DEFINITIONS 102
HISTORY OF PSYCHOSTIMULANT USE 104
PHYSIOLOGICAL EFFECTS 111
BEHAVIORAL EFFECTS 111
MEDICAL USES 114
PHARMACOKINETICS 114
BEHAVIORAL MECHANISM OF ACTION 
117 
USE, ABUSE, AND ADDICTION 118
NEUROBIOLOGICAL EFFECTS 121
SUMMARY 139
Suggested Reading 140
Chapter 5 - Opioids 142
DEFINITIONS 142
HISTORY OF OPIOID USE 143
PHYSIOLOGICAL EFFECTS 144
BEHAVIORAL EFFECTS 145
MEDICAL USES 145
PHARMACOKINETICS 148
BEHAVIORAL MECHANISM 149
USE, ABUSE, AND ADDICTION 151
NEUROBIOLOGICAL EFFECTS 163
SUMMARY 179
Suggested Reading 180
Chapter 6 - Alcohol 182
DEFINITIONS 182
HISTORY OF ALCOHOL USE 184
BEHAVIORAL EFFECTS 188
PHARMACOKINETICS 189
USE, ABUSE, AND ADDICTION 191
ALCOHOL TOXICITY 197
BEHAVIORAL MECHANISM OF ACTION 204
NEUROBIOLOGICAL EFFECTS 205
SUMMARY 226
Suggested Reading 227
Chapter 7 - Nicotine 230
DEFINITIONS 230
HISTORY OF USE 231
MEDICAL USE AND BEHAVIORAL EFFECTS 239
PHARMACOKINETICS 240
USE, ABUSE, AND ADDICTION 241
BEHAVIORAL MECHANISM 247
NEUROBIOLOGICAL EFFECTS 248
SUMMARY 267
Suggested Reading 268
Chapter 8 - Cannabinoids 270
DEFINITIONS 270
HISTORY OF CANNABINOID USE 277
MEDICAL USES 278
BEHAVIORAL EFFECTS 280
PHARMACOKINETICS 282
USE, ABUSE, AND ADDICTION 284
BEHAVIORAL MECHANISM OF ACTION 296
NEUROBIOLOGICAL EFFECTS 297
SUMMARY 315
Suggested Reading 316
Chapter 9 - Medications for the Treatment of Addiction – A Neurobiological Perspective 318
CONCEPTUAL APPROACH FOR UNDERSTANDING CURRENT AND FUTURE MEDICATIONS DEVELOPMENT 
319 
EFFECTS OF KNOWN MEDICATIONS ON ANIMAL MODELS OF ADDICTION – REVERSE VALIDITY (ROSETTA STONE APPROACH) 325
NOVEL TARGETS FOR MEDICATION DEVELOPMENT 331
HUMAN LABORATORY STUDIES 337
INDIVIDUAL DIFFERENCES AND MEDICATION DEVELOPMENT 340
CLINICAL TRIALS – UNIQUE 340
SUMMARY 340
Suggested Reading 341
Index 344

Chapter 2

Introduction to the Neuropsychopharmacology of Drug Addiction


Abstract


Drug addiction involves a three-stage cycle – binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation – that worsens over time and involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process.

The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain reward and stress systems. Acute withdrawal from all major drugs of abuse increases reward thresholds, decreases mesolimbic dopamine activity, increases anxiety-like responses, increases extracellular levels of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala, and increases dynorphin in the ventral striatum. Excessive drug taking also activates CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding.

Keywords


drug addiction; negative reinforcement; reward system; stress system; allostatic process; reward threshold; dopamine; corticotropin-releasing factor; pharmacology; pharmacokinetics; neurobiology of addiction

Outline

The Central Nervous System 30

Neurons 30

Neurotransmission 31

Glia 32

Pharmacology for Addiction 33

What is a Drug, and What is Pharmacology? 33

Drug Nomenclature 33

Drug Classification 34

Pharmacokinetics 35

Absorption 35

Drug Elimination 36

Drug Receptors and Signal Transduction 38

Dose-Response Functions 40

Therapeutic Ratio 41

Basic Neurobiology of Addiction 42

Dopamine 42

Norepinephrine 43

Opioid Peptides 44

Corticotropin-Releasing Factor 45

Vasopressin 48

Neuropeptide Y 49

Nociceptin 50

Brain Structures and Functions Relevant to the Three Stages of the Addiction Cycle 52

Binge/Intoxication Stage – Basal Ganglia 52

Withdrawal/Negative Affect Stage – Extended Amygdala 54

Preoccupation/Anticipation Stage – Prefrontal Cortex 59

Neuroadaptational Summary 62

Suggested Reading 63

Neuro-,” of or relating to the brain

The brain is not simply an amorphous mass of grayish tissue. It courses with blood and electrical impulses. It regulates the body’s temperature. It tells us how we feel. It allows us to interact with others and the world. It says when to wake up and when to fall asleep. It helps us put our shoes on in the morning. It also is susceptible to a host of external influences, including drugs. To better understand the subsequent chapters in this book and to put the medical, biological, and neurobiological mechanisms of drug addiction into context, we must take a step back to define and explain the common components of the body’s central nervous system, from the macro (brain regions) to the micro (neurons, neurotransmitters). Armed with this information, students will be able to appreciate the in-depth knowledge that has been gained from extensive scientific research during the past 100 years, with the hope that they, too, will be able to discover greater intricacies to explain why many individuals succumb to drug addiction.

