Selective Muscarinic Receptor Ligands as Targets for Cocaine Addiction Medication

项目摘要/摘要 这份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到独立的药物滥用职业生涯的转变 研究。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 小鼠和大鼠慢性静脉给药，专门评估可卡因自身 突变小鼠的给药。目前的提案将发展和确立候选人的 掌握其他程序，特别是：在自我管理中操纵灭绝 化验和药物歧视。在为期两年的指导阶段，应聘者计划区分 她的研究来自她导师的研究，并建立了一个原始系列的生产力记录 调查。她还将获得较少技术领域的经验和自力更生(例如，工作人员 监督、资助金管理)，为她的独立做好准备。候选人计划使 毒扁豆碱系统及其对药物成瘾障碍的潜在影响她的长期重点是 行为药理学和遗传学方面的学术研究人员。预期的未来方向 包括将本提案的调查结果推广到多种药物滥用的模式。该项目将是 在哈佛医学院麦克莱恩医院酒精和药物滥用研究中心进行 学校。该机构以及导师S·巴拉克·凯恩和共同导师南希·梅洛 具体地说，在药物滥用研究方面拥有非常成熟的记录，提供了理想的 为培养致力于这一领域的年轻研究人员的职业生涯创造了环境。汤姆森博士的 这一应用的研究项目建议评估在特定情况下作用的药物的潜力 M受体，以减少可卡因滥用相关的影响。在合作者的帮助下 P·杰弗里·康恩教授和约根·韦斯教授，汤姆森博士将结合新的、高度选择性的药物 用基因敲除技术评价M受体亚型介导的抗可卡因作用 毒扁豆碱类激动剂的作用，并调节不良作用。首先，一系列的药物将 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。弱化歧视的药物 刺激可卡因的不良影响很小或没有不良影响(降低行为率)，然后将在 小鼠和大鼠接受长期自我注射可卡因的训练。对于后一种分析，汤姆森博士将 评估药物选择性减少可卡因自身给药的能力(不减少 食物维持的行为)作为急性和慢性治疗，并促进一种行为的消除 与可卡因有关(在一种对灭绝表现出抵抗力的小鼠身上)。的最终目标是 该项目旨在确定治疗可卡因成瘾的潜在目标。

PROJECT SUMMARY/ABSTRACT 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.