BARBITURATE TOLERANCE/DPENDENCE AND GABA SYSTEM

巴比妥耐受性/依赖性和 GABA 系统

• 批准号: 2117218
• 负责人: Ing K. Ho
• 金额: $ 21.3万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2117218
• 关键词: GABA receptor; autoradiography; barbiturates; benzodiazepines; centrally acting drug; chemical binding; convulsants; drug addiction; drug tolerance; gamma aminobutyrate; in situ hybridization; laboratory rat; neurochemistry; pentobarbital; sedative /hypnotic; synaptosomes

The overall goal of this project is to investigate biochemical mechanism of how tolerance to and physical dependence upon barbiturates develop. The objective of this renewal application will focus on the role of GABAA and GABAB receptors in barbiturate tolerance and dependence. We will continue to utilize a rat model (intracerebroventricular, icv, infusion of pentobarbital) as an experimental model useful for determining how different binding sites [for GABA, benzodiazepines (BZ) and convulsants, e.g., picrotoxin and t-butylbicyclophosphorothionate (TBPS)] of the GABAA receptor complex and GABAB receptors in different regions of the brain are involved in chronic effects of pentobarbital. The specific aims are designed to test the hypothesis formulated. Specific Aim I. Characterization of GABAA receptors in different regions of the brain during the development of tolerance to and physical dependence upon pentobarbital. Studies on GABAA receptors in discrete areas of the brain will be the first step in gaining insight into the biochemical mechanisms of barbiturate actions. The investigations will be conducted at different time intervals during the development of tolerance to and physical dependence upon pentobarbital. The results obtained will be compared with those from acutely treated animals. The specific studies are as follows: 1. Biochemical characterization of different binding sites (GABA, BZ, TBPS) of the GABAA receptors; 2. Autoradiographic characterizations of different binding sites (GABA, BZ, TBPS) of the GABAA receptors; 3. In situ hybridization characterization of GABAA receptor subunit mRNA (alpha, beta, gamma, delta); and, 4. Cl- influx - functional characterization of GABAA receptors. Specific Aim II. Characterization of GABAB receptors in different regions of the brain during the development of tolerance to and physical dependence upon pentobarbital. The specific studies are: 1. Biochemical characterization of ligand binding to GABAB receptors; and 2. Autoradiographic characterization of ligand binding to GABAB receptors. Specific Aim III. Investigation of GABA release mechanisms in different regions of the brain during the development of tolerance to and physical dependence upon pentobarbital. The release of GABA affected by pentobarbital is intimately related to postsynaptic GABAA receptors and presynaptic GABAB receptors (autoreceptors). Specific Aim IV. Systematic assessments of the degree of the development of tolerance to and physical dependence upon pentobarbital. The results obtained from these experiments will be correlated with the results derived from those of Specific Aims I-III.

该项目的总体目标是研究生物化学机制 对巴比妥的耐受性和身体依赖性如何发展。 这 本次更新申请的目标将重点关注 GABAA 的作用和 GABAB 受体对巴比妥的耐受性和依赖性。 我们将继续 利用大鼠模型（脑室、ICV、输注 戊巴比妥）作为实验模型，可用于确定如何 不同的结合位点[GABA、苯二氮卓类药物 (BZ) 和惊厥药物， 例如，印防己毒素和 GABAA 的叔丁基二环硫代磷酸酯 (TBPS)] 大脑不同区域的受体复合物和 GABAB 受体 参与戊巴比妥的慢性作用。 具体目标是 旨在检验所提出的假设。 具体目标 I. 不同区域 GABAA 受体的表征 在耐受性和身体依赖性发展过程中大脑的变化 戊巴比妥。 对大脑离散区域的 GABAA 受体的研究将是第一个 深入了解巴比妥的生化机制的一步 行动。 调查将在不同的时间间隔进行 在耐受性和身体依赖性的发展过程中 戊巴比妥。 获得的结果将与来自的结果进行比较 接受急性治疗的动物。 具体研究如下：1. 不同结合位点（GABA、BZ、TBPS）的生化表征 GABAA受体； 2. 不同材料的放射自显影特征 GABAA 受体的结合位点（GABA、BZ、TBPS）； 3. 就地 GABAA 受体亚基 mRNA（α、β、 伽玛、德尔塔）； 4. Cl-流入-GABAA 的功能表征 受体。 具体目标二。 不同区域GABAB受体的特征 在耐受性和身体依赖性发展过程中大脑的变化 戊巴比妥。 具体研究有： 1.生化 配体与 GABAB 受体结合的表征；和 2. 配体与 GABAB 受体结合的放射自显影表征。 具体目标 III. 不同物质中GABA释放机制的研究 在耐受性和身体耐受性发展过程中的大脑区域 对戊巴比妥的依赖性。 GABA 的释放受到影响 戊巴比妥与突触后 GABAA 受体密切相关 突触前 GABAB 受体（自身受体）。 具体目标四。 发展程度的系统评估 对戊巴比妥的耐受性和身体依赖性。 结果 从这些实验中获得的结果将与得出的结果相关联 来自具体目标 I-III 的目标。