Neurobiology of Alcohol Dependence

Recent scientific advances have provided substantial information on the brain circuits and pathways relevant to various aspects of dependence. Neurobiology of Alcohol Dependence highlights the most recent data at the molecular, cellular, neurocircuitry, and behavioral levels, fostering an understanding how neuroplasticity and neuroadaptation occur, and how different neural pathways and neurocircuits contribute to dependence.

• Highlights recent advances in understanding alcohol addiction from molecular, cellular, neurocircuitry, and behavioral levels
• Integrates several emerging areas of research and discusses the application of novel research techniques to the understanding of alcohol dependence
• Chapters authored by leaders in the field around the globe — the broadest, most expert coverage available

• Language: English
• Publisher: Academic Press
• Release date: May 2, 2014
• ISBN: 9780124071551

Book preview

Neurobiology of Alcohol Dependence

First Edition

Edited by

Antonio B.C. Noronha

Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

Changhai Cui

Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

R. Adron Harris

Waggoner Center for Alcohol & Addiction Research, The University of Texas at Austin, Austin, TX, USA

John C. Crabbe

Portland Alcohol Research Center, Oregon Health & Science University and VA Medical Center, Portland, OR, USA

Table of Contents

Cover image

Title page

Copyright

Contributors

Preface

Section 1: Neurocircuitry of Alcohol Dependence

Chapter 1. Frameworks of Alcohol Addiction: Alcohol Addiction as a Reward Deficit and Stress Surfeit Disorder

Abstract

Acknowledgments

Definitions and Conceptual Framework for Negative Reinforcement in Alcoholism

Motivation, Withdrawal, Opponent Process, and Compulsive Use

Animal Models for Compulsive Alcohol Seeking

Neural Substrates of the Negative Emotional State Associated With Alcoholism

Protracted Withdrawal

Stress-Induced Reinstatement

Corticotropin-Releasing Factor, Stress, and the Frontal Cortex

Cellular Mechanisms that Mediate the Neuroplasticity of the Dark Side in the Extended Amygdala

Negative Reinforcement in Alcoholism: An Allostatic View

References

Chapter 2. Cortico-Basal Ganglia Networks and the Neural Substrates of Actions

Abstract

The Problem of Motivated Behavior

Neural Basis of Motivated Behavior

Implications for Alcohol Addiction

Conclusions

References

Chapter 3. Prefrontal Limbic-Striatal Circuits and Alcohol Addiction in Humans

Abstract

Introduction

The Prefrontal-Limbic-Striatal Circuit

Acute Effects of Alcohol on the Prefrontal-Limbic-Striatal Circuit

Alcohol Addiction and Effects on the Prefrontal-Limbic-Striatal Circuit Function

Dysfunction in the PLS Circuit and Alcohol-Relapse Risk

Conclusions and Future Directions

References

Chapter 4. Molecular Adaptations in Mesolimbic Circuitry and Pathological Ethanol Intake

Abstract

Introduction

Passive versus Active Exposure Models

Ion Channels in the NAcb

Ion Channels in the VTA

GABA Receptors

Dopamine Receptors

Dopamine Release

Adaptations in the CRF System

Other Peptides and Modulators

Summary

References

Chapter 5. The Bed Nucleus of the Stria Terminalis: A Critical Site of Ethanol-Induced Alterations in Neurotransmission

Abstract

BNST Chemoarchitecture and Major Divisions

Ethanol Effects on the BNST: Known and Potential Targets

Pathways of Interest

Conclusions and Future Directions

References

Chapter 6. The Effects of Stress on Measures of Alcohol Drinking in Rodents

Abstract

Introduction

Genetic Differences in Stress Systems Contribute to Alcohol Consumption

Relationship between Withdrawal and Alcohol Consumption

Effects of Stress on Alcohol Consumption/Intake

Stress-Induced Reinstatement

Effects of Ethanol Exposure on Stress-Related Behaviors

Conclusions

References

Chapter 7. Alcohol and Developing Neuronal Circuits

Abstract

Acknowledgments

Introduction

Hippocampal Circuits

Cerebellar Circuits

Reward Pathways

Conclusions

References

Chapter 8. Human Imaging Studies of Brain Circuitry Disrupted by Alcoholism

Abstract

Acknowledgment

Introduction

The Incomplete Lesion as the Underlying Neuropathology of Alcoholism

Alcoholism Affects Selective Brain Systems, Leaving Others Relatively Intact

Intrinsic Functional Networks: Resting-State Functional-Connectivity MRI (rs-fcMRI)

Evidence for a Structural Substrate of Functional Connectivity

Conclusions

References

Section 2: Neurosignaling and Neuroplasticity of Alcohol Dependence

Chapter 9. From Signaling Pathways to Behavior: The Light and Dark Sides of Alcohol

Abstract

Acknowledgments

Introduction

Adverse Actions of Alcohol

Acute Alcohol-Induced Sedation and Rapid Tolerance

Molecular Mechanisms Underlying Alcohol-Mediated Stress and Anxiety

Alcohol-Seeking and Excessive-Drinking Behaviors

Maladaptive Plasticity, Learning and Memory

Protective Signaling Pathways

Dysregulation of Protective Genes

Concluding Remarks and Future Directions

References

Chapter 10. Glutamate Signaling in Alcohol Abuse and Dependence

Abstract

Acknowledgments

Introduction and Review of Glutamate Receptors

Physiology of iGluRs

Association of iGluRs with Intracellular Proteins

Metabotropic Glutamate Receptors

Alcohol Effects on Glutamate Receptor Signaling

Defining a Site of Action of Ethanol on iGluRs

Involvement of GluRs in Ethanol Consumption and Dependence

Summary

References

Chapter 11. Central Amygdala Neuroplasticity in Alcohol Dependence

Abstract

Acknowledgments

Introduction

Central Amygdala

In Vitro Slice Electrophysiology in CeA

Alcohol Effects on CeA Excitatory Glutamatergic System

Alcohol Effects on CeA Inhibitory Gabaergic System

Neuropeptide Effects on Synaptic Transmission in the CeA

Conclusion: The Central Amygdala is a Hub for Alcohol Use Disorders

References

Chapter 12. Neural Plasticity in the Ventral Tegmental Area and Alcohol Addiction

Abstract

Introduction

Ethanol Effects on Intrinsic Excitability of DA Neurons

Ethanol Effects on Synaptic Inputs onto DA Neurons

Ethanol Effects on Activity-Dependent Synaptic Plasticity in DA Neurons

Effects of Other Life Experiences on VTA DA Neurons and Alcoholism/Addiction Vulnerability

Conclusion

References

Chapter 13. Extrasynaptic GABAA Receptors and Alcohol

Abstract

Introduction

Pharmacological Effects of Moderate-to-Low Concentrations of Alcohol

GABAA Receptors and Alcohol

Synaptic and Extrasynaptic GABAA Receptors

Alcohol’s Interaction with GABAA Receptors: Mediation of Alcohol’s Reinforcing Effects?

Knockdown of the GABAA δ Subunit in the Nucleus Accumbens Shell Reduces Alcohol’s Reinforcing Properties

Subregion Specificity in the Nucleus Accumbens Shell

How Do α4βδ GABAA Receptors in the Medial Shell Contribute to Alcohol’s Reinforcing Effects?

Alcohol’s Actions at α4βδ GABAA Receptors: Direct or Indirect?

