Chapter 3 - Neurocircuitry of alcohol addiction: synthesis from animal models

https://doi.org/10.1016/B978-0-444-62619-6.00003-3Get rights and content

Abstract

Alcoholism, more generically drug addiction, can be defined as a chronically relapsing disorder characterized by: (1) compulsion to seek and take the drug (alcohol); (2) loss of control in limiting (alcohol) intake; and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability), reflecting a motivational withdrawal syndrome, when access to the drug (alcohol) is prevented (defined here as dependence). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here, derived largely from animal models, is that a key component involves decreased brain reward function, increased brain stress function, and compromised executive function, all of which contribute to the construct of negative reinforcement. 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 decreases in reward neurotransmission in the ventral striatum, such as decreased dopamine and opioid peptide function in the nucleus accumbens (ventral striatum), but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Data from animal models that support this thesis show that acute withdrawal from chronic alcohol, sufficient to produce dependence, increases reward thresholds, increases anxiety-like responses, decreases dopamine system function, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by 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. 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. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include increases in norepinephrine function, increases in dynorphin activity, and decreases in neuropeptide Y. The combination of impairment of function in reward circuitry and recruitment of brain stress system circuitry provides a powerful neurochemical basis for the negative emotional states that are responsible for the negative reinforcement that drives the compulsivity of alcoholism.

Section snippets

Definitions and conceptual framework for neurocircuitry of alcoholism

Alcoholism has many definitions that vary from social frameworks to a psychiatric framework. Alcoholism, more generically drug addiction, can be defined as a chronically relapsing disorder characterized by: (1) compulsion to seek and take the drug (alcohol); (2) loss of control in limiting (alcohol) intake; and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability), reflecting a motivational withdrawal syndrome, when access to the drug (alcohol) is prevented

Animal models for compulsive alcohol seeking

Methods of inducing binge-like drinking with alcohol range from having animals drink alcohol solutions that are made extra palatable with the addition of a sweetener (Ji et al., 2008) to intermittent overnight access (Wise, 1973, Simms et al., 2010), to restricting intake to specific periods of the dark cycle (i.e., drinking-in-the-dark; Rhodes et al., 2005), to models that involve alcohol dependence in animals, such as alcohol vapor inhalation, intragastric alcohol infusion, and alcohol liquid

Animal models of motivation, withdrawal, and opponent process

The concept of motivation in addiction was inextricably linked with hedonic, affective, or emotional states in the context of temporal dynamics by Solomon's opponent process theory of motivation. Solomon and Corbit (1974) postulated that hedonic, affective, or emotional states, once initiated by drugs, are automatically modulated by the central nervous system with mechanisms that reduce the intensity of hedonic feelings. The a-process in drug use consists of positive hedonic responses, occurs

Neurocircuits for the binge/intoxication stage associated with alcoholism

Animal models for the acute reinforcing effects of alcohol and the use of selective antagonists for specific neurochemical systems have supported the hypothesis that alcohol at intoxicating doses has a wide but selective action on neurotransmitter systems in the brain reward systems. Neuropharmacologic studies have implicated multiple neurochemical systems in the acute reinforcing effects of alcohol, including γ-aminobutyric acid (GABA), opioid peptides, dopamine, serotonin, and glutamate (Fig.

Within-system neuroadaptations that contribute to the compulsivity associated with the dark side of alcoholism

Within-system neuroadaptations to chronic drug exposure include decreases in the function of the same neurotransmitter systems in the same neurocircuits implicated in the acute reinforcing effects of drugs of abuse. One prominent hypothesis is that dopamine systems are compromised in crucial phases of the addiction cycle, 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

Neural substrates for executive function deficits associated with alcoholism

The preoccupation/anticipation stage of the addiction cycle has long been hypothesized to be a key element of relapse in humans and defines addiction as a chronic relapsing disorder. Although often linked to the construct of craving, craving per se has been difficult to measure in human clinical studies (Tiffany et al., 2000) and often does not correlate with relapse. Nevertheless, the stage of the addiction cycle where the individual reinstates drug-seeking behavior after abstinence remains a

Compulsivity in alcoholism: an allostatic view

Compulsivity in alcoholism can derive from neurocircuitry changes at all three stages of the addiction cycle (Fig. 3.8). In the binge/intoxication stage, such changes involve neurocircuits that include enhanced incentive salience (Robinson and Berridge, 1993) and engagement of habit function (Everitt et al., 2008). In the withdrawal/negative affect stage, such changes involve neurocircuits involved in negative emotional states. In the preoccupation/anticipation stage, such changes involve

Acknowledgments

The author would like to thank Michael Arends and Mellany Santos for assistance with manuscript preparation and editing. Research was supported by National Institutes of Health grants AA006420, AA020608, and AA008459 from the National Institute on Alcohol Abuse and Alcoholism and the Pearson Center for Alcoholism and Addiction Research. This is publication number 24030 from The Scripps Research Institute.

References (222)

  • G. Colombo et al.

    Suppression by baclofen of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats

    Drug Alcohol Depend

    (2003)
  • F.T. Crews et al.

    Impulsivity, frontal lobes and risk for addiction

    Pharmacol Biochem Behav

    (2009)
  • A. Dahchour et al.

