Role of TAAR1 in Methamphetamine Self-Administration

描述（由申请人提供）：本前沿基础研究奖（CEBRA）申请的目的是响应PAR-09-222提交，旨在确定G蛋白偶联痕量胺相关受体1（TAAR 1）在多大程度上有助于静脉内（i. v.）甲基苯丙胺（METH）自我给药（SA）。全国范围内的甲基苯丙胺消费量正在下降，但在美国和世界各地的特定人口统计中，尽管与其使用和滥用相关的负面个人、家庭、社会和法律的后果非常严重，但甲基苯丙胺的使用仍然存在。50多年来，精神兴奋剂研究一直试图确定介导METH滥用潜力的生物基质。尽管阐明了METH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、去甲肾上腺素和囊泡单胺转运蛋白功能），但仍然没有广泛接受的药理学方法来医学管理METH戒断综合征或预防METH滥用复发。这一领域缺乏进展表明，除了酶和转运蛋白之外，导致METH滥用倾向的重要生物分子仍有待发现;这一观点得到了涉及基因工程小鼠的研究的支持。最近，我们报道了重组TAAR 1，G1 s-偶联G蛋白偶联受体，在体外直接激活纳摩尔浓度的甲基刺激cAMP的生产。此外，由于没有TAAR 1拮抗剂是可商购的，我们最近设计并合成了一种新的物质组合物，ET-92，其在体外充当TAAR 1拮抗剂。这些研究结果表明，TAAR 1可能是METH体内作用的新介质，ET-92可能是开发干扰与METH滥用相关行为的药物的先导。然而，确定TAAR 1参与METH滥用和ET-92作为抗METH先导化合物的潜力的必要步骤是在已建立的药物服用行为动物模型中评估它们两者。我们认为我们的建议是适当的CEBRA机制，因为要测试的假设是非常规的：i. v. METH SA是由TAAR 1介导的。为了验证我们的假设，我们提出了2个具体目标：（1）确定TAAR 1在成年野生型和TAAR 1缺陷型两种性别小鼠中介导静脉注射METH SA的程度，以及（2）确定新型TAAR 1拮抗剂ET-92是否干扰成年野生型两种性别小鼠中静脉注射METH SA的获得、维持、消退和/或恢复。我们预计这些目标的成功完成将通过以下方式显著影响精神兴奋剂研究领域：（1）建立长期回避该领域的METH作用的新机制，以及（2）引发对新型TAAR 1选择性化合物的兴趣，作为开发药物预防人类METH滥用复发的潜在线索。 公共卫生相关性：甲基安非他明（METH）的滥用在美国的许多社区已达到接近流行病的程度，其使用在全世界继续增长，给使用者、其家庭和社会造成了破坏性后果。虽然行为矫正策略可以延长一些人的戒断时间，但在大多数人中，它们并不能防止滥用的复发。目前，尚无药物治疗可用于预防甲基苯丙胺滥用复发。预期所提出的研究目标的成功完成将导致更好地理解G蛋白偶联痕量胺相关受体1（TAAR 1）在METH自我给药复发中所起的作用，并在此过程中确定TAAR 1是否是抗METH药物开发的重要新靶点。

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.