PHENETHYLAMINE (PEA), THE DOPAMINE TRANSPORTER AND COCAINE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：单胺转运体调节神经递质水平，将其从神经元释放或隔离到神经元中。可卡因和其他精神刺激剂抑制多巴胺(DAT)和去甲肾上腺素(NET)转运体，其相对效力与它们产生兴奋效应和滥用倾向的效力相关。微量氨基苯乙胺(PEA)与成瘾有关，但PEA、单胺转运体和药物之间的关系尚不清楚。我们推测PEA是DAT和Net的底物，药物能有效地抑制[~3H]PEA的转运，DAT抑制剂阻断(~3H)PEA的转运可能与类可卡因药物的兴奋和增强特性有关。方法：测定(3 H)PEA的转运动力学，比较药物对人DAT-HEK-2 93细胞的(3 H)PEA和(3 H)多巴胺转运的影响，并比较体外相对药物效价和已报道的产生灵长类动物行为效应的药物效价。结果：(3 H)PEA转运活跃，DAT和Net亲和力类似于(3 H)多巴胺或去甲肾上腺素亲和力。(-)-可卡因和其他药物剂量依赖性地抑制DAT对PEA的转运，其作用强于那些阻断(~3H)多巴胺转运的药物。在灵长类动物中，阻断(~3H)PEA转运的药物的相对效力与其产生精神运动刺激和维持自我给药的相对效力高度相关。结论：DAT和Net抑制PEA转运的药物可能提高了脑细胞外PEA的水平。这些结果表明，PEA和微量胺受体1的激活是DAT抑制剂的精神刺激和增强效应的贡献者。

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. AIMS: Monoamine transporters regulate neurotransmitter levels, which release or sequester them from and into neurons. Cocaine and other psychostimulants inhibit the dopamine (DAT) and norepinephrine (NET) transporters, with relative potencies that correlate with their potencies for producing stimulant effects and abuse liability. The trace amine phenylethylamine (PEA) is implicated in addiction, but the relationship between PEA, monoamine transporters and drugs is unknown. We postulated that PEA is a substrate for the DAT and NET, that drugs would potently inhibit [3H]PEA transport and that blockade of (3H)PEA transport by DAT inhibitors would be relevant to the stimulant and reinforcing properties of cocaine-like drugs. METHODS: We measured (3H)PEA transport kinetics, compared drug effects on (3H)PEA and (3H)dopamine transport in human DAT-HEK-293 cells, and compared relative drug potencies in vitro with reported drug potencies for producing behavioral effects in primates. RESULTS: (3H)PEA was actively transported, with DAT and NET affinities similar to (3H)dopamine or (3H)norepinephrine affinities. (-)-Cocaine and other drugs dose-dependently inhibited PEA transport by the DAT, at greater potencies than those that block (3H)dopamine transport. The relative potencies of drugs for blocking (3H)PEA transport correlated highly with their reported relative potencies for producing psychomotor stimulation and maintaining self-administration in primates. CONCLUSIONS: Drug inhibition of PEA transport by the DAT and NET conceivably elevates extracellular PEA levels in brain. These results implicate PEA and the trace amine receptor1 activation as contributors to the psychostimulant and reinforcing effects of DAT inhibitors.