    Central effects of acamprosate: Part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats

    Psychiatry Res

    (1998)
  • W. Dyr et al.

    Evidence that the amygdala is involved in the inhibitory effects of 5-HT3 receptor antagonists on alcohol drinking in rats

    Alcohol

    (1995)
  • M.T. Fillmore et al.

    Impaired inhibitory control of behavior in chronic cocaine users

    Drug Alcohol Depend

    (2002)
  • J.C. Froehlich et al.

    Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference

    Pharmacol Biochem Behav

    (1990)
  • C.K. Funk et al.

    Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats

    Biol Psychiatry

    (2007)
  • E.L. Gardner et al.

    Cannabinoid transmission and reward-related events

    Neurobiol Dis

    (1998)
  • O. George et al.

    Individual differences in prefrontal cortex function and the transition from drug use to drug dependence

    Neurosci Biobehav Rev

    (2010)
  • N.W. Gilpin et al.

    Neuropeptide Y in the central nucleus of the amygdala suppresses dependence-induced increases in alcohol drinking

    Pharmacol Biochem Behav

    (2008)
  • N.W. Gilpin et al.

    Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence

    Biol Psychiatry

    (2011)
  • M. Heilig et al.

    A key role for corticotropin-releasing factor in alcohol dependence

    Trends Neurosci

    (2007)
  • K. Hellevuo et al.

    Effect of GABAergic drugs on motor impairment from ethanol, barbital and lorazepam in rat lines selected for differential sensitivity to ethanol

    Pharmacol Biochem Behav

    (1989)
  • C.W. Hodge et al.

    Specific decreases in ethanol- but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930

    Alcohol

    (1993)
  • C.L. Hubbell et al.

    Opioidergic, serotonergic, and dopaminergic manipulations and rats’ intake of a sweetened alcoholic beverage

    Alcohol

    (1991)
  • P. Hyytia et al.

    GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats

    Eur J Pharmacol

    (1995)
  • P.H. Janak et al.

    Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose

    Alcohol

    (2003)
  • S.N. Katner et al.

    Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat

    Neuropsychopharmacology

    (1999)
  • D.J. Knapp et al.

    Zacopride, a 5-HT3 receptor antagonist, reduces voluntary ethanol consumption in rats

    Pharmacol Biochem Behav

    (1992)
  • D.J. Knapp et al.

    SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats

    Alcohol

    (2004)
  • G.F. Koob

    Drugs of abuse: anatomy, pharmacology, and function of reward pathways

    Trends Pharmacol Sci

    (1992)
  • G.F. Koob

    Corticotropin-releasing factor, norepinephrine and stress

    Biol Psychiatry

    (1999)
  • G.F. Koob

    A role for brain stress systems in addiction

    Neuron

    (2008)
  • G.F. Koob et al.

    Drug addiction, dysregulation of reward, and allostasis

    Neuropsychopharmacology

    (2001)
  • G.F. Koob et al.

    Effects of d-amphetamine on concurrent self-stimulation of forebrain and brain stem loci

    Brain Res

    (1977)
  • G.F. Koob et al.

    Opponent process theory of motivation: neurobiological evidence from studies of opiate dependence

    Neurosci Biobehav Rev

    (1989)
  • G.F. Koob et al.

    Corticotropin releasing factor, stress and behavior

    Semin Neurosci

    (1994)
  • W. Kostowski et al.

    The abilities of 5-HT3 receptor antagonist ICS 205-930 to inhibit alcohol preference and withdrawal seizures in rats

    Alcohol

    (1993)
  • G. Addolorato et al.

    Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study

    Alcohol Alcohol

    (2002)
  • G.F. Alheid et al.

    Amygdala and extended amygdala

  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2013)
  • G. Aston-Jones et al.

    The bed nucleus of the stria terminalis: a target site for noradrenergic actions in opiate withdrawal

  • T.B. Baker et al.

    Addiction motivation reformulated: an affective processing model of negative reinforcement

    Psychol Rev

    (2004)
  • A. Balakleevsky et al.

    Ro 19-4603, a benzodiazepine receptor inverse agonist, attenuates voluntary ethanol consumption in rats selectively bred for high ethanol preference

    Alcohol Alcohol

    (1990)
  • H.A. Baldwin et al.

    CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat

    Psychopharmacology (Berl)

    (1991)
  • H.C. Becker et al.

    Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice

    Alcohol Clin Exp Res

    (2004)
  • G.R. Breese et al.

    Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist

    Neuropsychopharmacology

    (2005)
  • G. Brown et al.

    Effects of repeated withdrawal from chronic ethanol on oral self-administration of ethanol on a progressive ratio schedule

    Behav Pharmacol

    (1998)
  • R. Ciccocioppo et al.

    Long-lasting resistance to extinction of response reinstatement induced by ethanol-related stimuli: role of genetic ethanol preference

    Alcohol Clin Exp Res

    (2001)
  • R. Ciccocioppo et al.

    Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone

    Psychopharmacology (Berl)

    (2003)
  • Cited by (165)

    • Meta-analysis of acute alcohol effects on response inhibition

      2023, Neuroscience and Biobehavioral Reviews
    View all citing articles on Scopus
    View full text