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: 7245873
• 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/7245873
• 关键词: Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Ataxia; Attenuated; Behavior; Behavior Control; Behavioral; Dependence; Development; Disruption; Dose; Ligands; Macaca mulatta; Medical; Methods; Modeling; Monkeys; Motor; Neurobiology; Observational Study; Oral; Performance; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Public Health; Purpose; 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; nonhuman primate; novel; pre-clinical; psychologic; receptor; reinforcer; social

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）：酗酒是一种公共健康问题，与医疗、社会和心理方面的衰弱后果有关。酒精的滥用是通过药物的多种作用来控制的，包括其主观作用和强化作用以及引发复发的能力。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。本提案的目的是研究 alpha1GABAA 和 alpha5GABAA 受体机制在酒精滥用相关影响的非人类灵长类动物模型中的作用。最近的研究结果支持 α1GABAA 和 α5GABAA 受体机制在酒精对猴子的辨别刺激作用及其对啮齿动物的增强作用中的作用。我们将在这些新发现的基础上，通过确定受体选择性激动剂和拮抗剂如何调节，系统地研究 alpha1GABAA（特定目标 1）和 alpha5GABAA（特定目标 2）受体机制对酒精行为影响的贡献：1）辨别刺激效应恒河猴中的酒精经过训练可以区分胃内施用的酒精和媒介物，2) 恒河猴口服自我施用酒精，以及3)恢复恒河猴的酒精寻求，其口服自我给药已被熄灭，随后通过酒精启动而恢复。 α1GABAA 和 α5GABAA 受体配体选择性改变酒精控制行为的作用程度（具体目标 3）将在自我施用蔗糖溶液而不是酒精的恒河猴中进行评估，并在这些配体的作用的同时观察研究中进行评估，单独或与酒精结合，对无条件运动行为进行影响。选定的 α1GABAA 和 α5GABAA 配体能够减弱酒精的歧视性刺激作用，减少酒精自我给药并减弱启动诱导的酒精恢复，寻求不产生普遍行为破坏或使人衰弱的副作用的剂量可能是预测潜在的治疗效用。这三个具体目标的结果整合将提供有关特定 GABAA 机制的必要信息，这些机制可能是酒精成瘾作用的基础，并将有助于识别受体靶标，用于酒精滥用和复发的药理学管理。