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The Journal of Neuroscience, May 1, 2002, 22(9):3765-3775

The GABA_A Receptor ₁ Subtype in the Ventral Pallidum Regulates Alcohol-Seeking Behaviors

Scott C. Harvey¹, Katrina L. Foster², Pete F. McKay², Michelle R. Carroll², Regat Seyoum², James E. Woods II², Collette Grey², Cecily M. Jones², Shannan McCane², Rancia Cummings², Dynesha Mason², Chunrong Ma³, James M. Cook³, and Harry L. June²

¹ Laboratory of Neuroscience, Eli Lilly and Company, Indianapolis, Indiana 46285, ² Psychobiology Program, Department of Psychology, Indiana University-Purdue University, Indianapolis, Indiana 46202, and ³ Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201

We investigated the potential role of the ₁-containing GABA_A receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy--carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the ₁ receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the ₁-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 µg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 µg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., ₁₃₂, ₂₃, and ₃₃₂). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the ₁-containing GABA_A receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.

Key words: alcohol reinforcement; ventral pallidum; GABA; ₁ subunit; alcohol-preferring (P) rat; benzodiazepine

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293765-11$05.00/0

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