GABAA receptors in the posterior, but not anterior, ventral tegmental area mediate Ro15-4513-induced attenuation of binge-like ethanol consumption in C57BL/6J female mice

GABAA receptors have been shown to modulate dopaminergic output from the ventral tegmental area (VTA) in studies of both natural and drug rewards, including alcohol. Ro15-4513, the imidazobenzodiazepine derivative and allosteric modulator at the GABAA receptor, reliably antagonizes the behavioral effects of alcohol. Various models of alcohol consumption show a decrease in consummatory behaviors, specific to ethanol, following acute administration of the drug. In the present study, Ro15-4513 was systemically administered, or microinjected into the anterior or posterior VTA, to explore the role of GABAA receptors at this region in modulating the high pattern of alcohol consumption by C57BL/6J inbred mice in the Drinking in the Dark (DID) model. Animals had 2 h access to ethanol for 6 days prior to drug manipulations. Immediately before the seventh day of access, mice were systemically (I.P.) or site-specifically administered Ro15-4513. Systemic Ro15-4513 (at 10 mg/kg) decreased binge-like ethanol intake in the DID paradigm. Additionally, there was a stepwise decrease in consumption following Ro15-4513 microinjection into the posterior VTA, with the highest dose significantly decreasing ethanol intake. There was no effect found following microinjection into the anterior VTA, nor was there an effect of systemic or intra-posterior VTA Ro15-4513 on consumption of a 5% sucrose solution or water. The present findings support a role for Ro15-4513 sensitive VTA-GABAA receptors in modulating binge-like ethanol consumption. Moreover, the work here adds to the growing body of literature suggesting regional heterogeneity in the VTA.

Research highlights
► Systemic Ro15-4513 significantly decreased binge-like ethanol intake at 10 mg/kg in C57BL/6J mice and did not alter sucrose or water intakes in the same limited access paradigm.
► Microinjection of Ro15-4513 into the posterior-ventral tegmental area (VTA) decreased drinking (at 1 ng/mouse) but no dose of Ro15-4513 altered drinking when microinjected into the anterior-VTA.
► The dose of Ro15-4513 that decreased binge-like ethanol intake did not alter sucrose or water consumption when microinjected into the posterior-VTA.
► The data therefore supports a role for Ro15-4513 sensitive GABAA receptors in the posterior VTA in mediating binge-like consumption of ethanol produced using the Drinking-in-the-Dark paradigm in C57BL/6J mice.