Other GABAA-Receptor Isoforms and Alcohol’s Reinforcing Properties

Summary

References

Chapter 14. Cannabinoids and the Neural Actions of Alcohol

Abstract

Acknowledgments

Introduction

Endocannabinoids: Molecular Properties, Synthesis, Degradation, and Receptors

Acute Interactions Between EtOH and Molecular Constituents of the EC System

Effects of CB1 Activation on EtOH-Associated Behaviors

Effects of Chronic Alcohol on the Endocannabinoid System

Allelic Variants of the CNR1 Gene and the Susceptibility to Alcohol Dependence

Summary

References

Chapter 15. Impact of Alcohol Abuse and Dependence on the Structure and Function of the Prefrontal Cortex

Abstract

Acknowledgements

Anatomy of the PFC

Effects of Alcohol on PFC Structure and Function

Cognitive Modulation of Ensemble Organization in the PFC

Chronic Alcohol and Resting-State Synchrony

Prefrontal-Striatal Networks and Top-Down Control of Behavior

Stress-Induced Changes in PFC Function

Alcohol and Stress

Adolescence and Delayed Cortical Development

Impact of Alcohol on Adolescent PFC Development

Conclusions

References

Chapter 16. Molecular Mechanisms Underlying the Development of Functional and Behavioral Tolerance to Alcohol

Abstract

Introduction

Attributes of Molecular Alcohol Tolerance in BK Channels

Ethanol Regulation of NMDA and AMPA Receptor Subunits

Ethanol Regulation of GABA-A Receptor Subunits

Kinase Regulation of Ion Channel Function

Scaffolding/Cytoskeletal Protein Interactions Regulating Channel Function

Lipid Environment Influences Molecular Tolerance Observed in the BK Channel

Role of Palmitoylation in Regulating Ion Channel Function and Distribution

Molecular Tolerance of Voltage-Gated Calcium Channels is Coordinated with Tolerance of the BK Channel in Nerve Terminals

Ethanol Regulation of Gene Transcription

Conclusions

References

Section 3: Gene and Behavior

Chapter 17. Alcohol and the Brain: An Epigenetic Viewpoint

Abstract

Acknowledgments

General Introduction

Epigenetics: A General Overview

Epigenetic Modifications: An Overview

Alcohol, Epigenetics, and Gene Expression: An Overview

Summary and Future Directions

References

Chapter 18. The Genetic Complexity of Alcohol Drinking in Rodents

Abstract

Acknowledgments

Introduction

Rodent Assays of Alcohol Drinking

Genetic Contributions to Alcohol Drinking Assays

Conclusions

References

Chapter 19. Alcohol Dependence, Withdrawal, and Relapse

Abstract

Acknowledgments

Introduction

Animal Models of Alcohol Dependence and Withdrawal

Alcohol Dependence, Withdrawal, and Relapse Drinking

Summary

References

Chapter 20. Drinking to Dependence Risk Factors in Nonhuman Primates

Abstract

Nonhuman Primate Models of Drinking to Dependence

Risk Factors: Genetics

Risk Factors: Stress

Risk Factors: Age of Onset

Risk Factors: Temperament

Summary

References

Chapter 21. The Potential Role of Glucocorticoids and the HPA Axis in Alcohol Dependence

Abstract

Acknowledgments

Introduction

The HPA Axis

Determinants of HPA Axis Activity

Glucocorticoid Mechanisms in the Etiology of AUDs

Therapeutic Targets in the Brain Stress System

Summary and Future Directions

References

Chapter 22. Anxiety and Alcohol Use Disorders: A Perspective from Molecular and Epigenetic Studies

Abstract

Acknowledgment

Introduction

Relationship between Anxiety and Alcoholism: A Clinical View

Relationship between Anxiety and Alcoholism: A Preclinical View

Brain Circuitry Involved in Comorbidity of Anxiety and Alcoholism

Anxiety and Alcohol Use Disorders: A Perspective from Molecular Studies

Anxiety and Alcohol Use Disorders: A Perspective from Epigenetic Studies

Conclusions

References

Chapter 23. The Genetics of Alcohol Responses of Invertebrate Model Systems

Abstract

Acknowledgments

Introduction

Ethanol Exposure and Behavioral Responses

Genes and Pathways Involved in Behavioral Ethanol Responses

Neuronal Circuits Mediating Ethanol Responses

Conclusion

References

Chapter 24. MicroRNAs in Alcohol Abuse and Toxicity

Abstract

Acknowledgments

Introduction

Emergence of ncRNAs (and miRNAs) as Dominant Transcriptional Output from Genomes

A Historical Perspective on miRNAs: Scientific Curiosity to Cellular Necessity

miRNA Biogenesis

RISC/miRNA Function

Mechanisms for Regulating miRNA Biogenesis and Function: Potential Targets of Ethanol or Determinants of Ethanol Susceptibility

Evidence for a General Model of Drug Abuse and miRNA Function

Conclusion and Potential for miRNA Therapeutics

References

Chapter 25. Contributions of Genomic and Informatic Approaches to Understanding Alcohol Dependence: From Genes to Networks

Abstract

Acknowledgments

Introduction

Data-Driven Methods to Discover the Biological Bases of Alcohol Dependence

A Systems Neurogenomic Network of Alcoholism

Bioinformatics Knowledge Systems and Integrative Functional Genomics

Summary: Integrative Networks of Alcoholism Beyond the Genome

References

Chapter 26. Complex Genetics of Alcoholism

Abstract

Acknowledgments

Alcohol Dependence Is a Complex Genetic Disease

Alcoholism and Related Phenotypes

The Search for Genes Contributing to Alcohol Dependence

Summary

References

Index

Copyright

Academic Press is an imprint of Elsevier

32 Jamestown Road, London NW1 7BY, UK

225 Wyman Street, Waltham, MA 02451, USA

525 B Street, Suite 1800, San Diego, CA 92101-4495, USA

Copyright © 2014 Elsevier Inc. All rights reserved

Except chapter 14 which is in the public domain

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [e-mail]. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information

Notice

No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

ISBN: 978-0-12-405941-2

For information on all Academic Press publications visit our website at elsevierdirect.com

Typeset by Scientific Publishing Services www.sps.co.in

Printed and bound in China

14 15 16 17 10 9 8 7 6 5 4 3 2 1

Contributors

R. Adron Harris,     Waggoner Center for Alcohol and Addiction Research, University of Texas–Austin, USA

Somayeh Ahmadiantehrani,     The Gallo Research Center, Department of Neurology, University of California, San Francisco, USA

Nigel S. Atkinson,     Waggoner Center for Alcohol & Addiction Research, Department of Neuroscience, University of Texas–Austin, USA

Erich J. Baker,     Computer Science Department, Baylor University, USA

Sridevi Balaraman,     Texas A&M Health Science Center, College of Medicine, Department of Neuroscience and Experimental Therapeutics, USA

Jacqueline M. Barker,     Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, USA

Howard C. Becker,     Charleston Alcohol Research Center, Departments of Psychiatry and Neurosciences, Medical University of South Carolina, Charleston, SC USA

Elizabeth J. Burnett,     Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, USA

Elissa J. Chesler,     The Jackson Laboratory, USA

John C. Crabbe,     Portland Alcohol Research Center, Veterans Affairs Medical Center, Department of Behavioral Neuroscience, Oregon Health & Science University, USA

Howard J. Edenberg,     Department of Biochemistry and Molecular Biology, and Department of Medical and Molecular Genetics, Indiana University School of Medicine, USA

Betsy Ferguson,     Division of Neurosciences, Oregon National Primate Research Center, USA

C. Fernando Valenzuela,     Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, USA

Tatiana Foroud,     Department of Medical and Molecular Genetics, Indiana University School of Medicine, USA

