GABAERGIC ADAPTATION IN ETHANOL TOLERANCE AND DEPENDENCE

功能耐受和身体依赖涉及适应性 中枢神经系统(CNS)的变化作为对 反复酒精中毒。潜在的细胞机制 乙醇的这些急性和慢性作用具有重要的 对任何合理的预防或治疗方法的影响 酗酒或酗酒。实验证据是 与双相兴奋剂和镇静剂的观点一致 乙醇的中枢神经系统作用涉及GABA能的易化 活跃度低。这项提案中正在测试的假设是 酒精的急性或慢性作用部分取决于 增强或降低GABA受体的功效 作为突触换能器。这个项目的目的是 严格测试GABA受体效率的变化 和/或功效本身在生理上起着重要的作用 在导致酒精中毒的机制中，急性和 慢性功能耐受或身体依赖。一位直接的 正在进行GABAA或GABAB受体功能变化的测试 使用GABA突触前和突触后传递模型 外周隔离器官(豚鼠回肠)，大脑皮质 脑片、海马片及亚细胞内的CA1神经元 正在进行生化评估的突触神经体， 生理和电生理手段。结果应该是 有助于阐明GABA能神经传递和 尤其是GABA受体在神经药理学中的作用 通过强化或反驳我们的工作假说。 这项研究项目是弗莱博士 他所在的职业发展计划(1 K02 AA00101) 接受电生理技术培训，并 加大跨学科研究力度 为提高他作为基础科学家的技能而进行的合作 对生物医学影响或乙醇感兴趣。

Functional tolerance and physical dependence involve adaptive changes in the central nervous system (CNS) as compensation for repeated ethanol intoxication. Cellular mechanisms underlying these acute and chronic actions of ethanol have important implications for any rational method of prevention or treatment of alcohol abuse or alcoholism. Experimental evidence is consistent with the idea that biphasic stimulant and depressant CNS actions of ethanol involve facilitation of GABAergic hypoactivity. The hypothesis being tested in this proposal is that, "acute or chronic actions of ethanol depend, in part, on increased or decreased efficacy, respectively, of GABA receptors as synaptic transducers". The purpose of this project is to critically test whether changes in GABA receptor efficiency and/or efficacy, alone, play a physiologically significant role in the mechanisms responsible for ethanol intoxication, acute and chronic functional tolerance or physical dependence. A direct test of changes in GABAA or GABAB receptor function is being made using models of GABA pre- and postsynaptic transmission in the peripheral isolated organ (guinea pig ileum), cerebral cortical brain slice, CA1 neurons in the hippocampal slice and subcellular synaptoneurosome which are being evaluated by biochemical, physiological and electrophysiological means. The results should help clarify the role of GABAergic neurotransmission and particularly the role of GABA receptors in the neuropharmacology of ethanol by strengthening or disproving our working hypothesis. This research project is an integral part of Dr. Frye's professional development plan (1 K02 AA00101) under which he is obtaining training in electrophysiological techniques and increasing his efforts in interdisciplinary research collaborations to improve his skills as a basic scientist interested in the biomedical impact or ethanol.