Role of GABA-A alpha1 in Locomotor Sensitization to Ethanol

描述（由申请人提供）：当前提案的目标是在森川仁博士和R。Adron Harris优秀的研究环境，教师和设施，在得克萨斯大学奥斯汀分校将使他能够提高他的技能作为一个年轻的研究人员，并学习电生理技术测量GABA-A受体电流在小鼠中脑切片。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效应的工具。缺乏GABA-A α 1受体亚单位的小鼠表现出对乙醇的运动刺激作用的高度敏感性（Blednov等人，2003 b; Kralic等人，2003），并且在重复乙醇暴露后，α 1亚基在腹侧被盖区（VTA）中下调（查尔顿等人，1997年）。本研究的总体目标是：1）确定α 1受体亚单位是否对乙醇在腹侧被盖区多巴胺神经元上GABA能突触的作用很重要; 2）确定乙醇增强的GABA能电流是否在导致行为（运动）敏化的重复乙醇暴露后降低; 3）确定α 1亚单位是否由于这种神经适应性过程而下调。我们将评估几个电生理参数（GABA离子电渗，电诱发的IPSC，mlPSC）在VTA多巴胺神经元的α 1敲除，敲入，致敏小鼠。鉴于腹侧被盖区在介导乙醇的运动刺激效应中的作用，（Imperato和DiChiara，1986），我们预测乙醇对α 1敲除和敲入小鼠的VTA多巴胺神经元中GABA-A受体电流的作用将降低，反复暴露于乙醇产生的自发致敏作用将导致乙醇和唑吡坦的作用降低（α 1-选择性苯二氮）在野生型动物的腹侧被盖区多巴胺神经元。最近的研究表明GABA-A受体多态性与人类酒精中毒有关，了解GABA能对酒精激活多巴胺神经元的调节有助于酒精中毒药物治疗的发展。

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.