Alfredo Ghezzi,     Waggoner Center for Alcohol & Addiction Research, Department of Neuroscience, University of Texas–Austin, USA

Nicholas W. Gilpin,     Department of Physiology, Louisiana State University Health Sciences Center, USA

William B. Glen,     Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, USA

Kathleen A. Grant

Division of Neurosciences, Oregon National Primate Research Center, USA

Department of Behavioral Neurosciences, Oregon Health and Science University, USA

Christa Helms,     Division of Neurosciences, Oregon National Primate Research Center, USA

Linzy M. Hendrickson,     Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, USA

Andrew Holmes,     Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA

Patricia H. Janak,     The Gallo Research Center, Department of Neurology, University of California, San Francisco, USA

L. Judson Chandler,     Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, USA

Thomas L. Kash,     The Bowles Center for Alcohol Studies and the Department of Pharmacology, The University of North Carolina at Chapel Hill, USA

George F. Koob,     Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, USA

Remi Legastelois,     The Gallo Research Center, Department of Neurology, University of California, San Francisco, USA

Virginia Long,     The Gallo Research Center, Department of Neurology, University of California, San Francisco, USA

David M. Lovinger,     Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA

Emily G. Lowery-Gionta,     The Bowles Center for Alcohol Studies and the Department of Pharmacology, The University of North Carolina at Chapel Hill, USA

Ketan Marballi,     Waggoner Center for Alcohol and Addiction Research, University of Texas–Austin, USA

R. Dayne Mayfield,     Waggoner Center for Alcohol and Addiction Research, University of Texas–Austin, USA

Mary E. McCaul

Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, USA

Department of Medicine, The Johns Hopkins University School of Medicine, USA

Megan McClintick,     Department of Behavioral Neurosciences, Oregon Health and Science University, USA

Rajesh C. Miranda,     Texas A&M Health Science Center, College of Medicine, Department of Neuroscience and Experimental Therapeutics, USA

Hitoshi Morikawa,     Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, USA

Russell A. Morton,     Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, USA

Subhash C. Pandey,     Department of Psychiatry, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois, USA

Matthew J. Pava,     Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA

Adolf Pfefferbaum

Neuroscience Program, SRI International, USA

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, USA

Charles L. Pickens,     Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA

Igor Ponomarev,     Waggoner Center for Alcohol and Addiction Research, University of Texas–Austin, USA

Anna K. Radke,     Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA

Marisa Roberto,     Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, USA

Dorit Ron,     The Gallo Research Center, Department of Neurology, University of California, San Francisco, USA

Adrian Rothenfluh,     Department of Psychiatry, Program in Neuroscience, UT Southwestern Medical Center, USA

Garrett E. Seale,     Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, Puerto Rico, USA

Dongju Seo,     Department of Psychiatry, Yale University School of Medicine, USA

Rajita Sinha,     Department of Psychiatry, Yale University School of Medicine, USA

Mary Ann C. Stephens,     Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, USA

Garret D. Stuber

Departments of Psychiatry & Cell and Molecular Physiology, Bowles Center for Alcohol Studies, University of North Carolina, USA

Department of Cell Biology and Physiology, Neuroscience Center, Bowles Center for Alcohol Studies, University of North Carolina, USA

Edith V. Sullivan,     Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, USA

Karen Szumlinski,     Department of Psychological and Brain Sciences, University of California–Santa Barbara, USA

Steven N. Treistman,     Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA

Benjamin R. Troutwine,     Waggoner Center for Alcohol & Addiction Research, Department of Neuroscience, University of Texas–Austin, USA

Gary S. Wand

Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, USA

Department of Medicine, The Johns Hopkins University School of Medicine, USA

Vincent Warnault,     The Gallo Research Center, Department of Neurology, University of California, San Francisco, USA

Leslie R. Whitaker,     Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, USA

John J. Woodward,     Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, USA

F. Woodward Hopf,     Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, USA

Henry H. Yin,     Department of Psychology and Neuroscience and Neurobiology, Center for Cognitive Neuroscience, Duke University, USA

Preface

Alcohol dependence is mediated by complex neural mechanisms that involve multiple brain circuits and neuroadaptive changes in a variety of neurotransmitter and neuropeptide systems. Recent research advances at the molecular, cellular, neurocircuitry, and behavioral levels have provided substantial information for our understanding of the neurobiological mechanisms contributing to various aspects of alcohol dependence (such as craving, tolerance, withdrawal, and relapse). The goal of this book is to integrate that current information and knowledge and provide a comprehensive and updated overview of the neurobiological mechanisms underlying alcoholism.

Neurobiology of Alcohol Dependence presents a breadth of topics on neurocircuitry, neuroplasticity, genes, and behaviors; these topics stem from both preclinical and clinical studies of alcohol dependence. It comprises three main sections. Section I focuses on the neurocircuitries of alcohol dependence. Alcohol has a profound impact on multiple neurocircuits related to reward, stress, habit formation, and executive function, which work in concert to contribute to alcohol dependence. The chapters in this section depict how dysfunction of various neurocircuits may be responsible for behavioral phenotypes associated with alcohol dependence, the developmental effects of alcohol on the central nervous system, and, lastly, the whole brain structural and functional changes associated with alcohol dependence.

Section II provides critical reviews of the neurosignaling and neuroplasticity associated with alcohol dependence. Unlike other drugs of abuse, alcohol does not have a specific receptor target in the brain. Instead, it interacts with multiple neurobiological systems. This section highlights alcohol’s actions on various neurotransmitters, neuropeptides, and signaling systems as well as the neuroplasticity of these systems implicated in alcohol dependence. It also discusses the structural and functional changes contributing to the alteration of brain networks associated with alcohol dependence.

Section III bridges genetic factors to behavioral phenotypes related to alcohol dependence. It emphasizes the importance of both genes and epigenetic modifications of gene expression contributing to alcohol dependence and alcohol-related traits. It discusses different experimental paradigms for studying alcohol dependence in laboratories and highlights advances in understanding risk factors for developing alcohol dependence, tolerance, and relapse using model systems. Collectively, these three sections summarize our current understanding of the neurobiological mechanisms underlying alcohol dependence at the molecular, cellular, circuitry, and behavioral levels.

Although this book provides a rather comprehensive overview of neurobiological mechanisms of alcohol dependence, it is not intended to be all inclusive. Several areas, including neuroimmune signaling, sleep disorders, and pain, are not covered as independent chapters but are briefly mentioned in the text. The close relevance of these topics to alcohol dependence warrants future discussion and further research efforts.

Neurobiology of Alcohol Dependence will appeal to scientists, students, and educators who are interested in this topic, particularly those in the research fields of alcohol-use disorders and addiction. Readers will benefit from critical insights provided by leading alcohol researchers. We would like to thank all the scientists who have contributed chapters to this book and those who have provided constructive comments and suggestions for the manuscripts.

