Benzodiazepine Choice and Polydrug Use

苯二氮卓类药物的选择和多种药物的使用

• 批准号: 10444445
• 负责人: Sally Huskinson
• 金额: $ 55.58万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 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/10444445
• 关键词: Address; 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; Pharmacology; 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; positive allosteric modulator; preclinical evaluation; predict clinical outcome; programs; receptor; side effect; therapeutic development

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.

项目摘要 适当使用时，苯二氮卓（BZS）（BZS）是有效且安全的，但是它们的效用受到不必要的限制 与其他药物结合使用时，副作用和降低了安全性。具有物质使用的人 疾病（SUDS）小姐BZS比一般人群高20倍，数量增加 归因于BZ的过量死亡主要由阿片类药物共同给药。鉴于多盘的速度很高 在也错过BZ的个人中使用，BZ的临床前评估应考虑Polydrug 他们被错过的场景。这项研究的目的是确定药物确定性 BZ滥用，目的是确定在多药物情况下滥用潜力降低的BZ型配体。 我们先前报道说，非选择性，部分效能BZ配体或在A1-中缺乏内在效率的配体的配体 相对于传统的BZ，含有GABAA（A1GABAA）受体的亚基的滥用潜力降低。 但是，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 受试者的毒品史。该新应用程序将使用选择模型来评估总体假设 药物体验是GABAA受体亚型在BZ型滥用潜力中的作用的关键决定者 配体。我们选择研究中的一个关键发现是，在自我的A1GABAA受体上有效 在可卡因经验的受试者中施用BZ，但不需要增强可卡因选择。这是 未知是否使用其他滥用药物，尤其是阿片类药物观察到这种影响模式。而且， 这些作用的基础药物机制尚不清楚，其中可能性包括（1）差异 A1GABAA受体在增强增强性增强与仅BZ的增强作用中的作用，或（2） 总体固有效率，无论亚型选择性如何。我们将在两个中解决这些潜在机制 通过独特的方法组织的目标。在AIM 1中，我们将使用药物与药物选择来评估 Bz型配体的效率和选择性各不相同 与可卡因，海洛因或阿普唑仑结合在单独的受试者中。在AIM 2中，我们将使用毒品V。 Nondrug的选择是评估非选择性，部分调节剂或A1 Sparing BZS的假设 在具有可卡因，海洛因，阿普唑仑或 食物选择。我们具有不同加固历史的猴子群的一个重要补充将是 经验丰富的动物，提供了未经药物初次暴露药物的定量模型 服用。在患有SUD的个体中使用BZ，在治疗中或无法治疗的人都越来越普遍，并且相关 随着BZ小姐和过量的风险增加。测试提出的假设将提供关键信息 为了了解过去和当前的药物使用如何影响BZ型药物的滥用责任。