HORMONES, GABA RESPONSES, AND BENZODIAZEPINE TOLERANCE

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 在长时间暴露期间，对其行为的耐受性发展。自.以来 苯二氮卓类药物的急性给药促进了抑制作用 γ-氨基丁酸(GABA)对神经元活动的影响 研究神经适应在儿童精神发育中的作用 苯二氮类药物的耐受性主要集中在GABA能系统。双性腺 激素和压力已被证明调节：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 苯二氮卓类。然而，性腺状态确实改变了表面上的 对阿司匹林抗惊厥作用的耐受性发展 苯二氮类药物及其伴随的神经GABA能适应 大鼠长期暴露于苯二氮类药物。这些与性腺相关的 GABA/BZ反应的差异可能与戏剧性性别有关 啮齿动物对应激的激素反应的差异。建议数 实验将表征性二型应激的作用 性腺对GABA/BZ受体及其受体影响的反应 大鼠的反应，包括与以下因素相关的GABA能适应 长期接触苯二氮卓类药物。研究将--探讨其机制 压力通过它来调节GABA/BZ系统。这些研究将 确定a)性二态、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)介导应激诱导的GABA/BZ变化 回应。第二个目标是确定应激是否调节神经元 性二相患者对GABA和/或苯二氮卓类药物的反应 举止。对GABA和苯二氮卓类药物的生理反应 用L对雄性和雌性大鼠几个脑区的测量) GABA激活的氯离子内流的生化分析(2) 神经元对GABA敏感性的电生理测定及其机制 脑片中的苯二氮卓类药物，以及3)对 清醒自由活动大鼠的神经元活动。最后，我们将评估 应激与性腺因子之间的相互作用 与慢性苯二氮类药物暴露相关的适应和 苯二氮类药物耐受性的相关发展。这些研究 应该有助于阐明与耐受有关的神经变化 苯二氮卓类药物和可能构成性别基础的神经系统- 对焦虑症或癫痫障碍病因的相关影响。

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.