Antonio Noronha

Changhai Cui

Adron Harris

John Crabbe

Section 1: Neurocircuitry of Alcohol Dependence

Outline

Chapter 1 Frameworks of Alcohol Addiction: Alcohol Addiction as a Reward Deficit and Stress Surfeit Disorder

Chapter 2 Cortico-Basal Ganglia Networks and the Neural Substrates of Actions

Chapter 3 Prefrontal Limbic-Striatal Circuits and Alcohol Addiction in Humans

Chapter 4 Molecular Adaptations in Mesolimbic Circuitry and Pathological Ethanol Intake

Chapter 5 The Bed Nucleus of the Stria Terminalis: A Critical Site of Ethanol-Induced Alterations in Neurotransmission

Chapter 6 The Effects of Stress on Measures of Alcohol Drinking in Rodents

Chapter 7 Alcohol and Developing Neuronal Circuits

Chapter 8 Human Imaging Studies of Brain Circuitry Disrupted by Alcoholism

Chapter 1

Frameworks of Alcohol Addiction

Alcohol Addiction as a Reward Deficit and Stress Surfeit Disorder

George F. Koob,    Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, USA

Abstract

Alcoholism has been hypothesized to be composed of multiple stages that feed into each other in a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Alcoholism can be defined as a compulsion to seek and take alcohol, loss of control in limiting intake, and the emergence of a negative emotional state when access to alcohol is prevented. Alcoholism impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from positive reinforcement to negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. Acute withdrawal from chronic alcohol sufficient to produce dependence increases reward thresholds, increases anxiety-like responses, and drives both hypothalamic-pituitary and extrahypothalamic stress response. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of specific neurochemical elements involved in reward and stress within basal forebrain structures that involve the ventral striatum (binge/intoxication stage), extended amygdala (withdrawal/negative affect stage), and prefrontal cortex (preoccupation/anticipation stage), respectively. Specific neurochemical dysregulations in these structures include decreases in reward neurotransmission, such as decreased dopamine and opioid peptide function in the ventral striatum. There is also recruitment of brain stress systems, such as corticotrophin-releasing factor and dynorphin, and possibly the frontal cortex. A brain stress-response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. The combination of the loss of reward function and recruitment of brain stress systems provides a powerful neurocircuitry basis for negative emotional states that are responsible for the negative reinforcement that drives, at least partially, the compulsivity of alcoholism.

Keywords

addiction; opponent process; stress; extended amygdala; corticotrophin-releasing factor

Acknowledgments

The author would like to thank Mellany Santos and Michael Arends for assistance with manuscript preparation and editing. Research was supported by National Institutes of Health grants AA013517, AA020608, AA06420, and AA08459 from the National Institute on Alcohol Abuse and Alcoholism and the Pearson Center for Alcoholism and Addiction Research. This is publication number 25003 from The Scripps Research Institute.

Definitions and Conceptual Framework for Negative Reinforcement in Alcoholism

Alcoholism has many symptoms that vary from behavioral and social dysfunction to physiological changes (tolerance and withdrawal) embedded in the diagnosis of Alcohol Use Disorders defined in the Diagnostic and Statistical Manual of the American Psychiatric Association, fifth edition (DSM-V; American Psychiatric Association, 2013). Alcohol Use Disorder is a composite of the previous abuse and dependence criteria outlined in the DSM-IV (American Psychiatric Association, 1994). Alcoholism, and more generically drug addiction, can be defined as a chronically relapsing disorder characterized by (i) compulsion to seek and take the drug (alcohol), (ii) loss of control in limiting (alcohol) intake, and (iii) emergence of a negative emotional state (such as dysphoria, anxiety, or irritability) reflecting a motivational withdrawal syndrome when access to the drug (alcohol) is prevented (Koob & Le Moal, 1997). Clinically and in animal models, the occasional but limited use of alcohol generally does not lead to escalated alcohol intake and the emergence of a chronic compulsive alcohol-seeking state that is termed alcoholism. Alcoholism and drug addiction in general have been hypothesized to be composed of multiple stages that feed into each other in a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving; Figure 1.1). The three stages are conceptualized as interacting with each other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob & Le Moal, 1997).

Figure 1.1 (Top left) Diagram showing the stages of impulse-control disorder and compulsive disorder cycles related to the sources of reinforcement. In impulse-control disorders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratification, or relief during the act. Following the act, there may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stress followed by repetitive behaviors (compulsions) that are aimed at preventing or reducing distress (American Psychiatric Association, 1994). Positive reinforcement (pleasure/gratification) is more closely associated with impulse-control disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. [Taken with permission from Koob, 2013.] (Top right) Collapsing the cycles of impulsivity and compulsivity results in the addiction cycle, conceptualized as three major components: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. [Taken with permission from Koob, 2008.] (Bottom) Change in the relative contribution of positive and negative reinforcement constructs during the development of substance dependence on alcohol. [Taken with permission from Koob, 2013.]

The thesis to be argued in the present synthesis is that alcoholism is a reward-deficit disorder and a stress-surfeit disorder and that the compulsivity observed in alcoholism has an important negative reinforcement component that perpetuates alcoholism. Positive reinforcement is defined as the process by which the presentation of a stimulus (usually appetitive) increases the probability of a response. Negative reinforcement can be defined as the process by which the removal of an aversive stimulus increases the probability of a response. Note that negative reinforcement is not punishment, although both involve an aversive stimulus. In punishment, the aversive stimulus suppresses behavior, including drug taking (e.g., disulfiram [Antabuse]). Negative reinforcement can be perhaps described in lay terms as reward via relief (i.e., relief reward), such as the removal of pain or, in the case of alcoholism, removal of the negative emotional state associated with acute withdrawal or protracted abstinence.

Negative reinforcement will be argued to be driven by negative emotional states that derive from genetic, epigenetic, or excessive alcohol intake. Such negative emotional states become sensitized over time and set up an allostatic state that perpetuates dependence. Alcoholism also involves substantial neuroadaptations that persist beyond acute withdrawal and trigger relapse and deficits in cognitive function that can also fuel compulsive drinking. However, the argument here is that a core deficit in reward function and stress function sets up vulnerability to relapse in alcoholism and possibly even deficits in cognitive function that perpetuate compulsive use and relapse to compulsive use.

To support this hypothesis, a compelling negative reinforcement view of alcoholism will be presented with the following key points. A negative emotional state is a common presentation in most alcoholics during withdrawal and protracted abstinence. Much is known about the neurobiological mechanisms that drive such negative emotional states. From this perspective, the neurobiological substrates that underlie the compulsive motivation to seek alcohol will be reviewed. An argument will be presented that it is the loss of reward function and gain of brain stress function that mediate the negative emotional state outlined as key to alcoholism.

Drug addiction has generally been conceptualized as a disorder that involves elements of both impulsivity and compulsivity. Impulsivity can be defined behaviorally as a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others (Moeller, Barratt, Dougherty, Schmitz, & Swann, 2001, p. 1784). Impulsivity is a core deficit in substance abuse disorders and is represented by DSM-V symptoms, such as recurrent alcohol use in situations in which it is physically hazardous or having a craving or a strong desire or urge to use alcohol. Compulsivity can be defined as elements of behavior that result in the perseveration of responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. Compulsivity is analogous to the symptoms of Substance Use Disorder outlined by the American Psychiatric Association: continued substance use despite knowledge of having persistent or recurrent social or interpersonal problems or despite knowledge of having a persistent or recurrent physical or psychological problem and a great deal of time spent in activities necessary to obtain the substance (American Psychiatric Association, 2013). Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle that consists of three stages noted above—preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect—in which impulsivity often dominates at the early stages and compulsivity dominates at terminal stages (Figure 1.1). As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob, 2004).

In alcoholism, a pattern of oral drug taking evolves that is often characterized by binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking and which are characterized by a severe emotional and somatic withdrawal syndrome. Many alcoholics continue with such a binge/withdrawal pattern for extended periods of time, but some individuals can evolve into a situation akin to opioid addiction in which they must have alcohol available at all times to avoid the negative consequences of abstinence. Here, intense preoccupation with obtaining alcohol (craving) develops that is linked not only to stimuli associated with obtaining the drug but also to stimuli associated with withdrawal and the aversive motivational state. A pattern develops in which alcohol must be obtained to avoid the severe dysphoria and discomfort of abstinence.

