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

酒精的滥用是由药物的多重作用控制的，包括其主观的，强化的，和重新的。 导致失误的影响。已经开发了临床前方法来评估这些控制的贡献- 的影响因素及其神经生物学基础，并提供基于经验的模型，以评估 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作用的关键机制， 人类和实验室动物，使该系统成为一个有吸引力的候选人的发展， peutics。GABAA受体的复杂分子生物学提出了亚型选择性 可以开发出对酒精具有治疗特异性的药物。在本申请中，我们将调查 非人灵长类和啮齿类动物α 4 GABAA和α 6 GABAA受体机制作用 酒精滥用相关影响的模型。我们将使用对α4δ有选择性的同类化合物， α6δ、α4γ和/或α6γGABAA受体，以研究这些亚型对以下方面的贡献：1）区分性GABAA受体亚型， 酒精在训练区分灌胃给药酒精和汽车给药酒精的猴子中的刺激作用， cle，2）酒精在口服自我给药酒精的猴子中的强化作用，以及3）复发- 酒精在大鼠中的诱导作用，无论是在线索诱导的恢复或酒精剥夺效应前训练， 具体目标1）。了解成瘾性EF的神经药理学机制- 酒精的作用是开发治疗酒精中毒的候选药物疗法的重要的第一步， 酒精滥用和依赖。γ-和δ-选择性α4GABAA和γ-选择性α4GABAA的作用程度 α 6 GABAA配体选择性地改变酒精控制行为将在自我调节的猴子中进行评估。 给予蔗糖溶液而不是酒精，并在经过线索诱导的蔗糖寻找过程训练的大鼠中， dure.在猴子中，同时进行的观察性研究将描述配体单独或联合的作用， 结合酒精，对非条件运动行为（具体目标2）。这些配体模拟或 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 寻求和复发样饮酒的剂量，不产生行为或衰弱的普遍中断， 副作用可能预示着潜在的治疗效用。最后，我们将研究selec的效用。 具有有利副作用特征的活性GABA能配体在药物治疗模型中用作共同治疗， 辅助治疗（具体目标3）。这些研究将利用一个新的复苏模型的偶然性 管理最近在我们的实验室开发，最初，配体，无论是模仿或减弱的是， 酒精的行为影响。综合各项目标的结果将继续产生所需的信息， 神经药理学机制的酒精成瘾作用和开始确定临床 药理学方法有望改善患者结局的情况。

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.