Selective Muscarinic Receptor Ligands as Targets for Cocaine Addiction Medication

描述(由申请人提供)：本申请描述了一个职业发展计划和研究项目，旨在促进摩根·汤姆森博士从指导研究员过渡到药物滥用研究领域的独立职业生涯。汤姆森博士在高度专业化的行为技术方面获得了专业知识，例如小鼠和大鼠的慢性静脉注射药物自我给药，专门评估突变小鼠的可卡因自我给药。目前的提案将发展和确立候选人对其他程序的掌握，特别是：自我给药分析中的灭绝操纵和药物歧视。在为期两年的指导阶段，候选人计划将她的研究与她的导师的研究区分开来，并在最初的研究领域建立生产力记录。她还将在技术含量较低的领域(如工作人员监督、赠款管理)获得经验和自力更生，为独立做好准备。作为一名行为药理学和遗传学的学术研究人员，这位候选人计划将毒碱系统及其在药物成瘾障碍中的潜在影响作为她的长期重点。预期的未来方向包括将本提案的调查结果扩展到多种药物滥用的模型。该项目将在哈佛医学院麦克莱恩医院的酒精和药物滥用研究中心进行。该机构总体上，特别是导师S.Barak Caine和共同导师Nancy Mello，在药物滥用研究方面有着非常良好的记录，为培养致力于该领域的年轻研究人员的职业生涯提供了理想的环境。汤姆森博士的这一应用研究项目建议评估作用于特定M受体的药物在减少可卡因滥用相关影响方面的潜力。在合作者P.Jeffery Conn教授和J|rgen Wess教授的帮助下，Thomsen博士将把新型、高度选择性的药物与基因敲除技术相结合，以评估哪些M受体亚型介导M受体激动剂的抗可卡因作用，以及哪些介导不良效果。首先，一系列药物将在经过训练以区分可卡因和生理盐水的小鼠身上进行测试。然后，将在接受长期自我注射可卡因的训练的小鼠和大鼠身上进行测试，这些药物可以减弱可卡因的歧视性刺激，但副作用很小或没有不良影响(行为发生率降低)。汤姆森博士将评估这些药物作为急性和慢性治疗药物选择性地减少可卡因自身给药(而不减少食物维持的行为)的能力，以及(在表现出对灭绝的抵抗力的品系中)促进与可卡因相关的行为消失的能力。该项目的最终目标是确定治疗可卡因成瘾的潜在目标。 与公共卫生相关：这位年轻研究人员的五年计划和终身职业目标的重点是开发针对脑乙酰胆碱受体的新药。这主要是为了治疗可卡因和苯丙胺成瘾，目前还没有有效的药物治疗，其次是改进现有的基于多巴胺的药物，这些药物对帕金森氏症、注意力缺陷多动障碍和精神分裂症等疾病的副作用要少得多。最后，由于已知乙酰胆碱可以调节记忆和认知，这项工作的任何突破都极有可能改善阿尔茨海默病和其他认知缺陷患者的生活。

DESCRIPTION (provided by applicant): This application describes a career development plan and research project designed to promote the transition of Dr. Morgane Thomsen from mentored fellow to an independent career in drug abuse research. Dr. Thomsen has acquired expertise in highly specialized behavioral techniques such as chronic intravenous drug self-administration in mice and rats, specializing in evaluating cocaine self- administration in mutant mice. The present proposal will develop and establish the candidate's mastery of additional procedures, specifically: manipulations of extinction in self-administration assays, and drug discrimination. During the 2-year mentored phase, the candidate plans to distinguish her research from her mentor's and establish a record of productivity in an original line of investigation. She will also gain experience and self-reliance in less technical areas (e.g., staff supervision, grants management) to prepare her for independence. The candidate plans to make muscarinic systems and their potential implications in drug addiction disorders her long-term focus as an academic researcher in behavioral pharmacology and genetics. Anticipated future directions include extending findings of the present proposal to models of polydrug abuse. The project will be conducted at the Alcohol and Drug Abuse Research Center at the McLean Hospital, Harvard Medical School. The institution generally, and the mentor S. Barak Caine and co-mentor Nancy Mello specifically, have extremely well-established records in drug abuse research, providing an ideal environment for fostering the careers of young researchers dedicated to this field. Dr. Thomsen's research project for this application proposes to evaluate the potential of drugs acting at specific muscarinic receptors to reduce abuse-related effects of cocaine. With the help of collaborators Professors P. Jeffery Conn and J|rgen Wess, Dr. Thomsen will combine novel, highly selective drugs with gene knockout technology to evaluate which muscarinic receptor subtypes mediate anti-cocaine effects of muscarinic agonists, and which mediate undesirable effects. First, a wide array of drugs will be tested in mice trained to discriminate cocaine from saline. Drugs that attenuate the discriminative stimulus of cocaine with little or no adverse effect (reduction in rates of behavior) will then be tested in mice and rats trained to self-administer cocaine chronically. With these latter assays, Dr. Thomsen will evaluate the ability of the drugs to selectively reduce cocaine self-administration (without decreasing food-maintained behavior) as acute and chronic treatment, and to facilitate extinction of a behavior associated with cocaine (in a strain of mice that show resistance to extinction). The ultimate goal of the project is to identify potential targets for treatment of cocaine addiction. PUBLIC HEALTH RELEVANCE: The focus of the five-year research plan as well as the lifelong career-objective of the young investigator is to develop new medications that target brain acetylcholine receptors. This is aimed principally at treating cocaine and amphetamine addictions, for which no effective medications currently exist, and secondly to improve upon existing dopamine-based medications with far fewer side-effects for disorders including Parkinson's Disease, Attention Deficit Hyperactivity Disorder, and Schizophrenia. Finally, because acetylcholine is known to modulate memory and cognition, it is highly likely that any breakthrough from this work would improve the lives of patients suffering from Alzheimer's Disease and other cognitive deficits.