The pattern of alcohol addiction, related to reward dysfunction, can be illustrated by excerpts from two case histories from Knapp (1996) and Goodwin (1981). In the first representative case history, an individual progressed from a point at which he stated, I drank when I was happy and I drank when I was anxious and I drank when I was bored and I drank when I was depressed, which was often, (Knapp, 1996, p. 3) to, I loved the way drink made me feel, and I loved its special power of deflection, its ability to shift my focus away from my own awareness of self and onto something else, something less painful than my own feelings, (ibid, p. 7) and, There’s a sense of deep need, and the response is a grabbiness, a compulsion to latch on to something outside yourself in order to assuage some deep discomfort (ibid, p. 54). Similarly, in a second representative case history, Alcohol seemed to satisfy some specific need I had, which I can’t describe, (Goodwin, 1981, p. 29) and, There were always reasons to drink. I was low, tense, tired, mad, happy, (ibid, p. 29) and, The goal, always, was to maintain a glow, not enough, I hoped, that people would notice, but a glow, (ibid, p. 29) and, By now I was hooked and knew it, but desperately did not want others to know it. I had been sneaking drinks for years—slipping out to the kitchen during parties and such—but now I began hiding alcohol, in my desk, bedroom, car glove compartment, so it would never be far away, ever. I grew panicky even thinking I might not have alcohol when I needed it, which was just about always, (ibid, p. 30) and, I loathed myself. I was waking early and thinking what a mess I was, how I had hurt so many others and myself. The words ’guilty’ and ‘depression’ sound superficial in trying to describe how I felt. The loathing was almost physical—a dead weight that could be lifted in only one way, and that was by having a drink (ibid, p. 30); see the Appendix in Koob & Le Moal, 2006, for full quotations).

These case histories illustrate numerous key points regarding the present thesis, but the main point to be elaborated is that there is a transition from drinking to feel good to drinking to avoid feeling bad. To some extent, the likelihood of such a transition is driven by inherent personality differences and personality differences that are shaped not only by genetics but also by developmental and social factors. As Khantzian cogently argued, seeking and taking drugs in addiction can be argued to be sources of self-medication for negative emotional-distress syndromes that vary with the individual from physical and emotional pain to chronic dysphoria to stress and anxiety to interpersonal difficulties (Khantzian, 1997). Additionally, he argued that self-medication may be drug-specific—patients may have a preferential use of drugs that fits with the nature of the painful feeling states that they are self-medicating (such as opiates to counter intense anger and rage, stimulants as augmenting agents for high-energy individuals, energizing agents for low-energy individuals, and depressants [e.g., alcohol] for individuals who are tense and anxious). The common element argued by Khantzian is that each class of drugs serves as an antidote or corrective to a dysphoric state and acts as a replacement for a defect in the psychological structure (Kohut, 1971, p. 46) of such individuals (Khantzian, 2003). However, even more importantly, as such self-medication evolves, the excessive taking of drugs changes the brain such that the withdrawal from the drug itself creates or exacerbates the state that requires self-medication (see Negative reinforcement in alcoholism: an allostatic view ahead).

Motivation, Withdrawal, Opponent Process, and Compulsive Use

Motivation is a state that involves arousal, expectation, and emotion, all of which direct behavior. William James wrote, Some expectation of consequences must in every case like this be aroused; and this expectation, according as it is, that of something desired or of something disliked, must necessarily either reinforce or inhibit the mere impulse (James, 1918, p. 390), and motivation can be defined as a tendency of the whole animal to produce organized activity (Hebb, 1972). Such motivational states are not constant but rather vary over time. The concept of motivation was inextricably linked with hedonic, affective, or emotional states in addiction in the context of temporal dynamics by Solomon’s opponent process theory of motivation (Solomon, 1980; Solomon & Corbit, 1974). Solomon and Corbit (1974) postulated that hedonic, affective, or emotional states, once initiated, are automatically modulated by the central nervous system through mechanisms that reduce the intensity of hedonic feelings. For drugs, the a-process includes affective or hedonic habituation (or tolerance), and the b-process includes affective or hedonic withdrawal (abstinence). The a-process in drug use consists of positive hedonic responses, occurs shortly after the presentation of a stimulus, correlates closely with the intensity, quality, and duration of the reinforcement (alcohol), and shows tolerance. In contrast, the b-process in drug use appears after the a-process has terminated, consists of negative hedonic responses, and is sluggish in onset, slow to build up to an asymptote, slow to decay, and gets larger with repeated exposure. The thesis elaborated here is that there are neurocircuitry changes of specific neurochemical systems that account for the b-process. Such opponent processes are hypothesized to begin early in drug taking, reflecting not only deficits in brain reward-system function but also recruitment of the function of brain stress systems. Furthermore, we hypothesize that recruitment of the brain stress systems forms one of the major sources of negative reinforcement in alcoholism.

Thus, we define dependence or the manifestation of a withdrawal syndrome after the removal of chronic drug administration in terms of motivational symptoms, such as the emergence of a negative emotional state (e.g., dysphoria, anxiety, or irritability) when access to the drug is prevented (Koob & Le Moal, 2001), which can be exacerbated or even caused by the physical signs of withdrawal. Indeed, some have argued that the development of such a negative affective state can define dependence as it relates to addiction (Baker, Piper, McCarthy, Majeskie, & Flore, 2004; Koob, Stinus, & Le Moal, 1989; Russell, 1976).

The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to extreme distress, or it may be equated with the amount of difficulty or effort required to do without the drug, object, etc. (Russell, 1976)

Alcoholics show dramatic evidence of dysphoric states during acute withdrawal that persist into protracted abstinence. Alcohol withdrawal in humans produces well-documented physical (somatic) symptoms, such as tremor, autonomic hyperactivity, nausea, vomiting, and seizures, but more importantly produces significant affective symptoms of anxiety, dysphoria, and depression-like symptoms. Acute withdrawal (i.e., the first week postalcohol) is characterized by Beck Depression Inventory scores of approximately 20, which is categorized within the range of moderate depression (15–30; Potokar et al., 1997), and Hamilton Depression Scale scores of 18, which is close to 20 (the cutoff for antidepressant medication in affective disorder; Brown & Schuckit, 1988). Depression scores decline during subsequent weeks of treatment but remain at close to 10 for Hamilton Depression Scale scores for up to four weeks of an inpatient treatment program (Brown & Schuckit, 1988). In another study of inpatient alcoholics during withdrawal, the Beck Depression Inventory score was 15 at withdrawal and remained at 12.8 two days into withdrawal and at 9.4 two weeks postwithdrawal (de Timary, Luts, Hers, & Luminet, 2008). Similar results were obtained for anxiety measures (de Timary et al., 2008; Potokar et al., 1997). In another study with a long-term follow-up six months after a four-week inpatient detoxification, Beck Depression Inventory scores remained at approximately 6, and trait anxiety scores (STAI-X2) remained above 33, even in subjects without comorbid anxiety or depression (Driessen et al., 2001). Independent of comorbidity status, individuals who relapsed had higher trait anxiety scores than those who abstained (Driessen et al., 2001). Therefore, although alcoholics show significant decreases in measures of depression and anxiety during withdrawal, there is a measurable level of depression-like symptoms that persist long after acute withdrawal into protracted abstinence that may be clinically (treatment) relevant.

