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Morgane Thomsen博士从受指导的研究员过渡到药物滥用研究的独立职业。Thomsen博士在高度专业化的行为技术方面拥有专业知识，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。本提案将发展和建立候选人对其他程序的掌握，特别是：在自我给药分析中操纵消光，以及药物区分。在2年的指导阶段，候选人计划将她的研究与导师的研究区分开来，并在原始的调查领域建立生产力记录。她还将在技术性较低的领域（例如，工作人员监督、赠款管理）获得经验和自力更生，为她的独立做好准备。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蕈碱系统及其在药物成瘾障碍中的潜在影响作为她的长期研究重点。预期的未来方向包括将本建议的研究结果扩展到多种药物滥用模型。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。总的来说，该机构，特别是导师s·巴拉克·凯恩（S. Barak Caine）和共同导师南希·梅洛（Nancy Mello），在药物滥用研究方面有着极其完善的记录，为致力于该领域的年轻研究人员的职业发展提供了理想的环境。Thomsen博士针对这一应用的研究项目建议评估作用于特定毒蕈碱受体的药物的潜力，以减少可卡因的滥用相关影响。在合作者P. Jeffery Conn教授和J bbbbgen Wess教授的帮助下，Thomsen博士将结合新型的高选择性药物和基因敲除技术来评估哪些毒毒碱受体亚型介导毒毒碱激动剂的抗可卡因作用，哪些介导不良影响。首先，一系列药物将在老鼠身上进行测试，训练它们区分可卡因和生理盐水。然后，将在小鼠和大鼠身上进行试验，这些小鼠和大鼠经过训练，可以长期自我服用可卡因，这些药物可以减弱可卡因的鉴别刺激，几乎没有副作用（减少行为率）。通过后一种试验，汤姆森博士将评估这些药物在急性和慢性治疗中选择性减少可卡因自我给药（不减少食物维持行为）的能力，以及促进与可卡因相关的行为消失的能力（在一种对灭绝表现出抵抗力的小鼠中）。该项目的最终目标是确定治疗可卡因成瘾的潜在目标。

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.