Role of GABA-A alpha1 in Locomotor Sensitization to Ethanol

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DESCRIPTION (provided by applicant): The goal of the current proposal is to provide Dr. Stephen Boehm with additional career development opportunities under the mentorship of Drs. Hitoshi Morikawa and R. Adron Harris. The excellent research environment, faculty, and facilities at the University of Texas at Austin will allow him to sharpen his skills as a young investigator, and to learn electrophysiotogical techniques for measuring GABA-A receptor currents in mouse midbrain slice. These opportunities will better prepare Dr. Boehm for a career in academic science, and compliment his expertise in neurobehavioral genetics, for example, by giving him the tools to assess the electrophysiological effects of single gene mutations in mice. Mice lacking the GABA-A alpha1 receptor subunit exhibit heightened sensitivity to ethanol's locomotor stimulant effects (Blednov et at., 2003b; Kralic et al., 2003), and alpha1 subunits are down-regulated in the ventral tegmental area (VTA) following repeated ethanol exposures (Charlton et al., 1997). The overall goals of this proposal are to 1) determine whether the alpha1 receptor subunit is important for ethanol's actions at GABAergic synapses on VTA dopamine neurons, 2) to determine whether ethanol-enhanced GABAergic current is reduced following repeated ethanol exposures that result: in behavioral (locomotor) sensitization, and 3) to establish whether alpha1 subunits are down-regulated as a result of this neuroadaptive process. We will assess several electrophysiological parameters (GABA iontophoresis, electrically-evoked IPSCs, mlPSCs) in the VTA dopamine neurons of alpha1 knock-out, knock-in, and sensitized mice. Given the role of the VTA in mediating the locomotor stimulant effects of ethanol (Imperato and DiChiara, 1986), we predict that the actions of ethanol on GABA-A receptor currents in VTA dopamine neurons of alpha1 knock-out and knock-in mice will be reduced, and that repeated exposures to ethanol producing locomotor sensitization will result in the reduced actions of ethanol and zolpidem (alpha1-selective benzodiazepine) in the VTA dopamine neurons of wild-type animals. Recent studies implicate GABA-A receptor polymorphisms in human alcoholism and understanding GABAergic modulation of alcohol activation of dopamine neurons should assist in development of pharmacotherapies for alcoholism.