CHRONIC BENZODIAZEPINES--BEHAVIOR AND NEUROCHEMISTRY

描述：(申请人摘要) 苯二氮卓类衍生物和其他GABA-苯二氮卓受体激动剂 配体，继续被广泛开出治疗焦虑的处方， 失眠和惊恐障碍。尽管他们总体上对 安全性和有效性，苯二氮卓类激动剂生产的倾向 长期服药期间的耐受性和依赖性，以及 戒断后的停药综合症，继续令人担忧。我们有 使用实验模型来描述行为和药效学 苯二氮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 可以消除或最小化问题的干预措施。模型 主要由一种啮齿类动物(雄性CD-1小鼠)组成 药物可以在几天或几周的时间内通过 皮下植入渗透泵。在期间和之后的不同时间 用药输液，对动物进行评估以确定：行为 运动活动的测量；化学诱发癫痫阈值；活体 苯二氮卓类受体占有率，受体数量的体外测量， 亲和力、功能和偶联；表达包括几个 苯二氮卓类受体亚单位；血浆和脑内药物浓度 被灌输。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(培养的皮质神经元；大鼠的脑电反应 植入电极)，该项目建议重点关注以下几点 研究问题：a.苯二氮类受体亚型(BZ-1)的作用 VS BZ-2)在耐受和戒断发展中的作用，有待研究 一种配体(唑吡坦)的慢性给药和停用 BZ-1的相对选择性；b.兴奋性氨基酸(EAA)的作用 苯二氮卓类耐受和戒断的共同调节受体系统 通过同时输注假定的EAA拮抗剂进行研究；c.年龄相关 慢性服用苯二氮卓类药物的疗效差异 戒断，以及EAA共同调节的可能作用，使用Match研究 一群年轻的和年长的动物。

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.