The role of GABA A receptors in the acute and chronic effects of ethanol

Grobin, A. Chistina; Matthews, Douglas B.; Devaud, Leslie L.; Morrow, A. Leslie

doi:10.1007/s002130050685

Cited by 433 publications

(363 citation statements)

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“…Covault et al (2004) replicated this haplotypic association in a region of the gene that overlaps the region identified by Edenberg et al (2004). These findings, together with evidence that GABA A receptors mediate several behavioral effects of alcohol (Grobin et al, 1998;Davies, 2003), underscore the potential contribution of variation at GABRA2 to the risk for alcohol dependence.…”

Section: Introductionmentioning

confidence: 58%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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GABA A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA A receptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

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Section: Introductionmentioning

confidence: 58%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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“…These behavioral effects of ALLO are similar to those exhibited by ethanol, which exerts some of its effects through an interaction with GABA A receptors (for review, see [18]). Furthermore, ALLO is capable of substituting for ethanol's stimulus effects within drug discrimination procedures employing rodents and primates [3,17,19].…”

Section: Introductionmentioning

confidence: 64%

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Ford

Mark

Nickel

et al. 2007

Behavioural Brain Research

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Although systemic allopregnanolone (ALLO; a positive modulator of GABA A receptors) has been shown to enhance ethanol-reinforced responding and to modulate drinking patterns in rodents, the effects of centrally administered ALLO on ethanol intake are not known. The current work examined the effects of intracranial ALLO on operant ethanol self-administration in food-and water-satiated mice, with a procedure designed to estimate ALLO's influence on appetitive versus consummatory processes. Male C57BL/6J (B6) mice were trained to press an ethanol-appropriate lever by being reinforced with 30-min of continuous access to a 10% ethanol solution. Following surgical implantation of a guide cannula aimed at the lateral ventricle and subsequent habituation to vehicle infusions, ALLO (50-400 ng; ICV) was delivered immediately prior to session start. ALLO doses of 100 and 400 ng were further evaluated for their effects on locomotor behavior within activity chambers. ALLO selectively modulated ethanol intake patterns associated with the onset and maintenance of self-administration, while leaving appetitive (i.e., ethanol seeking) measures unaltered. The effects of ALLO on drinking patterns were dissociable from changes in locomotor behavior, as evidenced by the absence of ALLO's influence on response frequency and horizontal distance traveled. These findings support the premise that manipulations in brain ALLO levels may influence the regulatory processes governing ethanol consumption.

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“…In contrast, a consistent finding in rodents is that chronic ethanol consumption decreases cortical mRNA and peptide levels of α 1 subunits but increases α 4 levels (Devaud et al, 1996(Devaud et al, , 1997Grobin et al, 1998;Matthews et al, 1998). Cortical peptide levels for β 2/3 and γ 1 and mRNA for γ 2S increase in ethanol-dependent rats (Devaud et al, 1997).…”

Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Comentioning

confidence: 97%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

197

181

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Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

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The role of GABA A receptors in the acute and chronic effects of ethanol

Cited by 433 publications

References 1 publication

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

The role of GABAA receptors in the development of alcoholism

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