GABA ENDOCRINE INTERACTIONS IN BENZODIAZEPINE TOLERANCE

苯二氮卓类药物（BZ）是广泛使用的处方药，可用于其 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有用性受到以下因素的阻碍： 在长时间接触期间对它们的行为产生耐受性。 这个RSDA将提高候选人的技术能力，分析 从基因水平探讨苯二氮卓类药物耐受性的神经改变 通过不同脑组织神经元活动的改变表达 在自由活动的动物身上。 减少正规教育， 服务义务将促进新研究的发展 候选人的技能，包括1）分子方法， 原位杂交研究，和2）电生理分析， 清醒的自由活动的动物的神经元活动。 自从急性 苯二氮卓类药物的给药促进了 γ-氨基丁酸（GABA）对神经元活动的影响，研究 苯二氮卓类药物发展背后的神经适应 耐受性将集中在GABA能系统。 性腺激素和 已经显示应激调节GABA/苯二氮系统， 包括对抗惊厥药的耐受性的明显发展 苯二氮卓类药物和伴随的神经GABA能 大鼠慢性暴露于苯二氮卓类药物后的适应。 这些 GABA/BZ反应的性腺相关差异可能与 啮齿类动物对压力的激素反应存在显著的性别差异。 的 拟议的实验将描述性二型的作用， 应激反应介导性腺对GABA/BZ受体的影响， 它们在大鼠中的反应，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）性二态性，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）介导应激引起的变化 GABA/BZ反应。 第二个目标是确定压力是否会调节 GABA和苯二氮卓类药物对几种脑的生理反应 雄性和雌性大鼠的区域，使用1）GABA的生化分析- 激活的氯离子内流，2）电生理测定 脑切片中神经元对GABA和苯二氮卓类药物的敏感性，以及 3)分析清醒大鼠中神经元活动的波动。 最后， 我们将评估压力和性腺因素之间的相互作用， 确定与慢性苯二氮卓类药物相关的适应性 暴露和苯二氮卓类耐受性的相关发展 大鼠 这些研究应该有助于阐明相关的神经变化 对苯二氮卓类药物具有耐受性，并表明神经系统 可能是性别对焦虑病因学的影响， 癫痫病 学院的师资和技术 资源使其成为候选人开始分子 研究与激素相关的神经元变化， 使用最先进的解剖分辨率进行苯二氮卓类药物暴露，以及 最终评估这些分子改变对 在自由活动的动物的确定的大脑部位的神经元活动。

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.