Binge Drinking: In Search of its Molecular Target via the GABAA Receptor

Andrew R S T Yang,Laure Aurelian,Werner Sieghart,Adam C Puche,Harry L June,Juan Liu,Ahmed Elnabawi,Heon S Yi,Mingfei Wang,Kaitlin T Warnock

doi:10.3389/fnins.2011.00123

Andrew R S T Yang, Laure Aurelian + Show 8 more

Open Access

https://doi.org/10.3389/fnins.2011.00123

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Abstract

Binge drinking, frequently referred to clinically as problem or hazardous drinking, is a pattern of excessive alcohol intake characterized by blood alcohol levels ≥0.08 g% within a 2-h period. Here, we show that overexpression of α1 subunits of the GABAA receptor contributes to binge drinking, and further document that this involvement is related to the neuroanatomical localization of α1 receptor subunits. Using a herpes simplex virus amplicon vector to deliver small interference RNA (siRNA), we showed that siRNA specific for the α1 subunit (pHSVsiLA1) caused profound, long-term, and selective reduction of gene expression, receptor density, and binge drinking in high-alcohol drinking rats when delivered into the ventral pallidum (VP). Scrambled siRNA (pHSVsiNC) delivered similarly into the VP failed to alter gene expression, receptor density, or binge drinking. Silencing of the α1 gene in the VP, however, failed to alter binge sucrose or water intake. These results, along with our prior research, provide compelling evidence that the α1-containing GABAA receptor subunits are critical in the regulation of binge-like patterns of excessive drinking. Collectively, these data may be useful in the development of gene-based and novel pharmacological approaches for the treatment of excessive drinking.

Highlights

Of the total US population 21 years and older, 23% are binge drinkers and 76% of the alcohol consumed in the US is in the form of binge drinking [National Survey on Drug Use and Health (NSDUH), 2002]
high-alcohol drinking (HAD) RATS EXPRESS ELEVATED LEVELS OF THE GABAA α1 SUBUNIT IN THE ventral pallidum (VP) AND central nucleus of the amygdala (CeA) THAN THEIR LAD COUNTERPARTS Duplicates of punch biopsies obtained from distinct neuroanatomical sites (VP, CeA, basolateral amygdala (BLA), and bed nucleus of the stria terminalis (BST)) of HAD and LAD rats were immunoblotted with α1- or α2-specific antibodies, with results quantitated by densitometric scanning as previously described (Smith et al, 1998; Liu et al, 2011)
HSV-BASED VECTORS DELIVER small interference RNA (siRNA) TO SPECIFIC NEUROANATOMICAL SITES Having seen that α1 is overexpressed in the VP and CeA, we wanted to know whether it is associated with vulnerability to engage in binge alcohol drinking

Summary

Introduction

Of the total US population 21 years and older, 23% are binge drinkers and 76% of the alcohol consumed in the US is in the form of binge drinking [National Survey on Drug Use and Health (NSDUH), 2002]. Novel gene therapies, which target candidate receptors linked to excessive alcohol drinking, may offer potential alternatives to psychosocial and pharmacotherapeutic interventions for treating binge drinking. Of the potential GABAA receptors, substantial evidence implicates the α1 subunit-containing receptors in regulating excessive alcohol drinking (Harvey et al, 2002; June et al, 2003; June and Eiler, 2007). Pharmacological studies demonstrate that microinfusion of α1-preferring ligands into the ventral pallidum (VP, a locus containing the highest concentrations of α1 subunits within the reward circuitry; Churchill et al, 1991) selectively regulates excessive alcohol drinking (June et al, 2003; Harvey et al, 2002; June and Eiler, 2007). Two lines of α1 knock-out [KO] mice evidence markedly decreased alcohol drinking (Boehm et al, 2004; June et al, 2007)

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