GABAa receptor subtype mechanisms in nonhuman primate models of alcohol abuse

非人灵长类酒精滥用模型中的 GABAa 受体亚型机制

• 批准号: 7631406
• 负责人: Donna M Platt
• 金额: $ 35.78万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631406
• 关键词: Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Ataxia; Attenuated; Behavior; Behavior Control; Behavioral; Dependence; Development; Dose; Ligands; Macaca mulatta; Medical; Methods; Modeling; Monkeys; Motor; Neurobiology; Observational Study; Oral; Performance; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Public Health; Relapse; Research; Rodent; Role; Sedation procedure; Self Administration; Self-Administered; Solutions; Stimulus; Sucrose; Techniques; Therapeutic; Training; alcohol craving; alcohol effect; alcohol seeking behavior; base; craving; drug discrimination; non-drug; nonhuman primate; novel; pre-clinical; psychologic; receptor; reinforcer; social; treatment strategy

DESCRIPTION (provided by applicant): Alcoholism is a public health problem that is associated with debilitating medical, social, and psychological consequences. The abuse of alcohol is controlled by multiple effects of the drug, including its subjective and reinforcing effects and its capacity to trigger relapse. Preclinical methods have been developed to assess the contribution of these controlling factors and their neurobiological underpinnings, and to provide empirically-based models for evaluating potential treatment strategies. The purpose of this proposal is to investigate the role of alpha1GABAA and alpha5GABAA receptor mechanisms in nonhuman primate models of the abuse-related effects of alcohol. Recent findings support a role for both alpha1GABAA and alpha5GABAA receptor mechanisms in alcohol's discriminative stimulus effects in monkeys and its reinforcing effects in rodents. We will build on these new findings to systematically investigate the contribution of alpha1GABAA (Specific Aim 1) and alpha5GABAA (Specific Aim 2) receptor mechanisms to the behavioral effects of alcohol by determining how receptor selective agonists and antagonists modulate: 1) the discriminative stimulus effects of alcohol in rhesus monkeys trained to discriminate intragastrically-administered alcohol from vehicle, 2) oral self- administration of alcohol in rhesus monkeys, and 3) reinstatement of alcohol seeking in rhesus monkeys whose oral self-administration has been extinguished and subsequently reinstated by alcohol priming. The degree to which the effects of alpha1GABAA and alpha5GABAA receptor ligands selectively modify alcohol-controlled behavior (Specific Aim 3) will be evaluated in rhesus monkeys that self-administer a sucrose solution instead of alcohol and in concurrent observational studies of the effects these ligands, alone or combined with alcohol, on unconditioned motor behavior. The ability of selected alpha1GABAA and alpha5GABAA ligands to blunt the discriminative stimulus effects of alcohol, reduce alcohol self-administration and attenuate priming- induced reinstatement of alcohol seeking at doses that do not produce a generalized disruption of behavior or debilitating side effects may be predictive of potential therapeutic utility. Integration of results from these three specific aims will provide needed information about specific GABAA mechanisms that may underlie the addictive effects of alcohol and will aid identification of receptor targets for the pharmacological management of alcohol abuse and relapse.

描述（由申请人提供）：酒精中毒是一个公共卫生问题，与医学，社会和心理后果衰弱有关。酒精的滥用受药物的多种影响，包括其主观和增强作用以及触发复发的能力。已经开发出临床前方法来评估这些控制因素及其神经生物学基础的贡献，并提供基于经验的模型来评估潜在的治疗策略。该提案的目的是研究α1Gabaa和α5Gabaa受体机制在酒精与滥用相关作用的非人类灵长类动物模型中的作用。最近的发现支持α1GABAA和α5GABAA受体机制在猴子的歧视性刺激效应及其对啮齿动物的增强作用中的作用。 We will build on these new findings to systematically investigate the contribution of alpha1GABAA (Specific Aim 1) and alpha5GABAA (Specific Aim 2) receptor mechanisms to the behavioral effects of alcohol by determining how receptor selective agonists and antagonists modulate: 1) the discriminative stimulus effects of alcohol in rhesus monkeys trained to discriminate intragastrically-administered alcohol from vehicle, 2)口服恒河猴中酒精的自我给药，以及3）恢复在恒河猴中寻求酒精的饮酒，其口服自我给药已被扑灭，随后通过酒精启动恢复了。 α1GabaA和α5GabaA受体配体的影响有选择地修改酒精控制的行为（特定目标3），将在恒河猴中进行评估，这些猴子会在恒河猴猴子中进行自我管理，而不是蔗糖溶液，而不是酒精以及对这些配合或与酒精相结合的无与伦比的效果的观察性研究中，无与伦比的运动。选定的α1Gabaa和α5Gabaa配体的能力钝化酒精的歧视性刺激作用，减少酒精自我给药并减轻启动引发诱导的启动诱导的剂量，以剂量恢复剂量的剂量，而这些剂量不会对行为或衰弱的副作用产生潜在的效果，从而可以预测具有潜在的效果。这三个特定目标的结果整合将提供有关特定GABAA机制的所需信息，这些机制可能是酒精的上瘾作用的基础，并将有助于鉴定受体靶标的药物治疗酒精滥用和复发。