METHAMPHETAMINE EFFECTS VIA TRACE AMINE ASSOCIATED RECEPTOR 1

甲基苯丙胺通过微量胺相关受体 1 发挥作用

• 批准号: 8357968
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357968
• 关键词: Amines; Brain; Cell Nucleus; Corpus striatum structure; Disease; Dopamine; Funding; Grant; In Vitro; Methamphetamine; Methamphetamine dependence; National Center for Research Resources; Neurophysiology - biologic function; Neurotransmitters; New England; Norepinephrine; Pharmaceutical Preparations; Play; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Role; Serotonin; Signal Transduction; Source; Synapses; Synaptic Cleft; United States National Institutes of Health; base; cost; dopamine transporter; monoamine; neurotransmitter release; novel therapeutics; psychostimulant; receptor; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the brain, monoamine transporters for dopamine, norepinephrine and serotonin play key roles in clearance of the cognate neurotransmitters released into the synaptic space which is essential for appropriate neural function of monoaminergic activity. Methamphetamine, a widely abused and highly addictive psychostimulant drug, interferes with these transporters to elevate the levels of neurotransmitters in the synaptic clefts, which results in immediate and long-term changes associated with psychostimulant effects and addiction of methamphetamine. Trace amine-associated receptor 1 (TAAR1) is widely expressed in brain monoaminergic nuclei, and recent studies have established that this receptor serves as a monoaminergic modulator in the brain. Methamphetamine can activate TAAR1 in vitro and its interaction with TAAR1 decreases dopamine uptake, induces dopamine efflux, and triggers dopamine transporter internalization in brain striatum. This indicates a correlation between TAAR1 signaling and methamphetamine action on the dopamine transporter. Methamphetamine is a transporter substrate thought to function through direct interaction with monoamine transporters. Our studies are uncovering new mechanisms that underlie the role of TAAR1 in methamphetamine influence on monoamine transporters, which may advance the understanding of methamphetamine addiction and promote new therapeutics for such disorder.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在脑中，多巴胺、去甲肾上腺素和5-羟色胺的单胺转运蛋白在清除释放到突触空间中的同源神经递质中起关键作用，这对于单胺能活性的适当神经功能是必不可少的。甲基苯丙胺是一种广泛滥用且高度成瘾的精神兴奋剂药物，它干扰这些转运体以提高突触裂隙中神经递质的水平，这导致与甲基苯丙胺的精神兴奋剂效应和成瘾相关的即时和长期变化。痕量胺相关受体1（TAAR 1）广泛表达于脑单胺能核团中，并且最近的研究已经确定该受体在脑中充当单胺能调节剂。甲基苯丙胺可以在体外激活TAAR 1，其与TAAR 1的相互作用降低多巴胺摄取，诱导多巴胺流出，并触发脑纹状体多巴胺转运蛋白内化。这表明TAAR 1信号传导和甲基苯丙胺对多巴胺转运蛋白的作用之间存在相关性。甲基苯丙胺是一种转运蛋白底物，被认为通过与单胺转运蛋白直接相互作用发挥作用。我们的研究揭示了TAAR 1在甲基苯丙胺影响单胺转运体中的作用的新机制，这可能会促进对甲基苯丙胺成瘾的理解，并促进这种疾病的新疗法。