TOLERANCE TO BENZODIAZEPINES & GABA-ERGIC SUBSENSITIVITY

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 这些药物的治疗作用。苯二氮卓类药物是 癫痫持续状态的首选治疗方法及潜力 抗惊厥药，可对抗各种类型的癫痫。然而，重要的是 耐受性发展为所有的抗惊厥作用 目前可用于临床的苯二氮卓类药物，限制了它们的 在维持治疗中的有效性。虽然细胞基础是 对慢性暴露的有效性降低还没有很好的理解， 目前对苯二氮类药物功能的认识表明， GABA能过程。我们已经提出了对 苯二氮类药物是通过GABA/BZ受体复合体的变化来调节的。 本供资期间的工作主要用于测试 这个假说。目前的建议将延长这些研究的期限， 结合了最近的发现，GABA敏感性的变化在 慢性安定是地区性的。关于差异的假设 中缝背侧和黑质的GABA能神经支配 网状结构是慢性阻塞性肺疾病患者GABA敏感性差异的基础 将对安定暴露进行测试。对GABA敏感性变化的评估 在苯二氮类药物慢性暴露于其他脑区后，使用 电生理和生化(氯离子通量)措施将 被执行。耐受性动物暴露于苯二氮卓类拮抗剂 已被证明能迅速恢复GABA敏感性，抗惊厥药物 有效并减少对身体的依赖。这种影响将会进一步 研究并推广到苯二氮卓类配体的考察 它们诱导耐受性的效力不同。可能的 形成耐受性的分子机制将是 通过测量确定的GABA/BZ的磷酸化状态进行检查 并通过比较编码受体亚单位的mRNA的稳态水平 幼稚和忍耐的动物体内的受体复合体。这项研究将 帮助我们了解与慢性疾病相关的神经适应 苯二氮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。

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.