TOLERANCE TO BENZODIAZEPINES & GABAERGIC SUBSENSITIVITY

对苯二氮卓类药物的耐受性

• 批准号: 3406626
• 负责人: DOROTHY W. GALLAGER
• 金额: $ 14.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3406626
• 关键词: GABA receptor; aminoacid inhibitor; anticonvulsants; azepines; benzodiazepine receptor; benzodiazepines; bicuculline; brain mapping; diazepam; drug interactions; drug metabolism; drug tolerance; electrophysiology; gamma aminobutyrate; laboratory rat; muscle relaxants; neuropharmacology; radiotracer; sedative /hypnotic; synapses

Clinical and behavioral studies have demonstrated that chronic administration of benzodiazepines results in tolerance to many of the therapeutic actions of these drugs. Benzodiazepines are the drugs of first choice for the treatment of status epilepticus and are potential anticonvulsants against a variety of seizure types. However, significant tolerance develops to the anticonvulsant effects of all of the benzodiazepines currently available for clinical use, limiting their usefulness in maintenance therapy. Although the cellular basis for decreasing effectiveness with chronic exposure is not well understood, present knowledge of benzodiazepine function points to involvement of GABAergic processes. We have proposed that tolerance to the benzodiazepines is mediated by changes in the GABA/Bz receptor complex. Work during the present funding period has been directed toward testing this hypothesis. The present proposal will extend these studies, incorporating recent findings that changes in GABA sensitivity seen after chronic diazepam are regionally specific. The hypothesis that differences in GABAergic innervation of the dorsal raphe and substantia nigra pars reticulata underlie differences in GABA sensitivity following chronic diazepam exposure will be tested. Evaluations of GABA sensitivity changes following chronic benzodiazepine exposure to other brain areas using electrophysiological and biochemical (chloride flux) measures will be carried out. Exposure of tolerant animals to a benzodiazepine antagonist has been shown to rapidly restore GABA sensitivity, anticonvulsant efficacy and to diminish physical dependence. This effect will be further investigated and extended to an examination of benzodiazepine ligands of differing efficacy for their tolerance-inducing potency. Possible molecular mechanisms underlying the development of tolerance will be examined by measuring the state of phosphorylation of identified GABA/Bz receptor subunits and by comparing steady state levels of mRNA coding for the receptor complex in naive and tolerant animals. This research will help us understand neural adaptations associated with chronic benzodiazepine exposure and may lead to the development of new chronic therapeutic strategies utilizing these drugs.

临床和行为研究表明，慢性 服用苯二氮卓类药物会导致对许多药物产生耐受性 这些药物的治疗作用。苯二氮卓类药物是 治疗癫痫持续状态的首选且有潜力 针对多种癫痫类型的抗惊厥药。然而，显着 对所有药物的抗惊厥作用产生耐受性 目前临床上使用的苯二氮卓类药物，限制了其 在维持治疗中的有用性。虽然细胞基础 长期暴露会降低有效性尚不清楚， 目前对苯二氮卓功能的了解表明， GABA能过程。我们建议容忍 苯二氮卓类药物是通过 GABA/Bz 受体复合物的变化介导的。 当前资助期间的工作主要用于测试 这个假设。目前的提案将扩展这些研究， 结合最近的发现，GABA 敏感性发生变化 慢性地西泮具有区域特异性。假设差异 中缝背侧和黑质部的 GABA 能神经支配 reticulata 是慢性病后 GABA 敏感性差异的基础 将测试地西泮暴露。 GABA敏感性变化的评估 长期暴露于其他大脑区域的苯二氮卓类药物后 电生理和生化（氯化物通量）措施将 执行。耐受动物接触苯二氮卓类拮抗剂 已被证明可以快速恢复 GABA 敏感性，抗惊厥 功效并减少身体依赖性。这一效应将进一步 研究并扩展到苯二氮卓配体的检查 其耐受诱导效力的功效不同。可能的 耐受性发展的分子机制将是 通过测量已识别的 GABA/Bz 的磷酸化状态进行检查 受体亚基并通​​过比较编码 mRNA 的稳态水平 幼稚动物和耐受动物中的受体复合物。这项研究将 帮助我们了解与慢性病相关的神经适应 苯二氮卓类药物暴露并可能导致新的慢性病的发展 利用这些药物的治疗策略。