Selective Muscarinic Receptor Ligands as Targets for Cocaine Addiction Medication

项目总结/摘要 本申请描述了一个职业发展计划和研究项目，旨在促进 Morgane Rehsen博士从接受指导的研究员过渡到药物滥用方面的独立职业 research. Dr. Rebecsen在高度专业化的行为技术方面获得了专业知识， 小鼠和大鼠的慢性静脉内药物自我给药，专门评估可卡因自我给药， 在突变小鼠中施用。目前的建议将发展和建立候选人的 掌握额外的程序，特别是：自我管理中的灭绝操作 分析和药物鉴别。在为期2年的指导阶段，候选人计划区分 她从导师那里获得了研究成果，并在原创系列中建立了生产力记录 调查她还将在技术性较低的领域（例如，工作人员 监督，赠款管理），以准备她的独立。候选人计划使 毒蕈碱系统及其在药物成瘾障碍中的潜在意义， 行为药理学和遗传学的学术研究员。预期的未来方向 包括将本建议的调查结果扩大到多种药物滥用的模式。该项目将 在哈佛医学院姆克林医院酒精和药物滥用研究中心进行 学校一般来说，机构和导师S。巴拉克·凯恩和共同导师南希·梅洛 特别是，在药物滥用研究方面有着非常完善的记录，提供了一个理想的 为培养致力于这一领域的年轻研究人员的职业生涯创造环境。Dr. Rebecsen's 该应用的研究项目建议评估药物在特定条件下发挥作用的潜力。 毒蕈碱受体，以减少可卡因滥用相关的影响。在合作者的帮助下 P. Jeffery Conn教授和J？rgen Wess博士将联合收割机新型的高选择性药物 用基因敲除技术来评估哪些毒蕈碱受体亚型介导抗可卡因 毒蕈碱激动剂的作用，并介导不希望的作用。首先，一系列药物将 在经过训练的老鼠身上进行测试，以区分可卡因和盐水。减少歧视的药物 然后，将测试具有很少或没有副作用（行为率降低）的可卡因刺激， 老鼠和老鼠训练自己长期服用可卡因。通过这些后一种测定，Dr. 评价药物选择性减少可卡因自我给药的能力（而不减少 食物维持行为）作为急性和慢性治疗，并促进行为的消失 与可卡因有关（在一种对灭绝有抵抗力的小鼠中）。的最终目标 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.