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Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol.

ABSTRACT: Alcohol has subjective and behavioral effects at the pharmacological levels typically reached during the consumption of one or two alcoholic drinks. Here we provide evidence that an alpha4-subunit-containing GABA(A) receptor contributes to the consumption of low-to-moderate levels of alcohol. Using viral-mediated RNA interference (RNAi), we found that reduced expression of the alpha4 subunit in the nucleus accumbens (NAc) shell of rats decreased their free consumption of and preference for alcohol. The time course for the reduced alcohol intake paralleled the time course of alpha4 mRNA reductions achieved after viral-mediated RNAi for alpha4. Furthermore, the reduction in drinking was region- and alcohol-specific: there was no effect of reductions in alpha4 expression in the NAc core on alcohol intake, and reductions in alpha4 expression in the NAc shell did not alter sucrose or water intake. These results indicate that the GABA(A) receptor alpha4 subunit in the NAc shell mediates alcohol intake.

SUBMITTER: Rewal M

PROVIDER: S-EPMC2768359 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol.

Rewal Mridula M Jurd Rachel R Gill T Michael TM He Dao-Yao DY Ron Dorit D Janak Patricia H PH

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090101 2

Alcohol has subjective and behavioral effects at the pharmacological levels typically reached during the consumption of one or two alcoholic drinks. Here we provide evidence that an alpha4-subunit-containing GABA(A) receptor contributes to the consumption of low-to-moderate levels of alcohol. Using viral-mediated RNA interference (RNAi), we found that reduced expression of the alpha4 subunit in the nucleus accumbens (NAc) shell of rats decreased their free consumption of and preference for alcoh ...[more]

PMID: 19144854

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Project description:BackgroundAlcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse-related effects and that subtype-selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5GABAA receptor ligands to alter selectively the reinforcing effects of alcohol.MethodsTwo groups of rhesus monkeys were trained to orally self-administer alcohol or sucrose under fixed-ratio schedules and limited daily access conditions. In addition, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors.ResultsConcentrations of 1 to 6% alcohol maintained self-administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self-administration. The α5GABAA receptor agonist QH-ii-066 enhanced and the α5GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5GABAA receptor antagonist XLi-093. However, L-655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect.ConclusionsThese findings suggest a prominent and specific role for α5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.

Dataset Information

Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol.

Publications

Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol.

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