Trends in Neurosciences
Volume 30, Issue 8, August 2007, Pages 399-406
Journal home page for Trends in Neurosciences

Review
A key role for corticotropin-releasing factor in alcohol dependence

https://doi.org/10.1016/j.tins.2007.06.006Get rights and content

Recent data indicate that alcohol dependence induces long-term neuroadaptations that recruit a negative emotional state. This leads to excessive alcohol ingestion motivated by relief of negative emotionality. A key mechanism in this transition to negative reinforcement is a recruitment of corticotropin-releasing factor (CRF) signaling within the amygdala. Long term upregulation of CRF1 receptors is observed in the amygdala following a history of dependence, and CRF antagonists selectively block emotionality, excessive alcohol drinking and stress-induced reinstatement of alcohol-seeking in post-dependent animals. Innate upregulation of CRF1 receptor expression mimics the post-dependent phenotype, both with regard to emotional responses and ethanol self-administration. Therefore, the CRF system is emerging as a key element of the neuroadaptive changes driving alcoholism and as a major target for its treatment.

Section snippets

Introduction – a neuroadaptive perspective on alcohol dependence

Alcohol use accounts for 4% of global disease burden [1]. Alcohol dependence, or alcoholism, is a complex disorder in which heritable susceptibility factors contribute 50–60% of the disease risk, and interact with environmental factors to produce and maintain the disease state [2]. Alcoholism is characterized by uncontrolled heavy drinking and a chronic relapsing course [3]. Relapse, that is, return to heavy drinking after intervals of sobriety, is key to this process. Reduction of heavy

History of dependence and the post-dependent phenotype

Laboratory rodents do not voluntarily consume alcohol to intoxication, in part because of taste aversion similar to what humans experience when they first sample alcohol. Higher levels of consumption can be achieved by masking the taste of alcohol with a sweetener, which is faded out as alcohol concentrations are increased. However, even using fading procedures, rats that have not been bred for high alcohol preference will rarely consume in excess of 2 g alcohol/kg/day, and blood alcohol

CRF, behavioral stress responses and emotionality in the post-dependent state

CRF is a 41 amino acid polypeptide with a wide distribution throughout the brain. The highest densities of CRF-positive neurons are found within the paraventricular nucleus of the hypothalamus, but CRF-positive cells are also present in extrahypothalamic structures, including the central nucleus of the amygdala (CeA) and bed nucleus of stria terminalis (BNST), two components of the extended amygdala, and the brainstem 23, 24. CRF was discovered as the hypothalamic releasing factor for

CRF and dependence-induced excessive drinking

Experiments with the CRF system demonstrate that excessive post-dependent self-administration or intake of alcohol is fundamentally different from basal levels. Post-dependent animals tested two hours into withdrawal exhibited markedly elevated rates of self-administration. These were consistently brought down to non-dependent levels by systemic treatment with three different non-peptide, CRF1 selective antagonists: antalarmin, MJL-1–109–2 or R121919 (Figure 3). None of the antagonists affected

CRF and stress-induced relapse to alcohol-seeking

Three categories of environmental stimuli are known to trigger relapse in alcohol-dependent individuals 45, 46: small, ‘priming’ alcohol doses; conditioned cues associated with prior availability of alcohol; and stress. The relapse process can be modeled in experimental animals using reinstatement of alcohol-seeking by any of these stimuli (Box 2). Both the non-selective d-Phe CRF12–41 and the CRF1 selective antagonist CP-154 526 blocked stress-induced reinstatement [47]. A subsequent study in

Neural substrates of the post-dependent behavioral phenotype – the CRF system

Recruitment of CRF signaling within the extended amygdala is a major factor behind increased stress sensitivity, excessive self-administration and relapse in the post-dependent state. The mechanisms through which this occurs are beginning to emerge. During acute alcohol withdrawal, release of CRF is increased in the amygdala [34]. Presumably as a reflection of this, decreased tissue levels of CRF were seen within this structure in early withdrawal 42, 54. Six weeks after last alcohol exposure,

