Tolerance and Physical Dependence after Chronic Benzodiazepine Treatment

项目总结/摘要 虽然苯二氮卓类药物（BZ）被认为是现代最安全的处方药之一， 药物，它们的效用受到许多副作用的限制，包括耐受性的责任， 依赖本申请的总体目标是研究GABAA受体亚型在多大程度上 与急性和长期BZ相关的耐受性和身体依赖性有差异 exposure.这项更新申请建立在研究的基础上，研究表明α 1，α 2，α 3和α 5亚基的独特作用， 含有GABAA受体（分别为α 1 GABAA、α 2 GABAA、α 3 GABAA、α 5 GABAA受体）的BZ- 诱导耐受性和依赖性。在我们的上一个项目期间，我们获得了几个重要的 结果：（1）对与α 1GABAA受体相关的行为效应的耐受性迅速发展，但对与α 1GABAA受体相关的行为效应的耐受性不明显。 α 2/3GABAA受体;（2）BZ类药物诱导身体依赖的能力涉及α 1GABAA 受体;但（3）新的证据表明，其他GABAA亚型在身体疾病中具有独特的抑制作用。 依赖总之，这些发现构成了我们工作假设的框架，即α 1GABAA受体 是与暴露于BZ类药物相关的耐受性和身体依赖性的关键介质， 而身体依赖性可通过α 2GABAA和/或α 3GABAA亚型减轻。具体目标1、 我们将评估α 1GABAA亚型是急性和慢性身体疾病的关键介质的假设， 依赖性，以及耐受性，诱导BZ。具体目标2将评估以下假设： α 2/3GABAA受体具有独特的"保护性"作用，可防止戒断，对这种作用无耐受性 由这些亚型介导。我们还将探索α 5GABAA亚型作为促进剂的新的潜在作用 宽容。这项更新应用的研究通过系统地 探讨GABAA受体亚型在BZ型糖尿病耐受和依赖中的作用 药物，这是一个受到相对较少关注的研究领域。因为宽容和身体 依赖是使用BZ作为有效治疗剂的重大障碍，这项应用的研究将 用于开发具有降低的依赖性/滥用的改进的治疗剂的知情药物发现策略 潜力

PROJECT SUMMARY/ABSTRACT Although benzodiazepines (BZs) are considered to be among the safest prescription drugs in modern medicine, their utility is constrained by a number of side effects, including the liability for tolerance and dependence. The overall goal of this application is to investigate the extent to which GABAA receptor subtypes are differentially involved in tolerance and physical dependence associated with acute and long-term BZ exposure. This renewal application builds on research implicating unique roles for α1, α2, α3, and α5 subunit- containing GABAA receptors (α1GABAA, α2GABAA, α3GABAA α5GABAA receptors, respectively) in BZ- induced tolerance and dependence. During our previous Project Period, we obtained several important findings: (1) tolerance develops rapidly to behavioral effects associated with α1GABAA receptors, but not α2/3GABAA receptors; (2) the ability of BZ-type drugs to induce physical dependence involves α1GABAA receptors; but (3) new evidence has suggested a unique inhibitory role for other GABAA subtype(s) in physical dependence. Together, these findings form the framework for our working hypothesis that α1GABAA receptors are key mediators of both tolerance and physical dependence associated with exposure to BZ-type drugs, whereas physical dependence may be mitigated by α2GABAA and/or α3GABAA subtypes. In Specific Aim 1, we will evaluate the hypothesis that α1GABAA subtypes are key mediators of acute and chronic physical dependence, as well as tolerance, induced by BZs. Specific Aim 2 will evaluate the hypotheses that α2/3GABAA receptors play a unique “protective” role of preventing withdrawal, with no tolerance to the effects mediated by these subtypes. We also will explore a novel potential role for α5GABAA subtypes as facilitators of tolerance. The research in this renewal application addresses a key gap in knowledge by systematically exploring the role that GABAA receptor subtypes play in tolerance and dependence associated with BZ-type drugs, an area of research that has received relatively little attention. Because tolerance and physical dependence are significant barriers to use of BZs as effective therapeutics, the research in this application will inform drug discovery strategies for developing improved therapeutics with reduced dependence/abuse potential.