More compelling for the present thesis, during a two-week inpatient withdrawal study, alexithymia (defined as a state of deficiency in understanding, processing, or describing emotions; from the Greek a for lack, lexis for word, and thymos for emotion; Sifneos, 1973; Taylor & Bagby, 2000), which results in poor emotional regulation and stress-management abilities, remained high and stable during the two-week period (de Timary et al., 2008). Alexithymia scores did not decline between the zero-day and two-day time points but remained high at a score of 57 and declined only to 53 at the three-week time point (de Timary et al., 2008). The authors argued that alexithymia is a stable personality trait in alcoholics rather than a state-dependent phenomenon, providing support for the self-medication hypothesis outlined previously.

Work in animal models can also support the hypothesis that there are opponent process-like motivational changes associated with the development of alcohol dependence. Electrical brain stimulation reward or intracranial self-stimulation has a long history as a measure of activity of the brain reward system and the acute reinforcing effects of drugs of abuse. All drugs of abuse, when administered acutely, decrease brain stimulation reward thresholds (Kornetsky & Esposito, 1979), and when drugs of abuse are administered chronically, there is an increase in reward thresholds during withdrawal. Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest thresholds involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area with the basal forebrain (Koob, Winger, Meyerhoff, & Annau, 1977; Olds & Milner, 1954). Although much emphasis was focused initially on the role of the ascending monoamine systems in the medial forebrain bundle in brain stimulation reward, other nondopaminergic systems in the medial forebrain bundle clearly play a key role (Hernandez et al., 2006).

Rats made dependent using chronic ethanol-vapor exposure at blood alcohol levels sufficient to drive excessive drinking showed an increase in brain reward thresholds during withdrawal that lasted up to three days postwithdrawal (Schulteis, Markou, Cole, & Koob, 1995). However, data suggest that, similar to other drugs of abuse, such opponent-like processes can begin with a single dosing (see Figure 1.2). An acute elevation in brain reward thresholds was observed during repeated acute withdrawal from ethanol, bearing a striking resemblance to human subjective reports (Schulteis & Liu, 2006; Figure 1.2). These results demonstrate that the elevation in brain reward thresholds following prolonged access to alcohol may fail to return to baseline levels between repeated, prolonged exposure to alcohol self-administration (i.e., a residual reward deficit), thus creating a greater elevation in reward thresholds observed during withdrawal from chronic ethanol. Rapid acute tolerance and opponent process-like effects in response to the hedonic effects of alcohol have been reported in human studies using the alcohol clamp procedure (Morzorati, Ramchandani, Flury, Li, & O’Connor, 2002). These data provide compelling evidence for brain reward dysfunction with chronic alcohol, which provides strong support for a hedonic allostasis model of alcoholism (Koob, 2003b).

Figure 1.2 (A) Withdrawal from a single bout of acute ethanol intoxication (Week 1) resulted in a significant but transient increase in brain reward threshold only with the highest dose of ethanol tested (2.0 g/kg, bottom panel, *p < 0.05, compared with vehicle controls at given time-point post-injection). The effect was significant at 6 h, a time when blood alcohol levels had declined to virtually undetectable levels following this dose of ethanol. Repeated treatment with this dose for two additional weeks resulted in a progressive broadening of the duration of significant threshold elevations. The data are expressed as the mean ± SEM percentage of baseline threshold. n = 8 − 10 per dose group. [Taken with permission from Schulteis & Liu, 2006.] (B) Time-dependent elevation of intracranial self-stimulation thresholds during ethanol withdrawal. Mean blood alcohol levels were 197.29 mg%. The data are expressed as the mean ± SEM percentage of baseline threshold. *p < 0.05, thresholds that were significantly elevated above control levels at 2–48 h postethanol. Open circles indicate the control condition. Closed circles indicate the ethanol withdrawal condition. [Taken with permission from Schulteis et al., 1995.]

The dysregulation of brain reward function associated with withdrawal from chronic administration of drugs of abuse is a common element of all drugs of abuse. Withdrawal from chronic cocaine (Markou & Koob, 1991), amphetamine (Paterson, Myers, & Markou, 2000), opioids (Schulteis, Markou, Gold, Stinus, & Koob, 1994), cannabinoids (Gardner & Vorel, 1998), nicotine (Epping-Jordan, Watkins, Koob, & Markou, 1998), and ethanol (Schulteis et al., 1995) leads to increases in reward thresholds during acute abstinence, and some of these elevations in threshold can last for up to one week. These observations lend credence to the hypothesis that opponent processes can set the stage for one aspect of compulsivity in which negative reinforcement mechanisms are engaged.

More recently, the opponent process theory has been expanded into the domains of the neurobiology of drug addiction from a neurocircuitry perspective. An allostatic model of the brain motivational systems has been proposed to explain the persistent changes in motivation that are associated with dependence in addiction (Koob & Le Moal 2001; Koob & Le Moal 2008). In this formulation, addiction is conceptualized as a cycle of increasing dysregulation of brain reward/anti-reward mechanisms that results in a negative emotional state that contributes to the compulsive use of drugs. Counteradaptive processes that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range. These counteradaptive processes are hypothesized to be mediated by two mechanisms: within-system neuroadaptations and between-system neuroadaptations (Koob & Bloom, 1988).

In a within-system neuroadaptation, the primary cellular response element to the drug would itself adapt to neutralize the drug’s effects; persistence of the opposing effects after the drug disappears would produce the withdrawal response (Koob & Bloom, 1988, p. 720). Therefore, a within-system neuroadaptation is a molecular or cellular change within a given reward circuit to accommodate overactivity of hedonic processing associated with addiction, resulting in a decrease in reward function.

The emotional dysregulation associated with the withdrawal/negative affect stage also may involve between-system neuroadaptations in which neuro-chemical systems other than those involved in the positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation of the reward system. In the between-systems opposing process, a different cellular system and separable molecular apparatus would be triggered by the changes in the primary drug response neurons and would produce the adaptation and tolerance (Koob & Bloom, 1988). Therefore, a between-system neuroadaptation is a circuitry change in which another different circuit (antireward circuit) is activated by the reward circuit and has opposing actions, again limiting reward function. The remainder of this review explores the neuroadaptational changes that occur in the brain emotional systems, to account for the neurocircuitry changes that produce opponent processes and that are hypothesized to play a key role in the compulsivity of addiction.

The development of the aversive emotional state that drives the negative reinforcement of addiction is defined here as the dark side of addiction. We have argued that drug addiction progresses from a source of positive reinforcement that may indeed involve a form of sensitization of incentive salience, as argued by Robinson and Berridge (1993), to a sensitization of the brain stress and antireward systems that sets up a powerful negative reinforcement process. Antireward is a concept developed by Koob and Le Moal (2008), based on the hypothesis that brain systems are in place to limit reward (Koob & Le Moal, 1997), with an opponent process concept that forms a general feature of biological systems. Our concept of an antireward system is derived from the hypothesis of both within- and between-system neuroadaptations to excessive activation of the reward system at the neurocircuitry level.

Animal Models for Compulsive Alcohol Seeking

Methods of inducing compulsive-like drinking of alcohol range from having animals drink alcohol solutions that are made more palatable with the addition of a sweetener (Ji, Gilpin, Richardson, Rivier, & Koob, 2008) to intermittent overnight access (Simms, Bito-Onon, Chatterjee, & Barlett, 2010; Wise, 1973) to restricting intake to specific periods of the dark cycle (i.e., drinking in the dark; Rhodes, Best, Belknap, Finn, & Crabbe, 2005) to models that involve alcohol dependence in animals, such as alcohol-vapor inhalation, intragastric alcohol infusion, and alcohol liquid diet. Compulsive-like drinking can be defined in animal models as drinking in the face of punishment (quinine adulteration or drinking suppressed by footshock), drinking in the face of increased work requirements (increased responding in a progressive-ratio schedule), resistance to extinction when alcohol is removed, and escalation in intake with chronic access (tolerance). The compulsive use of alcohol derives from multiple sources of reinforcement, and animal models have been developed not only for the acute positive reinforcing effects of ethanol but also for the negative reinforcing effects associated with removal of the aversive effects of ethanol withdrawal. A major early breakthrough was the development of a training procedure that obviated the aversiveness of the ethanol taste by beginning access via a sweetened solution and subsequently fading in ethanol or, more recently, allowing animals 24 hour access for several days (for reviews, see Koob, 2012; Samson, 1987).

