Role of GABA-A alpha1 in Locomotor Sensitization to Ethanol

描述（由申请人提供）：当前提案的目标是为Stephen Boehm博士提供额外的职业发展机会。森川仁和R. Adron Harris。德克萨斯大学奥斯汀分校优秀的研究环境、教师和设施将使他能够提高自己作为一名年轻研究者的技能，并学习测量小鼠中脑切片中GABA-A受体电流的电生理学技术。这些机会将更好地为Boehm博士在学术科学领域的职业生涯做好准备，并补充他在神经行为遗传学方面的专业知识，例如，通过为他提供评估小鼠单基因突变的电生理影响的工具。缺乏GABA-A α - 1受体亚基的小鼠对乙醇的运动刺激作用表现出更高的敏感性（Blednov等）。, 2003 b;Kralic et al., 2003)，并且在反复接触乙醇后，腹侧被盖区（VTA）的α 1亚基下调（Charlton et al., 1997）。本研究的总体目标是：1)确定α 1受体亚基是否对乙醇在VTA多巴胺神经元上的GABAergic突触上的作用起重要作用；2)确定乙醇增强的GABAergic电流是否在反复暴露于乙醇导致的行为（运动）致敏后减少；3)确定α 1亚基是否在这一神经适应过程中下调。我们将在alpha1敲除、敲入和致敏小鼠的VTA多巴胺神经元中评估几种电生理参数（GABA离子导入、电诱发IPSCs、mlPSCs）。考虑到VTA在介导乙醇的运动刺激作用中的作用（Imperato和DiChiara， 1986），我们预测乙醇对α 1敲除和敲入小鼠VTA多巴胺神经元中GABA-A受体电流的作用将会降低，并且反复暴露于乙醇产生的运动致敏将导致乙醇和唑吡坦（α 1选择性苯二氮卓）在野生型动物VTA多巴胺神经元中的作用降低。最近的研究暗示GABA-A受体在人类酒精中毒中的多态性，了解gaba能调节酒精激活多巴胺神经元，有助于开发酒精中毒的药物治疗方法。

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.