The Central Nervous System


The human brain consists of two types of cells: roughly 100 billion neurons and a greater number of glia. Neurons are highly specialized cells that have an important and unique functional property that is not shared with any other cells in the body. Neurons communicate with each other through both electrical and chemical mechanisms. More importantly for the theme of this book, neurons communicate through circuits, and these circuits form the structural bases of feelings, thoughts, and behavior, the ultimate functional output of the brain.

Neurons


Neurons have four major components: (1) cell body, (2) axons, (3) dendrites, and (4) synapses (Figure 2.1). The cell body contains the nucleus and receives inputs, providing the machinery for the generation of neurotransmitters and action potentials. An action potential occurs when a neuron’s membrane is depolarized beyond its threshold. This depolarization is propagated along the axon. The axon is the “sending” part of the neuron, and it conducts these action potentials to the synapse to release neurotransmitters. The synapse is a specialized space or contact zone between neurons that allows interneuronal communication. One or more dendrites comprise the “receiving” part of the neuron, providing a massive receptive area for the neuronal surface (Figure 2.2).
Neurons act on other neurons to exert three major functions: inhibition, excitation, and neuromodulation. Inhibition means that one neuron inhibits another neuron, often through the release of an inhibitory neurotransmitter at the synapse. Excitation means that one neuron activates another neuron through the release of an excitatory neurotransmitter at the synapse. Neuromodulation means that a neuron influences neurotransmission, often at a long distance.

FIGURE 2.1 Anatomy of a neuron.

Neurotransmission


The communication between neurons can be distilled into six major steps of neurotransmission relevant to the neuropharmacology of addiction (Figure 2.3).
Step 1: Neurotransmitter synthesis, involving the molecular mechanisms of peptide precursors and enzymes for further synthesis or cleavage.
Step 2: Neurotransmitter storage.
Step 3: Neurotransmitter release from the axon terminal into the synaptic cleft (or from a secreting dendrite some cases).
Step 4: Neurotransmitter inactivation caused by removal from the synaptic cleft through a reuptake process, or neurotransmitter breakdown by enzymes in the synapse or presynaptic terminal.
Step 5: Activation of the postsynaptic receptor, triggering a response of the postsynaptic cell.
Step 6: Subsequent signal transduction that responds to neurotransmitter receptor activation.
Drugs of abuse or drugs that counteract the effects of drugs of abuse can interact at any of these steps to dramatically or subtly alter chemical transmission to dysregulate or re-regulate, respectively, homeostatic function.

FIGURE 2.2 Neurons, synapses, and neurotransmitters. A typical example is shown for the neurotransmitter dopamine.

FIGURE 2.3 Synaptic neurotransmission. The figure shows a generalized process of synaptic transmission. (1) Various components of the neurotransmission machinery, such as enzymes, proteins, mRNA, and so on (depending on the neurotransmitter in question) are transported down the axon from the cell body. (2) The axonal membrane is electrically excited. (3) Organelles and enzymes in the nerve terminal synthesize, store, and release the neurotransmitter and activate the reuptake process. (4) Enzymes in the extracellular space and within the glia catabolize excess neurotransmitters released from nerve terminals. (5) The postsynaptic receptor triggers the response of the postsynaptic cell to the neurotransmitter. (6) Organelles within postsynaptic cells respond to the receptor trigger. (7) Interactions between genetic expression and postsynaptic nerve cells influence cytoplasmic organelles that respond to neurotransmitter action. (8) Certain steps are modifiable by events that occur at the synaptic contact zone. (9) The electrical portion of the nerve cell membrane integrates postsynaptic potentials in response to various neurotransmitters and produce an action potential. (10) The postsynaptic cell sends an action potential down its axon. (11) The neurotransmitter is released. The neurotransmitter that is released from the nerve terminal can be modulated by autoreceptors that respond to the neurotransmitter. [Modified with permission from Iversen LL, Iversen SD, Bloom FE, Roth RH. Introduction to Neuropsychopharmacology. Oxford, New York, 2009, p. 26.]

Glia


In addition to neurons, the central nervous system contains supporting cells. Supporting cells, generically called glia, can outnumber neurons by a factor of ten. Historically, glia were defined as the “nerve glue” that holds neurons together in the central nervous system. However, glia are now known to have key dynamic functions in the central nervous system, from myelin synthesis, to synapses, to serving as the innate brain defensive system against pathology. Glia consist of three types of supporting cells: oligodendrocytes, astrocytes, and microglia.
Oligodendrocytes synthesize myelin and provide an expedient way, via the myelin sheath, to significantly increase how fast an axon can conduct an action potential. Myelin is a long plasma membrane sheet that wraps around...

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