METHAMPHETAMINE EFFECTS VIA TRACE AMINE ASSOCIATED RECEPTOR 1

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 痕量胺相关受体1（TAAR 1）是一种GS-偶联受体， 甲基苯丙胺的目标在小鼠和灵长类动物脑中，它共定位于黑质多巴胺神经元的子集中。DAT极大地增强了TAAR 1的甲基苯丙胺激活，并且TAAR 1激活导致DAT功能改变，这是cAMP升高和磷酸化的结果。因此，TAAR 1可能在多巴胺神经元功能中起重要作用，并且可能对甲基苯丙胺对脑多巴胺系统的作用特别重要。这项资助的重点是确定TAAR 1对甲基苯丙胺生物学效应的贡献，以及该受体是否是开发甲基苯丙胺成瘾新疗法的合理靶点。拟议的研究利用新型TAAR 1受体敲除小鼠。没有关于该小鼠系的公开信息;它尚未进行表型分析，但具有活力并被证实为转基因。我们将利用这些小鼠在体外和离体的行为、细胞和基因表达水平上探索TAAR 1在甲基苯丙胺神经生物学中的作用，以：1）确定TAAR 1敲除小鼠与它们的杂合和野生型同窝仔相比是否改变了对甲基苯丙胺的行为反应; 2）确定TAAR 1作为甲基苯丙胺对多巴胺转运体作用的介体的作用;和3）通过比较TAAR 1敲除小鼠与杂合和野生型同窝出生小鼠中甲基苯丙胺诱导的c-FOS表达模式，并检查受甲基苯丙胺影响的已知和候选基因的基因表达水平的变化，探索TAAR 1是否影响甲基苯丙胺诱导的体内基因表达变化。我们提供了大量的初步数据来支持这一假设 甲基苯丙胺的作用是介导的，部分地，通过TAAR 1和甲基苯丙胺的反应在TAAR 1是功能相互作用与DAT。因此，我们将探讨TAAR 1在甲基苯丙胺神经生物学中的作用，使用一个新开发的转基因TAAR 1基因敲除小鼠。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Trace Amine-Associated Receptor 1 (TAAR1) is a Gs-coupled receptor that is a direct target of methamphetamine. It is co-localized in a subset of Substantia nigra dopamine neurons in both mouse and primate brain. Methamphetamine activation of TAAR1 is greatly enhanced by DAT, and TAAR1 activation results in altered DAT function as a consequence of cAMP elevation and phosphorylation. Accordingly, TAAR1 may play an important role in dopamine neuron function, and may be of particular importance to methamphetamine effects on the brain dopamine system. The focus of this grant is to determine the contribution of TAAR1 to the biological effects of methamphetamine, and whether the receptor is a plausible target for the development of novel therapeutics for methamphetamine addiction. The proposed studies utilize novel TAAR1 receptor knockout mice. There is no public information available on this mouse line; it has not been phenotyped, but is viable and confirmed to be transgenic. We will explore the role of TAAR1 in methamphetamine neurobiology at behavioral, cellular and gene expression levels in vitro and ex vivo using these mice to: 1) determine whether TAAR1 knockout mice have altered behavioral responses to methamphetamine, compared to their heterozygous and wild-type littermates; 2) define a role for TAAR1 as a mediator of methamphetamine action on the dopamine transporter; and 3) explore whether TAAR1 influences methamphetamine-induced changes in gene expression in vivo, by comparing the pattern of methamphetamine-induced c-FOS expression in TAAR1 knockout mice vs. heterozygous and wild-type littermates and examining changes in the level of gene expression of both known and candidate genes that are affected by methamphetamine. We provide extensive preliminary data to support the hypothesis that methamphetamine action is mediated, in part, via TAAR1 and that methamphetamine response at TAAR1 is functionally interactive with DAT. Accordingly, we will explore the role of TAAR1 in methamphetamine neurobiology using a newly developed transgenic TAAR1 knockout mouse.