Tolerance and Physical Dependence after Chronic Benzodiazepine Treatment

慢性苯二氮卓治疗后的耐受性和身体依赖性

• 批准号: 10162574
• 负责人: JAMES K ROWLETT
• 金额: $ 40.27万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162574
• 关键词: Acute; Address; Agonist; Alprazolam; Anti-Anxiety Agents; Anticonvulsants; Behavioral; Behavioral Model; Benzodiazepines; Chronic; Dependence; Development; Diazepam; Drug Prescriptions; Exposure to; Female; Goals; Grant; Ligands; Macaca mulatta; Mediating; Mediator of activation protein; Medical; Mental disorders; Modeling; Modern Medicine; Monkeys; Muscle relaxants; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Play; Psychotropic Drugs; Public Health; Research; Role; Self Administration; Series; Therapeutic; Therapeutic Effect; Withdrawal; Work; Xanax; arm; benzodiazepine abuse; clinical effect; drug development; drug discovery; drug of abuse; epidemiology study; hypnotic; innovation; nonhuman primate; novel; novel therapeutics; programs; receptor; sedative; side effect; treatment of anxiety disorders; zolpidem

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.

尽管苯二氮卓（BZ）被认为是现代最安全的处方药之一 医学，它们的效用受到许多副作用的限制，包括依赖的责任和 最近的流行病学研究表明，美国的BZ滥用正在增加 应用是研究GABAA接收器亚型与公差不同的程度 使用相关的非人类私人模型与长期BZ暴露相关的身体依赖性。 这一新应用是基于研究在滥用相关和治疗性效果的α1，α2，α3和α5GABAA受体（分别为α1GABAA，α2GABAA，α2GABAA，α2GABAA，α2GABAA，α2GABAA，α2GABAA，α2GABAA，分别为α1GABAA，α2GABAA，分别）的研究基础上。作为上一笔赠款的一部分，我们获得了几个关键的初步 调查结果：（1）耐受性可能会迅速发展到与α1Gabaa受体相关的行为效应，但不会迅速发展 α2/3GABAA受体； （2）BZ型药物诱导身体依赖的能力可能涉及 α1GABAA受体。这些发现共同支持了α1GABAA受体是关键的工作假设 耐受性和身体依赖性的介体与长期暴露于BZ型药物有关的介体。 但是，α2GABAA，α3GABAA和α5GABAA受体在多大程度上参与了耐受性和 身体依赖仍然不清楚。在特定目标1中，我们将评估容忍度和 物理依赖性将通过镇静/抗焦虑BZ的慢性治疗诱导 （Xanax），最常见的BZ。暴露30天后，我们将评估差异公差 行为影响，包括自我管理，以及评估的赞助和珍贵的戒断。 在特定目标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诱导的身体依赖性。使用 在AIM 1中建立的参数，我们将使用一系列新型配体进行研究，这些配体是激动剂或 对α1GABAA，α2GABAA，α3GABAA和α5GABAA亚型的拮抗剂。我们假设这一点 耐受性的发展需要α1GABAA和α5GABAA受体亚型共同激活，并且 物理依赖性涉及α1GabaA受体亚型。这个新申请地址的研究 通过系统地探索接收器子类型在行为中扮演的角色，成为公共卫生的关键主题 长期暴露于BZ型药物的影响。该提议的创新是在（1）严格的使用 慢性物理依赖性的定量行为模型在具有高转化有效性的物种中 （恒河猕猴）; （2）使用具有独特亚型选择性的第一型BZ配体。