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

酒精的滥用受到药物的多种影响的控制，包括其主观的、强化的和重新的影响。 导致失误的效果。已经开发了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，并为评估提供基于经验的模型 潜在的治疗策略。酒精对γ-氨基丁酸活性的影响 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，使该系统成为开发Thera--的一个有吸引力的候选者。 童话家。GABAA受体的复杂分子生物学增加了亚型选择性的可能性 药物可能开发出对酒精具有治疗特异性的药物。在此应用程序中，我们将调查 含γ和δ的α4GABAA和α6GABAA受体机制在非人灵长类和啮齿动物中的作用 酒精滥用相关影响的模型。我们将使用对α4δ具有选择性的首创化合物， α6δ，α4γ和/或α6γGABA受体研究这些亚型在以下方面的贡献：1)辨别性 酒精对被训练为区分胃内给药酒精和维生素H的猴子的刺激效应-- CLE，2)酒精对猴子口服酒精的强化作用，以及3)复发- 在线索诱导的恢复训练和酒精剥夺训练的大鼠中，酒精的诱导效应是可能的。 目标(具体目标1)。了解成瘾效应背后的神经药理学机制 酒精的作用是开发治疗这种疾病的候选药物疗法的重要的第一步。 酗酒和依赖的治疗。γ和δ选择性α4GABAA和 α6GABAA配体选择性地改变酒精控制的行为将在猴子身上进行评估 用蔗糖溶液代替酒精，并在经过线索诱导的蔗糖寻找过程中进行训练的大鼠身上- 在此期间。在猴子身上，同时进行的观察研究将表征配体的影响，无论是单独的还是共同的- 酗酒，对无条件的运动行为(特定目标2)。这些配基的模拟或 调节酒精、酒精自我给药和线索诱导酒精的辨别性刺激效应 寻求和复发--就像饮酒一样，剂量不会导致行为全面中断或虚弱-- ING的副作用可能预示着潜在的治疗效果。最后，我们将研究selec- 具有良好副作用的活性GABA能配体在药物模型中用作辅助治疗- 辅助治疗(特定目标3)。这些研究将利用一种新的偶然性复苏模型。 我们实验室最近开发了一种管理方法，最初是模拟或减弱Be的配体- 酒精对行为的影响。综合AIMS的结果将继续产生关于以下方面的必要信息 酒精成瘾作用的神经药理学机制及临床研究 药理学方法有望改善患者预后的情景。

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.