Tolerance and Physical Dependence after Chronic Benzodiazepine Treatment

尽管苯二氮类药物(BZS)被认为是现代最安全的处方药之一 药物，其效用受到一些副作用的限制，包括依赖的可能性，以及 最近的流行病学研究表明，苯并苯滥用在美国呈上升趋势。总体目标是 其应用是研究GABAA受体亚型在耐受中的不同程度 以及与长期接触BZ相关的身体依赖，使用相关的非人类灵长类动物模型。 这一新的应用建立在包含α1、α2、α3和α5亚单位的GABA AA受体(分别为α1GABAA、α2GABAA和α3GABAAα5GABAA受体)在BZS的滥用相关和治疗作用中的独特作用的研究基础上。作为之前拨款的一部分，我们获得了几个关键的初步 发现：(1)耐受性可能迅速发展为与α1GABAA受体相关的行为效应，但不是 α2/3GABAA受体；以及(2)BZ类药物诱导身体依赖的能力可能涉及 α1GABAA受体。总之，这些发现支持了α1GABAA受体是关键的工作假说 与长期接触BZ类药物有关的耐受性和身体依赖的介体。 然而，α2GABAA、α3GABAA和α5GABAA受体参与耐受和 身体上的依赖仍然不清楚。在具体目标1中，我们将评估容忍和 使用镇静剂/抗焦虑药BZ、阿普唑仑进行慢性治疗会导致身体依赖 (Xanax)，最常被滥用的BZ。在30天的暴露后，我们将评估差异耐受性 对行为影响，包括自我管理，以及评估自发和突然戒断。 在特定的目标2中，我们将评估α1GABAA和α5GABAA受体亚型介导的假设 耐受性，而α1GABAA受体亚型介导BZS诱导的身体依赖。使用 目标1中确定的参数，我们将使用一系列新的激动剂或 对α1GABAA、α2GABAA、α3GABAA和α5GABAA亚型具有选择性的拮抗剂。我们假设 耐受性的形成需要α1GABAA和α5GABAA受体亚型的共同激活 身体依赖涉及α1GABAA受体亚型。对这一新应用的研究解决了 通过系统地探索受体亚型在行为中所起的作用，成为公共卫生的关键话题 长期接触BZ类药物的影响。这一建议的创新之处在于(1)使用了严谨的 翻译效度高的物种慢性身体依赖的定量行为模型 (2)首次使用具有独特亚型选择性的BZ配体。

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 dependence, and recent epidemiological research suggests BZ abuse is on the rise in the U.S. 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 long-term BZ exposure, using relevant nonhuman primate models. This new application builds on research that has implicated unique roles for α1, α2, α3, and α5 subunit-containing GABAA receptors (α1GABAA, α2GABAA, α3GABAA α5GABAA receptors, respectively) in the abuse-related and therapeutic effects of BZs. As part of a previous grant, we obtained several key preliminary findings: (1) tolerance may develop rapidly to behavioral effects associated with α1GABAA receptors, but not α2/3GABAA receptors; and (2) the ability of BZ-type drugs to induce physical dependence may involve α1GABAA receptors. Together, these findings support the working hypothesis that α1GABAA receptors are key mediators of both tolerance and physical dependence associated with chronic exposure to BZ-type drugs. However, the extent to which α2GABAA, α3GABAA, and α5GABAA receptors are involved in tolerance and physical dependence remains unclear. In Specific Aim 1 we will evaluate the extent to which tolerance and physical dependence will be induced by chronic treatments with the sedative/anxiolytic BZ, alprazolam (Xanax), the most commonly-abused BZ. Following 30 days of exposure, we will evaluate differential tolerance to behavioral effects, including self-administration, as well as assess spontaneous and precipitated withdrawal. In Specific Aim 2, we will evaluate the hypothesis that α1GABAA and α5GABAA receptor subtypes mediate tolerance, whereas α1GABAA receptor subtypes mediate physical dependence induced by BZs. Using the parameters established in Aim 1, we will conduct studies with a novel series of ligands that are agonists or antagonists with selectivity for α1GABAA, α2GABAA, α3GABAA, and α5GABAA subtypes. We hypothesize that tolerance development requires co-activation of both the α1GABAA and α5GABAA receptor subtypes and that physical dependence involves the α1GABAA receptor subtype. The research in this new application addresses a key topic for public health by systematically exploring the role that receptor subtypes play in the behavioral effects of chronic exposure to BZ-type drugs. Innovation of this proposal is in (1) the use of rigorous quantitative behavioral models of chronic physical dependence in a species with high translational validity (rhesus macaque); and (2) the use of first-in-kind BZ ligands with unique subtype selectivity.