The extension of these procedures to measures of self-administration in dependent rats and postdependent rats has yielded a number of procedures that reliably produce levels of alcohol self-administration that generate blood alcohol levels well above the legal intoxication limit (0.08 gm%; O’Dell et al., 2004; Roberts, Cole, & Koob, 1996). In an alcohol liquid–diet procedure, the diet is typically the sole source of calories available to the rats (e.g., Moy, Knapp, Criswell, & Breese, 1997), thereby forcing the rats to consume the alcohol. Typically, rats are provided a palatable liquid diet that contains 5–8.7% v/v ethanol as their sole source of calories; this is sufficient to produce dependence and maintain blood alcohol levels of 100–130 mg% during the dark (active drinking) cycle (Brown, Jackson, & Stephens, 1998; Schulteis, Hyytia, Heinrichs, & Koob, 1996; Valdez, Sabino, & Koob, 2004). High responders during withdrawal from a liquid diet will reach blood alcohol levels of approximately 80–100 mg% (Gilpin et al., 2009; Schulteis et al., 1996).

Reliable self-administration of ethanol in dependent animals using ethanol-vapor exposure has been extensively characterized in rats, in which animals reach blood alcohol levels in the 100–150 mg% range (Roberts, Heyser, Cole, Griffin, & Koob, 2000; Roberts, Heyser, & Koob, 1999a; Figure 1.3). Similarly, rats with a history of alcohol dependence show increased self-administration of ethanol even weeks after acute withdrawal (Roberts et al., 2000). In a variant of alcohol-vapor exposure with perhaps more validity for the human condition, intermittent exposure to chronic ethanol using alcohol-vapor chambers (14 hours on, 10 hours off) produces more rapid escalation to increased ethanol intake and higher amounts of intake (O’Dell et al., 2004; Rimondini, Arlinde, Sommer, & Heilig, 2002), and blood alcohol levels are reliably above 140 mg% after a 30 minute session of self-administration in dependent animals (Richardson, Lee, O’Dell, Koob, & Rivier, 2008; Richardson, Zhao et al., 2008). In both the liquid-diet and ethanol-vapor procedures, alcohol intake is directly related to the blood alcohol range and the pattern of intermittent high-dose alcohol exposure (Gilpin et al., 2009). Although the alcohol-vapor model may have limited face validity, considering that alcohol is passively administered to animals, numerous studies demonstrated that it also has robust predictive validity for alcohol addiction (Heilig & Koob, 2007; Koob, Lloyd, & Mason, 2009).

Figure 1.3 (Left) Ethanol self-administration in ethanol-dependent and non-dependent animals. Induction of ethanol dependence following chronic intermittent ethanol vapor exposure. ***p < 0.001, significant group × test session interaction. (Right) All of the analyses were conducted when ethanol-dependent animals were in acute (6 h) withdrawal, a time point coinciding with diminished blood alcohol levels (BALs) and increased ethanol self-administration behavior. ***p < 0.001, significant effect of withdrawal time point. [Taken with permission from Edwards, Guerrero, Ghoneim, Roberts, & Koob, 2011.]

Similar procedures have been developed in mice using withdrawal-induced drinking now termed chronic intermittent ethanol dependence (CIED) in dependent animals. Withdrawal-induced drinking usually involves C57BL/6 mice that are exposed to intermittent durations of ethanol vapor (three cycles of 16 hours of vapor and eight hours of air) and then tested in a two-hour, limited-access, ethanol-preference drinking test during the circadian dark period (Becker & Lopez, 2004; Finn et al., 2007; Lopez & Becker, 2005). Intermittent ethanol-vapor exposure significantly increased 15% (v/v) ethanol intake by 30–50% in the postvapor period, usually after multiple cycles and usually after 24 hours of withdrawal (Finn et al., 2007). Similar results have been reported using an operant response in mice in 60 minute test sessions for 10% (w/v) ethanol with intermittent vapor exposure of 14 hours on, 10 hours off (Chu, Koob, Cole, Zorrilla, & Roberts, 2007).

High doses of alcohol solution will also be self-administered intragastrically in mice and rats after the animals are made dependent via passive intragastric infusion (Fidler, Clews, & Cunningham, 2006; Fidler et al., 2012). Here, the rats will self-infuse 4–7 g/kg per day of ethanol, and blood alcohol levels average 0.12 g%, measured 30 minutes after the start of a bout in which rats infuse 1.5 g/kg every 30 minutes. Reliable increases in bouts of binge-like drinking in mice have been obtained using the drinking-in-the-dark paradigm. Drinking in the dark involves mice that are allowed to drink 20% ethanol three hours after lights out for two hours for three consecutive days; on the fourth day, they are allowed four hours of access, also three hours after lights out (Rhodes et al., 2005).

Neural Substrates of the Negative Emotional State Associated With Alcoholism

Within-System Neuroadaptations that Contribute to the Compulsivity Associated with the Dark Side of Alcoholism

One prominent hypothesis is that dopamine systems are compromised in crucial phases of the addiction cycle in alcoholism, such as withdrawal and protracted abstinence. This decrease in dopamine function is hypothesized to lead to decreased motivation for non-drug-related stimuli and increased sensitivity to the abused drug (Melis, Spiga, & Diana, 2005). Activation of the mesocorticolimbic dopamine system has long been known to be critical for the acute rewarding properties of psychostimulant drugs and to be associated with the acute reinforcing effects of alcohol (Koob, 1992; McBride & Li, 1998; Nestler, 2005). However, the magnitude of the increase in dopaminergic activity produced by alcohol pales in comparison to that of psychostimulant intoxication. For example, intravenous cocaine self-administration produces a 200% increase in extracellular dopamine (Weiss, Markou, Lorang, & Koob, 1992) compared with ethanol (which produces a 20–50% increase in extracellular dopamine in the nucleus accumbens for alcohol; Doyon et al., 2003; Ramchandani et al., 2011). Such a relationship changes with the development of dependence.

