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CHRONIC BARBITURATES - CNS BIOCHEMISTRY

慢性巴比妥酸盐 - CNS 生物化学

基本信息

批准号：
3069406
负责人：
WILLIAM W MORGAN
金额：
$ 5.36万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-04-01 至 1987-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3069406
关键词：
aggression aminoacid metabolism barbiturates benzodiazepines brain brain metabolism centrally acting drug dosage drug interactions drug metabolism drug tolerance drug withdrawal gamma aminobutyrate neurochemistry neuropharmacology retina tranquilizer

项目摘要

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.

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的抑制作用，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。