GABA-A receptor subtype mechanisms and the abuse-related effects of alcohol

GABA-A 受体亚型机制和酒精滥用相关的影响

• 批准号: 10666480
• 负责人: Donna M Platt
• 金额: $ 47.29万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666480
• 关键词: Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Aminobutyric Acids; Attenuated; Behavior; Behavior Therapy; Behavioral; Benzodiazepines; Clinic; Clinical; Combined Modality Therapy; Complex; Cues; Data; Development; Diazepam; Dose; Exhibits; FDA approved; GABA-A Receptor; Goals; Human; Laboratories; Laboratory Animals; Learning; Ligands; Literature; Mediating; Mediator; Methods; Modeling; Molecular Biology; Monkeys; Naltrexone; Neurobiology; Neurons; Observational Study; Oral; Patient-Focused Outcomes; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Population; Primates; Procedures; Rattus; Relapse; Research; Research Personnel; Rodent; Rodent Model; Role; Self Administration; Specificity; Stimulus; Sucrose; System; Therapeutic; Training; alcohol abuse therapy; alcohol effect; alcohol relapse; alcohol seeking behavior; alcohol use disorder; contingency management; craving; deprivation; drinking; gamma-Aminobutyric Acid; human subject; improved; medication-assisted treatment; motor behavior; non-drug; nonhuman primate; novel; pharmacologic; pre-clinical; receptor; reinforcer; side effect; therapeutic development; treatment strategy

The abuse of alcohol is controlled by multiple effects of the drug, including its subjective, reinforcing, and re- lapse-inducing effects. Preclinical methods have been developed to assess the contribution of these control- ling factors and their neurobiological underpinnings, and to provide empirically based models for evaluating potential treatment strategies. Alcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the abuse-related effects of alcohol in both humans and laboratory animals, making this system an attractive candidate for the development of thera- peutics. The complex molecular biology of GABAA receptors raises the possibility that subtype-selective agents might be developed with therapeutic specificity against alcohol. In this application, we will investigate the role of γ- and δ-containing α4GABAA and α6GABAA receptor mechanisms in nonhuman primate and rodent models of the abuse-related effects of alcohol. We will use first-in-kind compounds that are selective for α4δ, α6δ, α4γ, and/or α6γGABAA receptors to investigate the contribution of these subtypes to: 1) the discriminative stimulus effects of alcohol in monkeys trained to discriminate intra-gastrically-administered alcohol from vehi- cle, 2) the reinforcing effects of alcohol in monkeys orally self-administering alcohol, and 3) the relapse- inducing effects of alcohol in rats trained in either cue-induced reinstatement or alcohol deprivation effect pro- cedures (Specific Aim 1). Understanding the neuropharmacological mechanisms underlying the addictive ef- fects of alcohol is an important initial step in the development of candidate pharmacotherapies for the treat- ment of alcohol abuse and dependence. The degree to which the effects of γ- and δ-selective α4GABAA and α6GABAA ligands selectively modify alcohol-controlled behavior will be evaluated in monkeys that self- administer a sucrose solution instead of alcohol and in rats trained in a cue-induced sucrose seeking proce- dure. In monkeys, concurrent observational studies will characterize the effects of the ligands, alone or com- bined with alcohol, on unconditioned motor behavior (Specific Aim 2). The ability of these ligands to mimic or modulate the discriminative stimulus effects of alcohol, alcohol self-administration, and cue-induced alcohol seeking and relapse-like drinking at doses that do not produce a generalized disruption of behavior or debilitat- ing side effects may be predictive of potential therapeutic utility. Finally, we will investigate the utility of selec- tive GABAergic ligands with favorable side effect profiles to serve as co-therapies in a model of medication- assisted treatment (Specific Aim 3). These studies will make use of a novel resurgence model of contingency management developed recently in our laboratory and, initially, ligands that either mimic or attenuate the be- havioral effects of alcohol. Integration of results from the aims will continue to yield needed information about neuropharmacological mechanisms underlying the addictive effects of alcohol and begin to identify clinical scenarios in which pharmacological approaches might be expected to produce improved patient outcomes.

酒精的滥用是通过药物的多种作用来控制的，包括其主观作用、强化作用和再作用。 已经开发出临床前方法来评估这些控制的贡献。 ling因素及其神经生物学基础，并提供基于经验的评估模型 潜在的治疗策略。酒精增强γ-氨基丁酸（GABA）活性的能力。 GABAA 受体被认为是酒精滥用相关影响的关键机制。 人类和实验动物，使该系统成为治疗开发的有吸引力的候选者 GABAA 受体的复杂分子生物学提出了亚型选择性的可能性。 可能会开发出具有针对酒精的特异性治疗作用的药物。在此应用中，我们将进行研究。 含 γ 和 δ 的 α4GABAA 和 α6GABAA 受体机制在非人灵长类动物和啮齿类动物中的作用 我们将使用对 α4δ 具有选择性的同类首创化合物， α6δ、α4γ 和/或 α6γGABAA 受体，以研究这些亚型对以下方面的贡献：1) 判别性 酒精对经过训练以区分胃内注射的酒精和车辆的猴子的刺激作用 cle，2）酒精对猴子口服自我饮酒的增强作用，以及3）复发- 酒精对经过提示诱导恢复或酒精剥夺效应训练的大鼠的诱导作用 程序（具体目标 1）。了解成瘾作用背后的神经药理学机制。 酒精的影响是开发治疗酒精的候选药物疗法的重要的第一步。 γ-和δ-选择性α4GABAA 和酒精滥用和依赖性的影响程度。 α6GABAA 配体选择性地改变酒精控制行为将在自我控制的猴子中进行评估 使用蔗糖溶液代替酒精，并在接受提示诱导蔗糖寻找程序训练的大鼠中- 在猴子中，同时进行的观察性研究将表征配体单独或组合的作用。 与酒精结合，影响无条件运动行为（具体目标 2）。 调节酒精、酒精自我管理和提示诱导酒精的辨别刺激效应 寻求和复发样饮酒的剂量不会产生普遍的行为破坏或衰弱 最后，我们将研究选择的效用。 具有良好副作用的活性 GABA 配体可作为药物模型中的联合疗法 辅助治疗（具体目标 3）。这些研究将利用一种新颖的应急复苏模型。 我们实验室最近开发了管理方法，最初是模拟或减弱效果的配体 酒精对身体的影响。整合目标结果将继续产生所需的信息。 酒精成瘾作用的神经药理学机制并开始确定临床 在这种情况下，药理学方法有望改善患者的治疗结果。