GABA A/alpha5 Ligands in Primate Models of Alcohol Abuse

灵长类动物酒精滥用模型中的 GABA A/alpha5 配体

• 批准号: 6711035
• 负责人: ROGER D SPEALMAN
• 金额: $ 15.3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711035
• 关键词: GABA receptor; Macaca mulatta; alcoholic beverage consumption; alcoholism /alcohol abuse; craving; disease /disorder model; drug addiction; ethanol; gamma aminobutyrate; ligands; relapse /recurrence

DESCRIPTION (provided by applicant): Alcoholism is a worldwide public health problem that is associated with debilitating medical, social, and psychological consequences. Alcoholism is characterized by persistent alcohol self-administration that is refractory to conventional interventions and by high vulnerability to relapse even after successful detoxification and abstinence. No broadly effective medications have been identified to combat alcohol abuse or relapse. Thus, the development of pharmacotherapies that reduce alcohol consumption and/or eliminate craving for alcohol remains a formidable challenge for the treatment of alcohol addiction. The purpose of this R21 proposal (RFA-AA-02-004) is to explore the role of GABAA/alpha5 receptor mechanisms in the behavioral effects of alcohol in nonhuman primates and to evaluate promising GABAA/alpha5 ligands as novel pharmacotherapies to treat alcohol addiction. Recent findings support a role for GABAA/alpha5 receptor mechanisms in alcohol's discriminative stimulus effects in monkeys and its reinforcing effects in rodents. In the proposed studies, the capacity of GABAA/alpha5 ligands to reduce oral self-administration of alcohol in rhesus monkeys will be investigated. In order to gauge the pharmacological specificity of these effects, GABAA/alpha5 ligands will also be evaluated in monkeys that self-administer sucrose solution instead of alcohol. In addition, concurrent observational studies will assess the degree to which GABAA/alpha5 ligands engender sedative and/or motoric side effects. Finally, in monkeys whose drug-seeking behavior has been extinguished and subsequently reinstated by alcohol priming, GABAA/alpha5 ligands will be evaluated for their ability to inhibit relapse to alcohol-seeking behavior. The ability of selected GABAA/alpha5 ligands to reduce oral alcohol self-administration and 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. The proposed studies will provide fundamental information regarding the viability of GABAA/alpha5 receptors as pharmacological targets for novel medications to reduce alcohol abuse and relapse.

描述（由申请人提供）： 酒精中毒是一个全球公共卫生问题，与医学，社会和心理后果衰弱有关。酒精中毒的特征是持续的酒精自我给药，即使在成功的排毒和戒酒后，对常规干预措施的难治性以及高脆弱性。尚未确定有效的药物来打击酒精滥用或复发。因此，减少饮酒和/或消除饮酒的药物治疗的发展仍然是治疗酒精成瘾的巨大挑战。该R21提案（RFA-AA-02-004）的目的是探讨GABAA/alpha5受体机制在非人类灵长类动物中酒精饮酒的行为影响中的作用，并评估有希望的GABAA/Alpha5配体作为治疗酒精饮酒成瘾的新型药物治疗的新型GABAA/Alpha5配体。最近的发现支持GABAA/Alpha5受体机制在猴子中酒精的歧视性刺激效应中的作用及其在啮齿动物中的增强作用。在拟议的研究中，将研究GABAA/Alpha5配体减少恒河猴中酒精的口服自我给药的能力。为了衡量这些作用的药理特异性，还将在自助式蔗糖溶液而不是酒精的猴子中评估GABAA/alpha5配体。此外，同时的观察性研究将评估GABAA/alpha5配体产生镇静剂和/或摩托副作用的程度。最后，在猴子的猴子行为被灭绝并随后被酒精启动恢复的猴子中，将评估GABAA/Alpha5配体的抑制能力，以抑制寻求酒精的行为的复发。选定的GABAA/Alpha5配体减少口服酒精自我给药的能力和启动引起的恢复剂量的剂量，而剂量不产生一般性破坏行为或衰弱的副作用可能可以预测潜在的治疗效用。拟议的研究将提供有关GABAA/Alpha5受体的生存能力的基本信息，作为减少酒精滥用和复发的新型药物的药理靶标。