It has been hypothesized that alcohol addiction is mediated, at least in part, by specific gamma-aminobutyric acid(A) (GABA(A)) receptors within the ventral pallidum (VP). Among the potential GABA(A) receptor isoforms regulating alcohol-seeking behaviors within the VP, the GABA(A) alpha1 receptor subtype (GABA(A1)) appears pre-eminent. In the present study, we developed beta-carboline-3-carboxylate-t-butyl ester (betaCCt), a mixed agonist-antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VP(A1) receptors in the euphoric properties of alcohol. The in vivo actions of betaCCt 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 betaCCt (0.5-40 microg) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of betaCCt 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 betaCCt (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 betaCCt 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 betaCCt acted as a low-efficacy partial agonist at alpha3beta3gamma2 and alpha4beta3gamma2 receptors and as a low-efficacy inverse agonist at alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors. The present study indicates that betaCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of betaCCt are primarily mediated via the GABA(A1) receptor. betaCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics.

• AA10406/AA/NIAAA NIH HHS/United States
• AA11555/AA/NIAAA NIH HHS/United States
• MH46851/MH/NIMH NIH HHS/United States