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.

尽管苯二氮卓类药物 (BZ) 被认为是现代最安全的处方药之一 药物，其效用受到许多副作用的限制，包括依赖性的责任，以及 最近的流行病学研究表明，BZ 滥用现象在美国呈上升趋势。 应用是研究 GABAA 受体亚型差异参与耐受性的程度 使用相关的非人类灵长类动物模型，研究与长期暴露于 BZ 相关的身体依赖性。 这项新应用建立在研究的基础上，该研究表明含有 α1、α2、α3 和 α5 亚基的 GABAA 受体（分别为 α1GABAA、α2GABAA、α3GABAA α5GABAA 受体）在 BZ 的滥用相关和治疗作用中发挥着独特的作用。在之前的资助中，我们获得了几项关键的初步资助 研究结果：(1) 对与 α1GABAA 受体相关的行为效应的耐受性可能会迅速发展，但不会 α2/3GABAA 受体；以及（2）BZ 类药物诱导身体依赖性的能力可能涉及 α1GABAA 受体，这些发现共同支持了 α1GABAA 受体是关键的假设。 与长期接触 BZ 类药物相关的耐受性和身体依赖性的介质。 然而，α2GABAA、α3GABAA 和 α5GABAA 受体参与耐受和耐受的程度 身体依赖性仍不清楚。在具体目标 1 中，我们将评估耐受性和耐受性的程度。 长期使用镇静/抗焦虑药 BZ、阿普唑仑治疗会引起身体依赖性 (Xanax)，最常滥用的 BZ 暴露 30 天后，我们将评估差异耐受性。 行为影响，包括自我给药，以及评估自发和突然戒断。 在具体目标 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 BZ 诱导的身体依赖性。 根据目标 1 中建立的参数，我们将使用一系列新颖的配体进行研究，这些配体是激动剂或 我们竞争了对 α1GABAA、α2GABAA、α3GABAA 和 α5GABAA 亚型具有选择性的拮抗剂。 耐受性的发展需要α1GABAA和α5GABAA受体亚型的共同激活，并且 这项新申请的研究涉及身体依赖性。 通过系统地探索受体亚型在行为中所起的作用，成为公共卫生的一个关键主题 长期接触BZ类药物的影响 本建议的创新点在于（1）严格使用。 具有高转化有效性的物种慢性身体依赖的定量行为模型 （恒河猴）；（2）使用具有独特亚型选择性的同类首创 BZ 配体。