Contribution of other neurotransmitter systems to the post-dependent phenotype

Expression of the astroglial glutamate transporter GLAST is elevated both in post-dependent rats [16] and brains of human alcoholics [60]. GLAST removes extracellular glutamate [61], and its upregulation is presumably compensatory to elevated glutamate release in the post-dependent state [21]. Given an established role for glutamate in stress pathology [62], functional glutamate antagonists might be able to suppress excessive drinking by reducing negative reinforcement by alcohol. Acamprosate,

Summary and translational perspective

Recent data demonstrate a recruitment of extrahypothalamic CRF systems following a history of alcohol dependence, or owing to genetic selection for high alcohol preference. This does not necessarily confer an overt phenotype, but when faced with a stressor, individuals with a hyperactive CRF system have exaggerated emotional responses. Furthermore, either post-dependent or innate upregulation of the CRF system gives rise to excessive rates of alcohol self-administration, presumably through

Acknowledgements

Work by M.H. has been supported by intramural funding from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Swedish Medical Research Council. Part of this work has been carried out under a collaborative research and development agreement (CRADA) with Eli Lilly and Co. Work by G.F.K. has been supported by funding from the Pearson Center for Alcoholism and Addiction Research, and by NIH grants AA08459 and AA06420 from the NIAAA, and DK26741 (G.F.K.) from the National

References (71)

  • S. Rassnick

    Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal

    Brain Res.

    (1993)
  • M.F. Olive

    Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake

    Pharmacol. Biochem. Behav.

    (2002)
  • G.R. Valdez

    Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence

    Alcohol

    (2003)
  • D.J. Knapp

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

    Alcohol

    (2004)
  • D.H. Overstreet

    Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors

    Pharmacol. Biochem. Behav.

    (2004)
  • C.K. Funk

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

    Biol. Psychiatry

    (2007)
  • D. Funk

    Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: relationship to the reinstatement of alcohol seeking

    Neuroscience

    (2006)
  • J.D. Rothstein

    Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate

    Neuron

    (1996)
  • R. Rimondini

    Suppression of ethanol self-administration by the neuropeptide Y (NPY) Y2 receptor antagonist BIIE0246: evidence for sensitization in rats with a history of dependence

    Neurosci. Lett.

    (2005)
  • A. Thorsell

    Effects of neuropeptide Y and corticotropin-releasing factor on ethanol intake in Wistar rats: interaction with chronic ethanol exposure

    Behav. Brain Res.

    (2005)
  • S.P. Kelley

    Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration

    Peptides

    (2001)
  • M. Heilig

    Corticotropin-releasing factor and neuropeptide Y: role in emotional integration

    Trends Neurosci.

    (1994)
  • S.N. Katner

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

    Neuropsychopharmacology

    (1999)
  • D. Goldman

    The genetics of addictions: uncovering the genes

    Nat. Rev. Genet.

    (2005)
  • C. Dackis et al.

    Neurobiology of addiction: treatment and public policy ramifications

    Nat. Neurosci.

    (2005)
  • C. Åmark

    A study in alcoholism; clinical, social-psychiatric and genetic investigations

    Acta Psychiatr. Neurol. Scand.

    (1951)
  • C.A. McCarty

    Continuity of binge and harmful drinking from late adolescence to early adulthood

    Pediatrics

    (2004)
  • D.A. Dawson

    Another look at heavy episodic drinking and alcohol use disorders among college and noncollege youth

    J. Stud. Alcohol

    (2004)
  • A. Heinz

    Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake

    Alcohol Alcohol.

    (2003)
  • P. Sterling et al.

    Allostasis: a new paradigm to explain arousal pathology

  • G.F. Koob et al.

    Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction

    Nat. Neurosci.

    (2005)
  • M. Egli

    Can experimental paradigms and animal models be used to discover clinically effective medications for alcoholism?

    Addict. Biol.

    (2005)
  • R. Rimondini

    Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol

    FASEB J.

    (2002)
  • L.E. O’Dell

    Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure

    Alcohol. Clin. Exp. Res.

    (2004)
  • G.R. Breese

    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)
  • Cited by (411)

    View all citing articles on Scopus
    *

    G.F.K. consults for Alkermes, Lipha, and Forest Pharmaceuticals.

    View full text