Treatment Development for Methamphetamine Abuse

描述(由申请人提供)：这是一份修订后的新调查员发起的R01申请，旨在了解甲基苯丙胺成瘾的神经生物学机制，以及旨在遏制药物滥用的药物治疗的效果。具体地说，烟碱型乙酰胆碱受体(NAChRs)在甲基苯丙胺滥用相关效应中的作用尚不清楚。例如，临床前和临床研究中的间接nAChR激动剂或拮抗剂报告了甲基苯丙胺滥用相关影响的减少。这项申请建议解决科学进步的这一关键障碍，即nAChR在甲基苯丙胺滥用相关影响中的作用。我们的工作假设是，甲基苯丙胺的滥用相关效应是通过多巴胺(DA)和乙酰胆碱(ACh)的联合释放来调节的。因此，我们利用恒河猴的受试者内设计，提出了以下具体目标。目的研究DA和nAChR激动剂和拮抗剂对甲基苯丙胺的区别性刺激效应的影响。目的#2确定间接DA激动剂或DA拮抗剂nAChR拮抗剂维持对甲基苯丙胺增强效应的影响。 公共卫生相关性：甲基苯丙胺滥用是一个主要的公共卫生问题，没有食品和药物管理局批准的药物疗法或有效的治疗策略。用非处方感冒药(伪麻黄碱)秘密制造甲基苯丙胺也构成公共健康风险，因为其成分高度易燃和易爆。这项申请建议进行临床前研究，以确定甲基苯丙胺滥用的药理学机制，以开发药物疗法。我们的公共卫生目标是促进在治疗甲基苯丙胺滥用方面将临床前结果转化为积极的临床结果。

DESCRIPTION (provided by applicant): This is a revised New Investigator-initiated R01 application designed to understand the neurobiological mechanisms underlying methamphetamine addiction, as well as the effects of pharmacological treatments aimed at curbing substance abuse. Specifically, the role of nicotinic acetylcholine receptors (nAChRs) in the abuse-related effects of methamphetamine is poorly understood. For example, indirect nAChR agonists, or antagonists in preclinical and clinical studies have reported decreases in the abuse-related effects of methamphetamine. This application proposes to address this critical barrier to scientific progress regarding the role of nAChR in the abuse-related effects of methamphetamine. Our working hypothesis is that the abuse-related effects of methamphetamine are mediated through combined dopamine (DA) and acetylcholine (ACh) release. Accordingly, we propose the following Specific Aims using a within-subjects design in rhesus monkeys. Aim#1 will determine the effects of DA and nAChR agonists and antagonists on the discriminative stimulus effects of methamphetamine. Aim#2 will determine the effects of maintenance on an indirect DA agonist or DA antagonist ¿ nAChR antagonist on the reinforcing effects of methamphetamine. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse is a major public health problem with no Food and Drug Administration-approved pharmacotherapies or effective treatment strategies. The clandestine manufacture of methamphetamine from over-the-counter cold remedies (pseudoephedrine) also poses a public health risk because the ingredients are highly flammable and explosive. This application proposes preclinical studies to determine the pharmacological mechanisms of methamphetamine abuse towards the development of pharmacotherapies. Our public health goal is to promote the translation of preclinical results to positive clinical outcomes in treating methamphetamine abuse.