Neurobiology of Alcohol Dependence

Antonio Noronha, Changhai Cui, Robert Adron Harris, John C. Crabbe

• Publisher: Academic Press
• Year: 2014
• Print ISBN:
  9780124059412
• eBook ISBN:
  9780124071551
• Topic: Biological Sciences
• Subtopic: Addiction in Psychology
• Index: Biological Sciences

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

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...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Section 1: Neurocircuitry of Alcohol Dependence
• Section 2: Neurosignaling and Neuroplasticity of Alcohol Dependence
• Section 3: Gene and Behavior
• Index