GABA ENDOCRINE INTERACTIONS IN BENZODIAZEPINE TOLERANCE

GABA 内分泌相互作用对苯二氮卓类药物耐受性的影响

• 批准号: 2390969
• 负责人: Marlene A. Wilson
• 金额: $ 6.02万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2390969
• 关键词: GABA receptor; benzodiazepine receptor; benzodiazepines; brain electrical activity; brain mapping; drug tolerance; gamma aminobutyrate; gender difference; hormone regulation /control mechanism; in situ hybridization; laboratory rat; neuroendocrine system; sex hormones; stress

The benzodiazepines (BZs) are widely prescribed drugs, useful for their anxiolytic, anticonvulsant, sedative and muscular relaxant properties. However, the clinical usefulness of the benzodiazepines is hampered by the development of tolerance to their actions during prolonged exposure. This RSDA will enhance the candidate's technical capabilities to analyze neural changes associated benzodiazepine tolerance from the level of gene expression through alterations in neuronal activity of distinct brain loci in freely moving animals. A reduction in formal teaching and service obligations will facilitate the development of new research skills by the candidate, including 1) molecular approaches initiated with in situ hybridization studies, and 2) electrophysiological analysis of neuronal activity in awake, freely moving animals. Since the acute administration of benzodiazepines facilitates the inhibitory effects of gamma-aminobutyric acid (GABA) on neuronal activity, studies examining the neural adaptations underlying the development of benzodiazepine tolerance will focus on GABAergic systems. Both gonadal hormones and stress have been shown to modulate the GABA/benzodiazepine system, including the apparent development of tolerance to the anticonvulsant effects of the benzodiazepines and the concomitant neural GABAergic adaptations following chronic exposure to benzodiazepines in rats. These gonad-related differences in GABA/BZ responses may be related to the dramatic sex differences in hormonal responses to stress in rodents. The proposed experiments will characterize the role of sexually dimorphic stress reactions in mediating gonadal influences on GABA/BZ receptors and their responses in rats, including the GABAergic adaptations associated with chronic benzodiazepine exposure. Studies will investigate the mechanisms through which stress modulates the GABA/BZ system. These studies will determine if a) the sexually dimorphic, stress-induced release of peripheral hormones or b) the central activation of corticotropin releasing factor (CFR) mediate the stress-induced changes in GABA/BZ responses. A second goal is to determine if stress modulates physiological responses to GABA and benzodiazepines in several brain areas of male and female rats using 1) biochemical analysis of GABA- activated chloride influx, 2) electrophysiological determination of neuronal sensitivity to GABA and the benzodiazepines in brain slices, and 3) analysis of fluctuations in neuronal activity in awake rats. Finally, we will assess the interaction between stress and gonadal factors in determining the adaptations associated with chronic benzodiazepine exposure and the associated development of benzodiazepine tolerance in rats. These studies should help elucidate the neural changes associated with tolerance to the benzodiazepines and indicate neural systems which might underlie gender-related influences on the etiology of anxiety or epileptic disorders. The institutional faculty and technological resources make this an ideal site for the candidate to begin molecular investigations of neuronal changes associated with hormones and benzodiazepine exposure using state-of-the-art anatomical resolution, and to ultimately assess the impact of these molecular alterations on neuronal activity in defined brain sites of freely moving animals.

苯二氮卓类药物(BZS)是广泛使用的处方药，对他们的 抗焦虑、抗惊厥、镇静和肌肉松弛特性。 然而，苯二氮卓类药物的临床应用受到以下因素的阻碍 在长时间暴露期间，对其行为的耐受性的发展。 RSDA将增强应聘者的技术分析能力 从基因水平探讨与苯二氮类药物耐受相关的神经变化 通过不同脑区神经元活动的改变来表达 在自由移动的动物中的轨迹。减少正规教学和 服务义务将促进新研究的发展 应聘者的技能，包括1)分子方法 原位杂交研究；2)电生理分析 清醒、自由活动动物的神经元活动。自急性起 苯二氮卓类药物的给药促进了对大鼠的抑制作用 伽马氨基丁酸(GABA)对神经元活动的研究 苯二氮类药物发展的神经适应机制 耐受性将集中在GABA能系统上。性腺激素和 已有研究表明，应激可调节GABA/苯二氮卓系统， 包括对抗惊厥剂的明显耐受性 苯二氮类药物及其伴生神经GABA能的作用 大鼠长期暴露于苯二氮类药物后的适应。这些 性腺相关的GABA/BZ反应的差异可能与 啮齿动物对应激激素反应的显著性别差异。这个 拟议的实验将特征性二形者的角色 应激反应介导性腺对GABA/BZ受体和 它们在大鼠体内的反应，包括与GABA能适应相关的 长期接触苯二氮卓类药物。研究将调查 应激调节GABA/BZ系统的机制。这些 研究将确定a)性二态、压力诱导的 外周激素的释放或b)中枢激活 促肾上腺皮质激素释放因子(CFR)介导应激诱导的改变 在GABA/BZ反应中。第二个目标是确定压力是否会调节 几种脑组织对GABA和苯二氮卓类药物的生理反应 用1)GABA生化分析测定雄性和雌性大鼠的面积 活化氯离子内流，2)电生理测定 脑片中神经元对GABA和苯二氮卓类药物的敏感性，以及 3)清醒大鼠神经元活动的波动分析。最后， 我们将评估压力和性腺因子之间的相互作用 确定与慢性苯二氮类药物相关的适应性 人群暴露与苯二氮卓类药物耐受性的关系 老鼠。这些研究应该有助于阐明相关的神经变化。 对苯二氮类药物有耐受性，并表明神经系统 可能是性别因素对焦虑症的病因的影响 癫痫症。机构师资和技术 资源使这里成为候选人开始分子研究的理想地点 与激素和激素相关的神经元变化的研究 使用最先进的解剖分辨率暴露苯二氮卓类药物，以及 为了最终评估这些分子变化对 自由活动动物脑内特定部位的神经元活动。