GABAERGIC ADAPTATION IN ETHANOL TOLERANCE AND DEPENDENCE

功能耐受和身体依赖似乎涉及适应性 中枢神经系统(CNS)的变化，以补偿重复的 酒精中毒。这些变化可能在以下方面发挥重要作用 维持酒精饮料的病态消费。为 因此，对细胞机制的理解 功能耐受和身体依赖可能具有重要的 对合理开发预防或治疗方法的影响 酗酒或酗酒。在这方面，越来越多的试验性 有证据表明GABA能神经传递，更具体地说， GABA受体可能是乙醇的靶标。这项提议将检验 假设：对…的功能耐受性和身体依赖性 乙醇导致GABA受体下调的部分原因是 乙醇对GABA受体活性的初始增强作用 喝醉了。本申请中提出的实验将表征 GABA-A和GABA-B受体功能下调的程度 与对酒精的身体依赖的发展相关的建模 在老鼠身上。此外，负责适应性的驱动力 这些GABA受体的功能变化将被探索以 确定受体是否必须表现出急性乙醇敏感性 以进行功能性的下调。这些问题将是 通过比较六种不同的GABA受体反应解决 使用细胞内的解剖学鉴定的神经元群体 电生理记录技术。测量将在以下时间进行 组织切片取自海马体、大脑皮层、内侧和 被认为对酒精敏感或 抗药性的GABA受体。这一结果应该有助于澄清 乙醇神经药理学中的GABA受体。

Functional tolerance and physical dependence appear to involve adaptive changes in the central nervous system (CNS) which compensate for repeated ethanol intoxication. These changes may play an important role in maintaining the pathological consumption of alcoholic beverages. For this reason, an understanding of the cellular mechanisms responsible for functional tolerance and physical dependence could have important implications for the rational development of methods to prevent or treat alcohol abuse or alcoholism. In this regard, increasing experimental evidence suggests that GABAergic neurotransmission and more specifically, GABA receptors are a likely target for ethanol. This proposal will test the hypothesis that: Functional tolerance to and physical dependence on ethanol results in part from GABA receptor down-regulation in response to the initial enhancement of GABA receptor activity during ethanol intoxication. Experiments proposed in this application will characterize the extent of functional down-regulation of GABA-A and GABA-B receptors associated with the development of physical dependence on ethanol modeled in the rat. In addition, the driving forces responsible for adaptive changes in the function of these GABA receptors will be explored to determine whether receptors must exhibit acute ethanol sensitivity in order to undergo functional down-regulation. These questions will be addressed by comparing GABA receptor responses in six distinct populations of anatomically identified neurons using intracellular electrophysiological recording techniques. Measurements will be made in tissue slices prepared from the hippocampus, cerebral cortex, medial and lateral septum which are proposed to possess ethanol sensitive or resistant GABA receptors. The results should help clarify the role of GABA receptors in the neuropharmacology of ethanol.