Role of TAAR1 in Methamphetamine Self-Administration

描述（由申请人提供）：这项针对PAR-09-222提交的CUTTING EDGE BASIC RESEARCH AWARD （CEBRA）申请的目标是确定G蛋白偶联微量胺相关受体1 （TAAR1）对静脉注射（i.v）甲基苯丙胺（METH）自我给药（SA）的贡献程度。在全国范围内，冰毒的消费量正在下降，但在美国和世界各地的特定人口统计中，仍有大量使用冰毒，尽管它的使用和滥用对个人、家庭、社会和法律产生了压倒性的负面影响。50多年来，精神兴奋剂研究一直试图确定介导甲基苯丙胺滥用潜力的生物基质。尽管澄清了冰毒作用的一些生物学机制（例如干扰单胺氧化酶活性以及多巴胺、去甲肾上腺素和囊状单胺转运蛋白的功能），但仍然没有广泛接受的药理学方法来医学上控制冰毒戒断综合征或防止再次滥用冰毒。这一领域缺乏进展表明，除了酶和转运体之外，导致甲基苯丙胺滥用的重要生物分子仍有待发现；这一观点得到了转基因老鼠研究的支持。最近，我们报道了重组TAAR1，一种gs偶联G蛋白偶联受体，在体外被纳摩尔浓度的甲基安非他明直接激活以刺激cAMP的产生。此外，由于没有商业上可用的TAAR1拮抗剂，我们最近设计并合成了一种新的物质组合物ET-92，它在体外作为TAAR1拮抗剂。这些发现表明，TAAR1可能是甲基苯丙胺在体内作用的一种新的介质，ET-92可能是开发一种干扰与甲基苯丙胺滥用相关行为的药物的先导。然而，确定TAAR1参与甲基苯丙胺滥用和ET-92作为抗甲基苯丙胺先导化合物的潜力的关键步骤是在已建立的药物服用行为动物模型中对它们进行评估。我们认为我们的建议是适合于CEBRA机制的，因为要测试的假设是非常规的：i.v.甲基SA是由TAAR1介导的。为了验证我们的假设，我们提出了两个具体目标：(1)确定TAAR1在成年野生型和TAAR1缺陷小鼠中介导iv甲基安非他明SA的程度；(2)确定新型TAAR1拮抗剂ET-92是否干扰成年野生型小鼠中iv甲基安非他明SA的获得、维持、消失和/或恢复。我们预计这些目标的成功完成将通过以下方式对精神兴奋剂研究领域产生重大影响：(1)建立一个长期以来逃避该领域的甲基苯丙胺作用的新机制；(2)激发人们对新型taar1选择性化合物的兴趣，作为开发预防人类甲基苯丙胺滥用复发的药物的潜在线索。

DESCRIPTION (provided by applicant): The goal of this CUTTING EDGE BASIC RESEARCH AWARD (CEBRA) application, submitted in response to PAR-09-222, is to determine the extent to which the G protein-coupled trace amine-associated receptor 1 (TAAR1) contributes to intravenous (i.v.) methamphetamine (METH) self-administration (SA). METH consumption is declining nation-wide yet significant use persists in specific demographics of the United States and around the world in spite of the overwhelmingly negative personal, familial, societal, and legal consequences associated with its use and abuse. For more than 50 years psychostimulant research has attempted to identify the biological substrates mediating METH's abuse potential. In spite of clarifying some of the biological mechanisms underlying METH's actions (e.g. interference with monoamine oxidase activity as well as dopamine, norepinephrine and vesicular monoamine transporter functions) there is still no widely accepted pharmacologic approach to medically managing the METH abstinence syndrome or preventing relapse to METH abuse. The lack of progress in this area suggests important biological molecules that contribute to METH's abuse liability other than enzymes and transporters remain to be discovered; a view supported by research involving genetically engineered mice. Recently we reported recombinant TAAR1, a G1s-coupled G protein-coupled receptor, is directly activated in vitro by nanomolar concentrations of METH to stimulate cAMP production. Furthermore, as no TAAR1 antagonist is commercially available we recently designed and synthesized a novel composition of matter, ET-92, that acts as a TAAR1-antagonist in vitro. These findings suggest to us TAAR1 might be a novel mediator of METH's actions in vivo and ET-92 could be a lead in developing a medication that interferes with behaviors relevant to METH abuse. However, an essential step in establishing the involvement of TAAR1 in METH abuse and the potential of ET-92 as an anti- METH lead compound is to evaluate them both in established animal models of drug taking behavior. We think our proposal is appropriate for the CEBRA mechanism because the hypothesis to be tested is unconventional: i.v. METH SA is mediated by TAAR1. To test our hypothesis we propose 2 specific aims: (1) Determine the extent to which TAAR1 mediates i.v. METH SA in adult wild type and TAAR1-deficient mice of both sexes and (2) Determine whether the novel TAAR1 antagonist ET-92 interferes with the acquisition, maintenance, extinction and/or reinstatement of i.v. METH SA in adult wild type mice of both sexes. We anticipate the successful completion of these aims will significantly influence the field of psychostimulant research by: (1) establishing a novel mechanism of METH's action that has long eluded the field and (2) by sparking interest in novel TAAR1-selective compounds as potential leads in the development of medications for preventing relapse to METH abuse in humans. PUBLIC HEALTH RELEVANCE: The abuse of methamphetamine (METH) has reached near epidemic proportions in many communities in the United States and its use continues to grow worldwide with devastating consequences for users, their families and society. Although behavioral modification strategies can prolong abstinence in some they do not prevent relapse to abuse in most individuals. At the present time no pharmacological treatment is available to prevent relapse to METH abuse. It is expected that the successful completion of the proposed research aims will result in a better understanding of the role the G protein-coupled trace amine-associated receptor 1 (TAAR1) plays in relapse to METH self- administration and in the process establish whether TAAR1 as an important new target for anti-METH medication development.