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: 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
• 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

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 苯二氮卓类药物（BZ）在适当使用时是有效和安全的，但它们的效用受到不必要的限制。 副作用，如误用和安全性降低时，与其他药物结合。物质使用者 滥用BZ的人比一般人群多20倍， 由BZ引起的过量死亡主要是由阿片类药物联合给药引起的。鉴于高比率的多种药物 在滥用BZ的个体中使用，BZ的临床前评价应考虑多药 他们被滥用的情况。这项研究的目的是确定药理学决定因素 的BZ滥用，与确定的目标BZ型配体减少滥用的可能性在多种药物的情况下。 我们以前报道过，非选择性的，部分有效的BZ配体或那些在a1- 含有GABAA亚基（α 1 GABAA）受体的BZ具有相对于传统BZ降低的滥用可能性。 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 受试者的药物史。这个新的应用程序将使用选择模型来评估整体假设， 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。 配体。我们选择研究的一个关键发现是，对a1 GABAA受体的功效可能是自我调节所必需的。 在可卡因经历的受试者中给予BZ，但不需要增加可卡因的选择。是 尚不清楚在其他滥用药物特别是类阿片中是否也观察到这种效应模式。此外，委员会认为， 这些作用的药理学机制尚不清楚，可能包括：（1） α 1 GABAA受体在BZ单独的增强与增强作用中的作用，或（2） 总体内在疗效，与亚型选择性无关。我们将分两部分讨论这些潜在机制 以独特的方式组织目标。在目标1中，我们将使用药物与药物选择来评估 BZ型配体在功效和选择性方面的变化将增强或减弱作为药物递送时的药物选择。 与可卡因、海洛因或阿普唑仑的组合。在目标2中，我们将使用药物与 非药物选择，以评估非选择性，部分调节剂或α 1保留BZ将具有 在有可卡因、海洛因、阿普唑仑或 食物选择我们的猴子群体中有一个重要的补充，具有不同的强化历史， 食物经验丰富的动物，提供了药物初治个体初始暴露于药物的定量模型 拿。在SUD患者中，无论是否接受治疗，BZ的使用越来越普遍， BZ滥用和过量的风险增加。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。