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TOLERANCE TO BENZODIAZEPINES & GABA-ERGIC SUBSENSITIVITY

对苯二氮卓类药物的耐受性

基本信息

批准号：
3406630
负责人：
DOROTHY W. GALLAGER
金额：
$ 14.77万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-02-01 至 1992-01-31
项目状态：
已结题

项目摘要

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，苯二氮卓类药物的给药导致对许多这些药物的治疗作用。苯二氮卓类药物是是治疗癫痫持续状态的首选药物，抗惊厥药，针对各种类型的癫痫发作。然而，重要的耐受性发展到所有的抗惊厥作用，目前可用于临床使用的苯二氮卓类药物，限制了其在维持治疗中的有用性。虽然细胞基础慢性接触的有效性降低还没有得到很好的理解，目前对苯二氮卓类药物功能的了解表明， GABA能过程。我们已经提出，容忍苯二氮卓类药物的作用是由GABA/Bz受体复合物的变化介导的。本供资期间的工作主要是测试这个假设。本提案将扩大这些研究，结合最近的发现，GABA敏感性的变化后，慢性地西泮具有区域特异性。假设差异中缝背核和黑质部的GABA能神经支配慢性脑缺血后GABA敏感性的差异将测试地西泮暴露。GABA敏感性变化的评价在慢性苯二氮卓暴露于其他大脑区域后，电生理和生化（氯通量）测量将被贯彻耐受动物暴露于苯二氮卓类拮抗剂已被证明可以迅速恢复GABA的敏感性，抗惊厥功效和减少身体依赖性。这种影响将进一步研究并扩展到苯并二氮杂卓配体的检查其耐受性诱导效力不同。可能耐受性发展的分子机制将是通过测量鉴定的GABA/Bz的磷酸化状态进行检查受体亚单位，并通过比较稳态水平的mRNA编码受体复合物在幼稚和耐受动物中的作用。这项研究将帮助我们理解慢性疾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利用这些药物的治疗策略。