Role of GABA-A alpha1 in Locomotor Sensitization to Ethanol

GABA-A α1 在乙醇运动敏感性中的作用

• 批准号: 6983706
• 负责人: Stephen Lee Boehm
• 金额: $ 14.38万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983706
• 关键词: GABA receptor; behavioral /social science research tag; behavioral habituation /sensitization; benzodiazepines; body physical activity; dopamine; electrophysiology; ethanol; gamma aminobutyrate; genetically modified animals; laboratory mouse; tegmentum

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.

描述（由申请人提供）：当前提案的目标是在 Dr. Stephen Boehm 的指导下为 Stephen Boehm 博士提供额外的职业发展机会。森川仁和 R.阿德伦·哈里斯。德克萨斯大学奥斯汀分校优良的研究环境、师资和设施将使他能够提高年轻研究者的技能，并学习测量小鼠中脑切片中 GABA-A 受体电流的电生理技术。这些机会将为 Boehm 博士的学术生涯做好更好的准备，并补充他在神经行为遗传学方面的专业知识，例如，为他提供评估小鼠单基因突变电生理效应的工具。缺乏 GABA-A α1 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 等人，2003b；Kralic 等人，2003），并且在反复接触乙醇后，腹侧被盖区（VTA）的 α1 亚基下调（Charlton 等人，1997）。该提案的总体目标是 1) 确定 α1 受体亚基对于乙醇对 VTA 多巴胺神经元 GABA 能突触的作用是否重要，2) 确定重复乙醇暴露后乙醇增强的 GABA 电流是否会减少，从而导致：行为（运动）敏化，以及 3) 确定 α1 亚基是否作为 这种神经适应过程的结果。我们将评估 alpha1 敲除、敲入和致敏小鼠的 VTA 多巴胺神经元中的几个电生理参数（GABA 离子电渗疗法、电诱发 IPSC、mlPSC）。鉴于 VTA 在介导乙醇运动刺激作用中的作用（Imperato 和 DiChiara，1986），我们预测乙醇对 alpha1 敲除和敲入小鼠 VTA 多巴胺神经元中 GABA-A 受体电流的作用将减少，并且反复暴露于产生运动敏化的乙醇将导致乙醇和 野生型动物 VTA 多巴胺神经元中的唑吡坦（α1-选择性苯二氮卓类药物）。最近的研究表明 GABA-A 受体多态性与人类酒精中毒有关，并且了解多巴胺神经元的酒精激活的 GABA 能调节应有助于酒精中毒药物疗法的开发。