More compelling at the circuitry level in the mesocorticolimbic dopamine domain are the decreases in activity of the mesocorticolimbic dopamine system and decreases in serotonergic neurotransmission in the nucleus accumbens that occur during alcohol withdrawal in animal studies (Rossetti, Hmaidan, & Gessa, 1992; Weiss et al., 1992, 1996; Figure 1.4). In nondependent rats, operant ethanol self-administration increased both dopamine and serotonin release in the nucleus accumbens. In dependent Wistar rats trained to self-administer ethanol during withdrawal, the release of dopamine and serotonin was monitored by microdialysis in the nucleus accumbens at the end of a three to five week ethanol (8.7% w/v) liquid-diet regimen, during eight hours of withdrawal, and during renewed availability of ethanol involving the opportunity to operantly self-administer ethanol (10% w/v) for 60 minutes followed by unlimited access to the ethanol liquid diet. Withdrawal from the chronic-ethanol diet produced a progressive suppression in the release of these transmitters over the eight hour withdrawal period. Self-administration of ethanol reinstated and maintained dopamine release at prewithdrawal levels but failed to completely restore serotonin efflux (Figure 1.5). These findings suggest that deficits in nucleus accumbens monoamine release may contribute to the negative affective consequences of ethanol withdrawal and thereby motivate ethanol-seeking behavior in dependent subjects (Weiss et al., 1996). Similar dramatic decreases in extracellular dopamine in the nucleus accumbens, measured by microdialysis, were found in a study in which animals were tested eight hours into ethanol withdrawal produced by chronic repeated ethanol injections of up to 5 g/kg every six hours for six consecutive days using the Majchrowicz procedure (Majchrowicz, 1975; Rossetti, Isola, De Vry, & Fadda, 1999). Therefore, ethanol-dependent animals may show a much greater percentage increase in dopamine release in the nucleus accumbens during ethanol self-administration during withdrawal because baseline levels of dopamine are so low during withdrawal (Weiss et al., 1996). Such acute withdrawal is associated with decreased activity of the mesocorticolimbic dopamine system, reflected by electrophysiological recordings and in vivo microdialysis (Diana, Pistis, Carboni, Gessa, & Rossetti, 1993; Parsons, Koob, & Weiss, 1995; Figure 1.4).

Figure 1.4 The left panel shows the effect of ethanol withdrawal on absolute extracellular dopamine concentrations in the nucleus accumbens in ethanol-withdrawn rats. The middle and right panels show the spontaneous activity of antidromically identified ventral tegmental area-nucleus accumbens dopamine neurons in control (middle) and ethanol-withdrawn (right) rats. [Taken with permission from Diana et al., 1993.]

Figure 1.5 Effects of operant alcohol self-administration in dependent rats undergoing ethanol withdrawal on dopamine efflux in the nucleus accumbens. Average water intake in this group was negligible (0.8 ml) and is not shown. The top shows withdrawal dialysate concentrations of dopamine during hour 8 of withdrawal. The dashed line represents the mean prewithdrawal dialysate dopamine concentration. The bottom shows the amounts of self-administered alcohol (10% w/v) during 10 min intervals in the dependent group. Alcohol self-administration in dependent rats restored dopamine levels to prewithdrawal values. [Modified with permission from Weiss et al., 1996.]

Imaging studies in humans with alcoholism have consistently shown long-lasting decreases in the numbers of dopamine D2 receptors in subjects with alcoholism compared with controls (Volkow, Fowler, & Wang, 2002). Additionally, alcohol-dependent subjects had dramatically reduced dopamine release in the striatum in response to a pharmacological challenge with the stimulant drug methylphenidate (Volkow et al., 2007). Decreases in the number of dopamine D2 receptors, coupled with the decrease in dopaminergic activity, in cocaine, nicotine, and alcohol abusers are hypothesized to produce a decreased sensitivity of reward circuits to stimulation by natural reinforcers (Martin-Solch et al., 2001; Volkow & Fowler, 2000). These findings suggest an overall reduction of the function of the dopamine component of reward circuitry to natural reinforcers and other drugs in drug-addicted individuals.

Other within-system neuroadaptations under this conceptual framework include changes in receptor transduction mechanisms in the ventral striatum (nucleus accumbens). In the context of chronic alcohol administration, multiple molecular mechanisms have been hypothesized to counteract the acute effects of ethanol that could be considered within-system neuroadaptations. For example, chronic ethanol decreases γ-aminobutyric acid (GABA) receptor function, possibly through downregulation of the α1 subunit (Devaud, Fritschy, Sieghart, & Morrow, 1997; Mhatre, Pena, Sieghart, & Ticku, 1993). Chronic ethanol also decreases the acute inhibition of adenosine reuptake (i.e., tolerance develops to the inhibition of adenosine by ethanol; Sapru, Diamond, & Gordon, 1994).

Between-System Neuroadaptations that Contribute to Compulsivity Associated with the Dark Side of Alcoholism

Brain neurochemical systems involved in arousal–stress modulation may also be engaged within the neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug (alcohol) and to restore normal function despite the presence of drug. The neuroanatomical entity termed the extended amygdala (Heimer & Alheid, 1991) may represent a common anatomical substrate that integrates brain arousal–stress systems with hedonic processing systems to produce the between-system opponent process elaborated previously. The extended amygdala is composed of the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial (shell) subregion of the nucleus accumbens. Each of these regions has cytoarchitectural and circuitry similarities (Heimer & Alheid, 1991). The extended amygdala receives numerous afferents from limbic structures, such as the basolateral amygdala and hippocampus, and sends efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the extrapyramidal motor system (Alheid, De Olmos, & Beltramino, 1995).

The extended amygdala, notably the central nucleus of the amygdala and bed nucleus of the stria terminalis, has long been hypothesized to play a key role in fear conditioning and anxiety responses (Le Doux, 2000: Ciocchi et al. 2010; Davis, Walker, Miles, & Grillon 2010). The basolateral amygdala receives significant sensory input from thalamus and cortex and sends prominent glutamatergic projections to the central nucleus of the amygdala and bed nucleus of the stria terminalis, which mediate fear conditioning (Phelps & LeDoux, 2005) and extinction (Quirk & Mueller, 2008) processes. The central nucleus of the amygdala, however, is composed mostly of γ-aminobutyric acid (GABAergic) projection neurons and interneurons (Sun & Cassell, 1993; Veinante & Freund-Mercier, 1998), and the bed nucleus of the stria terminalis is a major target of the central nucleus of the amygdala projection neurons (Krettek & Price, 1978; Sun & Cassell, 1993; Veinante & Freund-Mercier, 1998; Weller & Smith, 1982).

The extended amygdala may also be involved in the emotional component of pain processing (Neugebauer, Li, Bird, & Han, 2004). Ascending pain pathways terminate in the lateral part of the central extended amygdala. This part of the central nucleus is known as the nociceptive amygdala (Bernard & Besson, 1990) and may be involved in the processing of emotional components of pain. The central nucleus of the extended amygdala (CeA) receives functionally distinct inputs from the pontine parabrachial area (PB, nociceptive information) and basolateral amygdala (BLA, sensory-affective information) circuits that are activated in chronic pain states (Neugebauer, Li, Bird, Bhave, & Gereau, 2003) as reflected in multiple electrophysiological and molecular neuroadaptations in the CeA, including a key role for CRF systems (Ji & Neugebauer, 2007). Such results suggest that elements of the extended amygdala also facilitate nociceptive signaling in persistent pain states (Neugebauer, 2007), and such altered processing may orient the organism’s motivational capacity to act toward alleviating the chronic pain condition via negative reinforcement mechanisms (Egli, Koob, & Edwards, 2012).

Corticotropin-releasing factor is a 41-amino-acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors (Bale & Vale, 2004; Vale, Spiess, Rivier, & Rivier, 1981). Central administration of CRF mimics the behavioral response to activation and stress in rodents, and administration of competitive CRF-receptor antagonists generally has antistress effects (for reviews, see Dunn & Berridge, 1990; Heinrichs & Koob, 2004; Sarnyai, Shaham, & Heinrichs, 2001). Two major CRF receptors have been identified, with CRF1-receptor activation associated with increased stress responsiveness and CRF2-receptor activation associated with decreases in feeding and decreases in stress responsiveness (Heinrichs & Koob, 2004). Note that CRF1 antagonists are most effective in states of acute stress and generally do not have major actions on nonstressed behaviors (Heinrichs & Koob, 2004). CRF neurons are heavily represented in the hypothalamus, extended amygdala, and autonomic midbrain and hindbrain nuclei but are also