Benzodiazepine Choice and Polydrug Use

苯二氮卓类药物的选择和多种药物的使用

基本信息

批准号：
10596141
负责人：
Sally Huskinson
金额：
$ 54.47万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596141
关键词：
Adult Affect Alprazolam Animals Anxiety Disorders Attenuated Benzodiazepines Clinical Data Cocaine Dangerousness Data Development Drug Modelings Drug usage Exhibits Exposure to Food GABA Modulators General Population Goals Heroin Individual Knowledge Ligands Macaca mulatta Modeling Monkeys Opioid Overdose Pattern Pharmaceutical Preparations Procedures Psychological reinforcement Recording of previous events Reporting Research Risk Role Safety Self Administration Sleep Disorders Stimulant Substance Use Disorder Testing Therapeutic Toxic effect Training abuse liability addiction benzodiazepine abuse benzodiazepine misuse drug of abuse epidemiologic data experience experimental study improved multiple drug use non-drug novel strategies overdose death pharmacologic positive allosteric modulator preclinical evaluation predict clinical outcome programs receptor side effect therapeutic development

项目摘要

Project Summary Benzodiazepines (BZs) are effective and safe when used appropriately, but their utility is limited by unwanted side effects like misuse and reduced safety when combined with other drugs. Individuals with substance-use disorders (SUDs) misuse BZs as much as 20x greater than the general population, and the rising number of overdose deaths attributed to BZs are largely driven by opioid co-administration. Given the high rates of polydrug use among individuals who also misuse BZs, preclinical evaluations of BZs should consider the polydrug scenarios in which they are being misused. The goal of this research is to identify pharmacological determinants of BZ misuse, with the goal of identifying BZ-type ligands with reduced abuse potential in polydrug situations. We reported previously that nonselective, partial-efficacy BZ ligands or those that lack intrinsic efficacy at a1- subunit containing GABAA (a1GABAA) receptors have reduced abuse potential relative to traditional BZs. However, our data suggest that the degree to which these BZ-type ligands exhibit abuse potential depends on the subject’s drug history. This new application will use choice models to evaluate the overall hypothesis that drug experience is a key determinant of the role of GABAA receptor subtypes in the abuse potential of BZ-type ligands. A key finding from our choice research is that efficacy at a1GABAA receptors may be necessary for self- administration of BZs in cocaine-experienced subjects, but not required for enhancement of cocaine choice. It is unknown whether this pattern of effects is observed with other drugs of abuse, in particular opioids. Moreover, the pharmacological mechanism underlying these effects is unknown, with possibilities including (1) a differential role for a1GABAA receptors in reinforcement-enhancing vs. reinforcing effects of BZs alone, or (2) differences in overall intrinsic efficacy, irrespective of subtype selectivity. We will address these potential mechanisms in two Aims organized by unique approaches. In Aim 1, we will use drug vs. drug choice to evaluate the extent to which BZ-type ligands varying in efficacy and selectivity will enhance or attenuate drug choice when delivered as a combination with cocaine, heroin, or alprazolam in separate groups of subjects. In Aim 2, we will use drug vs. nondrug choice to evaluate the hypothesis that nonselective, partial modulators or a1-sparing BZs will have reduced reinforcing effects when delivered alone in subjects with a history of cocaine, heroin, alprazolam, or food choice. A significant addition to our groups of monkeys with different reinforcement histories will be the food-experienced animals, providing a quantitative model of drug-naïve individuals’ initial exposure to drug taking. BZ use among individuals with a SUD, in or out of treatment, is increasingly common and is associated with increased risk of BZ misuse and overdose. Testing the hypotheses proposed will provide critical information for understanding how past and current drug use affects the abuse liability of BZ-type drugs.

项目概要苯二氮卓类 (BZ) 使用时有效且安全，但其效用受到适当不需要的限制与其他药物合用时会出现副作用，例如误用和安全性降低。疾病 (SUD) 滥用 BZ 的比例比普通人群高出 20 倍，而且滥用 BZ 的人数也在不断增加鉴于多种药物的高比例，由 BZ 引起的过量死亡主要是由阿片类药物联合用药造成的。在也滥用 BZ 的个体中使用，BZ 的临床前评估应考虑多种药物这项研究的目的是确定它们被滥用的情况。 BZ 滥用的研究，旨在识别在多种药物情况下减少滥用可能性的 BZ 型配体。我们之前报道过非选择性、部分功效的 BZ 配体或在 a1- 缺乏内在功效的配体与传统的 BZ 相比，含有 GABAA (a1GABAA) 受体的亚基降低了滥用可能性。然而，我们的数据表明这些 BZ 型配体表现出滥用潜力的程度取决于这个新应用程序将使用选择模型来评估受试者的药物史。药物经验是 GABAA 受体亚型在 BZ 型滥用潜力中作用的关键决定因素我们选择研究的一个重要发现是，a1GABAA 受体的功效对于自我调节可能是必要的。在有可卡因经历的受试者中施用 BZ，但不是增强可卡因选择所必需的。尚不清楚其他滥用药物（特别是阿片类药物）是否也观察到这种效应模式。这些作用背后的药理学机制尚不清楚，可能性包括（1）差异 a1GABAA 受体在强化增强与单独 BZ 的强化效果中的作用，或 (2) 总体内在功效，无论亚型选择性如何，我们将分两部分讨论这些潜在机制。通过独特方法组织的目标在目标 1 中，我们将使用药物与药物选择来评估其程度。 BZ 型配体的功效和选择性各异，当作为药物递送时，会增强或减弱药物选择。在目标 2 中，我们将在不同的受试者组中与可卡因、海洛因或阿普唑仑联合使用。非药物选择来评估非选择性、部分调节剂或保留 a1 BZ 的假设当单独给予有可卡因、海洛因、阿普唑仑或吸食史的受试者时，增强效果会降低食物选择对我们具有不同强化历史的猴子群体来说是一个重要的补充。有食物经历的动物，提供了未接触过药物的个体最初接触药物的定量模型在 SUD 患者中，无论是否接受治疗，服用 BZ 的情况都越来越普遍，并且与此相关。随着 BZ 滥用和过量风险的增加，测试所提出的假设将提供关键信息。了解过去和现在的药物使用如何影响 BZ 类药物的滥用倾向。