The Reinforcing Properties of Alcohol are Mediated by GABAA1 Receptors in the Ventral Pallidum

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Abstract
It has been hypothesized that alcohol addiction is mediated, at least in part, by specific γ-aminobutyric acidA (GABAA) receptors within the ventral pallidum (VP). Among the potential GABAA receptor isoforms regulating alcohol-seeking behaviors within the VP, the GABAA α1 receptor subtype (GABAA1) appears pre-eminent. In the present study, we developed β-carboline-3-carboxylate-t-butyl ester (βCCt), a mixed agonist–antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VPA1 receptors in the euphoric properties of alcohol. The in vivo actions of βCCt were then determined following microinfusion into the VP, a novel alcohol reward substrate that primarily expresses the A1 receptor. In two selectively bred rodent models of chronic alcohol drinking (HAD-1, P rats), bilateral microinfusion of βCCt (0.5–40 μg) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of βCCt exhibited both neuroanatomical and reinforcer specificity. Thus, no effects on alcohol-reinforced behaviors were observed following infusion in the nucleus accumbens (NACC)/caudate putamen (CPu), or on response maintained by saccharin. Parenteral-administered βCCt (1–40 mg/kg) was equally effective and selective in reducing alcohol-reinforced behaviors in P and HAD-1 rats. Additional tests of locomotor activity revealed that βCCt reversed the locomotor sedation produced by both chlordiazepoxide (10 mg/kg) and EtOH (1.25 g/kg), but was devoid of intrinsic effects when given alone. Studies in recombinant receptors expressed in Xenopus oocytes revealed that βCCt acted as a low-efficacy partial agonist at α3β3γ2 and α4β3γ2 receptors and as a low-efficacy inverse agonist at α1β3γ2, α2β3γ2, and α5β3γ2 receptors. The present study indicates that βCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of βCCt are primarily mediated via the GABAA1 receptor. βCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics.

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