CHRONIC BARBITURATES - CNS BIOCHEMISTRY

这一建议的基本假设是，中枢抑制剂，即。 巴比妥酸盐发挥了它们的药理作用的很大一部分 通过增强GABA（一种主要的抑制剂）的抑制作用而产生作用 中枢神经系统中的发射器。 进一步假设， GABA系统对慢性处理引起的长时程增强的影响 巴比妥类药物是发展耐受性的重要因素， 依赖这些化合物。 两个适应假设（1）a 功能性GABA受体减少和/或（2）功能性GABA受体减少 GABA神经元的活动。 由于这些适应性变化， 巴比妥类药物的停药会导致一段时间的GABA不足 中枢神经系统的抑制性调节和一段时间的过度兴奋 表现为巴比妥酸盐戒断综合征 GABA的新模型 视网膜中受体介导的抑制，高亲和力的测量 GABA结合和GABA周转率的测量将是主要的 采用的分析方法。 与Salvatore博士的合作 休斯顿的Enna和Susan Weintraub博士，Bill Stavinoha和大卫琼斯 计划在这个项目的过程中。 本研究结果 将提供相当深入的GABA在发展中的作用， 对巴比妥类药物的耐受性和依赖性。 一些 研究还将确定GABA在发展中的作用， 苯二氮耐受性 这些研究的结果可能会导致更好的 用于控制危及生命的表现的药理学方法 巴比妥类药物戒断，并可能导致了解的基本 神经化学机制参与耐受性和/或 对巴比妥类药物和其他中枢神经系统药物的依赖。

The basis hypothesis of this proposal is that the central depressants, i.e. the barbiturates, exert a significant portion of their pharmacological effects by potentiating the inhibitory actions of GABA, a major inhibitory transmitter in the CNS. It is further hypothesized that adaptations in the GABA system to long term potentiation induced by chronic treatment with the barbiturates are important factors in the development of tolerance to and dependence on these compounds. Two adaptations are hypothesized (1) a reduction in functional GABA receptors and/or (2) a decrease in the activity of GABA neurons. As a result of these adaptations the abrupt withdrawal of the barbiturate would lead to a period of insufficient GABA inhibitory regulation in the CNS and a period of hyperexcitability evidenced as the barbiturate abstinence syndrome. A new model for GABA receptor-mediated inhibition in the retina, measurements of high affinity GABA binding and measurements of GABA turnover will be the principal analytical procedures employed. Collaborative efforts with Dr. Salvatore Enna in Houston and Drs. Susan Weintraub, Bill Stavinoha and David Jones are planned during the course of this project. The results of this study will provide considerable insight into the role of GABA in the development of tolerance to and dependence on the depressant barbiturates. Some studies will also determine the role of GABA in the development of benzodiazepine tolerance. The results of these studies may lead to better pharmacological methods for controlling the life-threatening-manifestations of barbiturate withdrawal and may lead to an understanding of the basic neurochemical mechanisms involved in the development of tolerance to and/or dependence on the barbiturates and other central depressant agents.