THE TRACE AMINE PHENYLETHYLAMINE: ADHD AND COCAINE ABUSE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。微量胺苯乙胺（PEA）与药物滥用、多动症、抑郁症、精神分裂症等有关，但其生理和药理作用尚不清楚。外源性PEA通过多巴胺（DA）转运蛋白（DAT）调节多巴胺释放，但PEA转运的直接证据尚未报道。我们研究了PEA通过人DAT和去甲肾上腺素转运体（NET）的转运，以及精神兴奋剂药物和药物是否影响PEA的转运。结果：（3H）PEA对DAT和NET的亲和力相似((3H)PEA: Km: 724 nM；（3H）DA: 797 nM)，但（3H）PEA输运能力较低。（3H）PEA亲和力（695 nM）低于（3H）NE亲和力（478 nM）。在ADHD药物中，哌醋甲酯阻断（3H）PEA的DAT转运比（3H）DA更有效，而(d)-安非他明的作用较弱。精神兴奋剂阻断（3H）PEA和（3H）DA的转运，但可卡因同源物阻断（3H）PEA转运的效力是（3H）DA转运的3-6倍。这些不同的亲和力可能反映了不同的转运体底物结合域或DAT的构象变化。讨论：PEA水平可能受到ADHD药物和滥用精神兴奋剂药物的调节。作为一种运输底物和微量胺受体的激动剂，PEA可能与神经病理学、滥用精神兴奋剂药物的药理作用以及靶向单胺转运体的药物的治疗效果有关。

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. The trace amine phenylethylamine (PEA) is implicated in substance abuse, ADHD, depression, schizophrenia and others, but its physiological and pharmacological roles are poorly understood. Exogenous PEA regulates dopamine release via the dopamine (DA) transporter (DAT), but direct evidence for PEA transport has not been reported. We investigated PEA transport by the human DAT and norepinephrine transporter (NET) and whether psychostimulant drugs and medications affect PEA transport. Results: (3H)PEA affinities for the DAT and NET were similar ((3H)PEA: Km: 724 nM; (3H)DA: 797 nM), but (3H)PEA transport capacity was lower. (3H)PEA affinity (695 nM) was lower than (3H)NE affinity (478 nM) at the NET. Of ADHD medications, methylphenidate was more potent in blocking DAT transport of (3H)PEA than (3H)DA, whereas (d)-amphetamine was less potent. Psychostimulant drugs blocked (3H)PEA and (3H)DA transport but cocaine congeners were 3-6 times more potent in blocking (3H)PEA than (3H)DA transport. These contrasting affinities may reflect different binding domains of transporter substrates or conformational changes of the DAT. Discussion: PEA levels conceivably are modulated by ADHD medications and psychostimulant drugs of abuse. As a transport substrate and an agonist at the trace amine receptor1, PEA may contribute to neuropathology, to pharmacological effects of psychostimulant drugs of abuse and to the therapeutic efficacy of medications that target monoamine transporters.