CHRONIC BENZODIAZEPINES--BEHAVIOR AND NEUROCHEMISTRY

描述：（申请人摘要） 苯并二氮杂衍生物和其他GABA-苯并二氮杂受体激动剂 配体，继续被广泛用于治疗焦虑症， 失眠和恐慌症尽管他们的形象普遍良好， 安全性和有效性，苯二氮卓类激动剂产生 长期给药期间的耐受性和依赖性，以及 停药后的停药综合征仍然令人关切。我们有 使用实验模型来表征行为和药效学 苯二氮卓类药物耐受和戒断的特点，以及 这些现象的神经化学和分子机制，以及策略或 可以消除或减少问题的干预措施。模型 主要由啮齿类动物（雄性CD-1小鼠）组成， 药物可以在几天或几周的时间段内连续输送， 皮下植入渗透泵。在此期间和之后的不同时间， 药物输注后，评价动物以确定： 运动活动测量;化学诱导癫痫发作阈值;体内 苯并二氮杂卓受体占有率，受体数量的体外测量， 亲和力、功能和偶联; mRNA的表达，包括几个 苯二氮卓受体亚单位;药物的血药浓度和脑浓度 被注入。使用这个经过充分验证的模型，以及两个较新的模型， 发育中（培养的皮层神经元; 植入电极），该项目建议重点关注以下方面 研究问题：a.苯二氮卓类受体亚型（BZ-1）的作用 与BZ-2）在耐受性和戒断的发展中的作用，将通过 长期给药和停用配体（唑吡坦）， 相对BZ-1选择性; B.兴奋性氨基酸（EAA） 受体系统在协同调节苯二氮卓类药物耐受和戒断中的作用， 通过同时输注推定的EAA拮抗剂来研究; c.年龄依赖 对慢性苯二氮卓类药物给药的反应差异， 撤回，和EAA协同调节的可能作用，研究使用匹配的 年轻和年老的动物。

DESCRIPTION: (Applicant's Abstract) Benzodiazepine derivatives, and other GABA-benzodiazepine receptor agonist ligands, continue to be extensively prescribed for the treatment of anxiety, insomnia, and panic disorder. Despite their generally favorable profile of safety and efficacy, the propensity of benzodiazepine agonists to produce tolerance and dependence during chronic administration, and a discontinuation syndrome on withdrawal, continues to be of concern. We have used experimental models to characterize the behavioral and pharmacodynamic features of benzodiazepine tolerance and withdrawal, as well as the neurochemical and molecular mechanisms of these phenomena, and strategies or interventions that may eliminate or minimize the problems. The model consists principally of a rodent species (male CD-1 mice) to which medications can be delivered continuously over periods of days or weeks via subcutaneously-implanted osmotic pumps. At varying times during and after medication infusion, animals are evaluated to determine: behavioral measures of motor activity; chemically-induced seizure threshold; in vivo benzodiazepine receptor occupancy, in vitro measures of receptor number, affinity, function, and coupling; expression of mRNA including several benzodiazepine receptor subunits; plasma and brain concentrations of drugs being infused. Using this well-validated model, as well as two newer models under development (cultured cortical neurons; EEG responses in rats with implanted electrodes), the project proposes to focus on the following research questions: a. The role of benzodiazepine receptor subtypes (BZ-1 vs BZ-2) in the development of tolerance and withdrawal, to be studied by chronic administration and discontinuation of a ligand (zolpidem) that is relatively BZ-1 selective; b. The role of the excitatory amino acid (EAA) receptor system in coregulation of benzodiazepine tolerance and withdrawal, studied by concurrent infusion of putative EAA antagonists; c. Age-dependent differences in response to chronic benzodiazepine administration and withdrawal, and the possible role of EAA coregulation, studied using matched cohorts of young and old animals.