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）的变化作为补偿 反复酒精中毒 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 酒精滥用或酒精中毒。 实验证据 这与双相兴奋剂 乙醇的CNS作用涉及促进GABA能 活动减退。 本提案中检验的假设是 乙醇的急性或慢性作用部分取决于 GABA受体的功效分别增加或降低 as synaptic突触transducers换能器”. 该项目的目的是 严格测试GABA受体效率的变化 和/或功效单独地发挥生理上显著的作用 在酒精中毒的机制中，急性和 慢性功能性耐受或身体依赖。 直接 正在进行GABAA或GABAB受体功能变化试验 使用GABA突触前和突触后传递模型， 外周离体器官（豚鼠回肠），大脑皮质 脑片、海马CA 1区神经元和亚细胞 突触神经体正在通过生物化学， 生理学和电生理学手段。 结果应 有助于阐明GABA能神经传递的作用， 特别是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设来研究乙醇。 这个研究项目是弗莱博士 专业发展计划（1 K 02 AA 00101）， 接受电生理技术培训， 加强跨学科研究 合作来提高他作为基础科学家的技能 对生物医学或乙醇的影响感兴趣。

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.