Trace amine receptor-mediated methamphetamine response in brain

 描述(由申请人提供)： 项目概述兰德公司最近的一项研究表明，滥用甲基苯丙胺(MA)每年给美国造成的损失超过200-600亿美元。大约有1000万美国人至少使用过MA一次。长期使用MA具有深远的健康后果和巨大的社会影响。在V.A.医疗中心，MA滥用与设施资源的使用增加和退伍军人的有害后果有关，例如额外的精神障碍。目前还没有被批准的治疗MA成瘾的药物，因此迫切需要发现MA的药物疗法。最近，示踪胺相关受体1(TAAR1)已被确定为MA及其类似物的靶标，但不是可卡因的靶标。因此，TAAR1可能是一个独特的MA靶标。TAAR1基因敲除(KO)小鼠表现出对MA反应的增强，我们已经证明，与它们的野生型(Wt)小鼠相比，它们优先摄入更多的MA。此外，KO小鼠和表达非功能性TAAR1的小鼠对MA(体温过低，条件性味觉厌恶)的厌恶作用不敏感。目前还没有针对TAAR1的商业上可用的选择性激动剂或拮抗剂。开发干扰MA介导的TAAR1效应的新药具有临床意义，因为(部分)激动剂可以作为可能限制MA摄入量的治疗方法。相反，TAAR1拮抗剂可以作为进一步研究TAAR1介导的生理学的重要药理学工具。该项目将使用一种翻译方法来表征表达人类TAAR1的多个非同义单核苷酸多态(SNP)的培养细胞。此外，我们将在小鼠中使用病毒介导的人类TAAR1基因多态转移来确定合成的新型药物的效果，这些药物既能影响人类的TAAR1功能，又能在药理上与MA竞争。这些实验的结果将确定TAAR1在MA介导的药理学和行为中的作用，并将表征我们实验室合成的潜在的新药物疗法，这些药物可用于治疗MA滥用和成瘾的特定症状。

 DESCRIPTION (provided by applicant): Project Summary A recent study by the Rand Corporation indicated that methamphetamine (MA) abuse costs the United States over $20-$60 billion/year. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and a tremendous societal impact. At V.A. Medical Centers MA abuse is associated with increased use of facility resources and deleterious consequences for veterans, such as additional psychiatric disorders. There are currently no approved medications for treatment of MA addiction, and consequently there is an urgent need to discover MA pharmacotherapies. Recently the trace amine-associated receptor 1 (TAAR1) has been identified as a target for MA and its analogues, but not for cocaine. Therefore, TAAR1 is possibly a unique MA target. TAAR1 knockout (KO) mice show increased activity in response to MA and we have shown that they preferentially consume more MA as compared to their wild-type (wt) littermates. Additionally, KO mice, and mice expressing a non-functional TAAR1 are insensitive to the aversive effects of MA (hypothermia, conditioned taste aversion). There are no commercially available selective agonists or antagonists for the TAAR1. Developing new drugs that interfere with MA-mediated effects at TAAR1 has clinical implications in that (partial) agonists could serve as treatments to possibly limit MA intake. Conversely, TAAR1 antagonists can serve as important pharmacological tools to further study of TAAR1-mediated physiology. This project will use a translational approach to characterize cultured cells that express multiple non- synonymous single nucleotide polymorphisms (SNP) of human TAAR1. In addition, we will use viral-mediated gene transfer of human TAAR1 polymorphisms in mice to determine the effects of synthesized novel agents designed to both affect human TAAR1 function and to compete pharmacologically with MA. Results from these experiments will identify the role of TAAR1 in MA-mediated pharmacology and behaviors and will characterize potential new pharmacotherapies, synthesized in our laboratories, which can be used to treat specific symptoms of MA abuse and addiction.