HORMONES, GABA RESPONSES, AND 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，苯并二氮杂卓类的临床有用性受到以下因素的阻碍： 在长时间接触期间对其行为产生耐受性。以来 苯二氮卓类药物的急性给药有助于抑制 γ-氨基丁酸（GABA）对神经元活动的影响，研究 研究神经适应的发展， 苯二氮卓类耐受性集中在GABA能系统。双侧性腺 激素和压力已被证明可以调节：GABA/苯二氮卓类 系统在大鼠体内，性腺激素的波动调节 GABA能系统，但不是急性抗惊厥作用的 苯二氮卓类然而，性腺状态确实改变了 对抗惊厥作用的耐受性的发展 苯二氮卓类药物和伴随的GABA能神经适应 大鼠长期接触苯二氮卓类药物。这些与性腺有关的 GABA/BZ反应的差异可能与戏剧性的性别有关 啮齿类动物对压力的激素反应的差异。拟议 实验将描述性二态压力的作用， 介导性腺对GABA/BZ受体的影响的反应及其 大鼠的反应，包括与 慢性苯二氮卓类药物暴露研究将调查机制 应激通过其调节GABA/BZ系统。这些研究将 确定是否a）性二态性，压力诱导的释放 外周激素或B）促肾上腺皮质激素的中枢激活 释放因子（CRF）介导应激引起的GABA/BZ的变化 应答 第二个目标是确定压力是否调节神经元的 在性二形性中对GABA和/或苯二氮卓类的反应 方式对GABA和苯二氮卓类药物的生理反应 使用l）在雄性和雌性大鼠的几个脑区中测量 GABA激活的氯离子内流的生化分析，2） 神经元对GABA敏感性的电生理学测定和 苯二氮卓类药物在脑切片中的变化，以及3） 在清醒的自由活动的大鼠中的神经元活动。最后，我们将评估 压力和性腺因素之间的相互作用，在确定 与慢性苯二氮卓类药物暴露相关的适应， 与大鼠苯二氮卓耐受性的相关发展。这些研究 应该有助于阐明与耐受性相关的神经变化。 苯二氮卓类药物，并指出神经系统可能是性别的基础- 对焦虑症或癫痫症病因的相关影响。

The benzodiazepines (BZs) are widely prescribed drugs, useful for their anxiolytic, anticonvulsant, sedative and muscle relaxant properties. However, the clinical usefulness of the benzodiazepines is hampered by the development of tolerance to their actions during prolonged exposure. 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 have focused on GABAergic systems. Both gonadal hormones and stress have been shown to modulate the: GABA/benzodiazepine system. In rats, in vivo fluctuations in gonadal hormones modulate GABAergic systems, but not the acute anticonvulsant actions of the benzodiazepines. However, gonadal status does modify both 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 (CRF) mediate the stress-induced changes in GABA/BZ responses. A second goal is to determine if stress modulates neuronal responses to GABA and/or the benzodiazepines in a sexually dimorphic manner. Physiological responses to GABA and benzodiazepines will be measured in several brain areas of male and female rats using l) 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, freely moving 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.