Trends in Neurosciences
ReviewA key role for corticotropin-releasing factor in alcohol dependence
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)
Selected major risk factors and global and regional burden of disease
Lancet
(2002)Allostasis and allostatic load: implications for neuropsychopharmacology
Neuropsychopharmacology
(2000)- et al.
Drug addiction, dysregulation of reward, and allostasis
Neuropsychopharmacology
(2001) - et al.
Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms
Pharmacol. Ther.
(2006) Long-term ethanol administration methods for rats: advantages of inhalation over intubation or liquid diets
Behav. Neural Biol.
(1979)Excessive ethanol drinking following a history of dependence: animal model of allostasis
Neuropsychopharmacology
(2000)Alcohol and withdrawal: from animal research to clinical issues
Neurosci. Biobehav. Rev.
(2003)- et al.
The CRF peptide family and their receptors: yet more partners discovered
Trends Pharmacol. Sci.
(2002) - et al.
Getting closer to affective disorders: the role of CRH receptor systems
Trends Mol. Med.
(2004) Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress
Pharmacol. Biochem. Behav.
(2002)
Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal
Brain Res.
Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake
Pharmacol. Biochem. Behav.
Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence
Alcohol
SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats
Alcohol
Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors
Pharmacol. Biochem. Behav.
Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats
Biol. Psychiatry
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
Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate
Neuron
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.
Effects of neuropeptide Y and corticotropin-releasing factor on ethanol intake in Wistar rats: interaction with chronic ethanol exposure
Behav. Brain Res.
Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration
Peptides
Corticotropin-releasing factor and neuropeptide Y: role in emotional integration
Trends Neurosci.
Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat
Neuropsychopharmacology
The genetics of addictions: uncovering the genes
Nat. Rev. Genet.
Neurobiology of addiction: treatment and public policy ramifications
Nat. Neurosci.
A study in alcoholism; clinical, social-psychiatric and genetic investigations
Acta Psychiatr. Neurol. Scand.
Continuity of binge and harmful drinking from late adolescence to early adulthood
Pediatrics
Another look at heavy episodic drinking and alcohol use disorders among college and noncollege youth
J. Stud. Alcohol
Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake
Alcohol Alcohol.
Allostasis: a new paradigm to explain arousal pathology
Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction
Nat. Neurosci.
Can experimental paradigms and animal models be used to discover clinically effective medications for alcoholism?
Addict. Biol.
Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol
FASEB J.
Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure
Alcohol. Clin. Exp. Res.
Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist
Neuropsychopharmacology
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G.F.K. consults for Alkermes, Lipha, and Forest Pharmaceuticals.