MDMA (ECSTASY) AND HUMAN MONOAMINE TRANSPORTERS: NEUROTOXICITY AND TREATMENT

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。3,4-亚甲基二氧基甲基苯丙胺（MDMA，“摇头丸”）在不同剂量和给药方案下诱导不同物种神经元血清素（5-HT）标记物显著下降。在大鼠中，MDMA介导的作用部分归因于MDMA通过5-HT转运体（SERT）选择性高亲和力转运到5-HT神经元，随后广泛释放5-HT。为了阐明MDMA对人类单胺转运体的SERT选择性作用是否可以解释MDMA在灵长类脑中诱导的5 -羟色胺神经元的选择性毒性，我们研究了HEK-293细胞中（3H）(RS)-, (S)-和(R)-MDMA对人类SERT，多巴胺（DA）转运体（DAT）和去甲肾上腺素（NE）转运体（NET）的底物特异性。结果：人DAT、NET和SERT积极转运（3H）(RS)-MDMA。MDMA对NET的亲和力高于SERT或DAT， MDMA抑制（3H）DA、（3H）NE和（3H）5-HT转运和刺激（3H）单胺的释放的等级顺序相同，这与来自啮齿动物单胺转运体的报道不同。mdma诱导的5-HT释放程度高于DA或NE的释放程度。讨论：MDMA对人SERT的亲和力并不能阐明MDMA对5-羟色胺神经元的明显选择性毒性，尽管可以想象，其刺激5-羟色胺释放的更高功效可能是一个区别因素。研究结果强调，除了sert选择性抑制剂外，还需要研究NET抑制剂的治疗潜力，以减轻MDMA的药理作用。

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. 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") induces significant decrements in neuronal serotonin (5-HT) markers in various species, as a function of dose and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA into 5-HT neurons by the 5-HT transporter (SERT), followed by extensive 5-HT release. To clarify whether SERT-selective effects of MDMA at human monoamine transporters can account for the reported MDMA-induced selective toxicity of serotonin neurons in primate brain, we investigated substrate specificity of (3H)(RS)-, (S)-, and (R)-MDMA with the human SERT, dopamine (DA) transporter (DAT), and norepinephrine (NE) transporter (NET) in HEK-293 cells. Results: The human DAT, NET, and SERT actively transported (3H)(RS)-MDMA. MDMA exhibited the highest affinity for the NET greater than the SERT or DAT, the same rank order for MDMA inhibition of (3H)DA, (3H)NE, and (3H)5-HT transport and stimulated release of the (3H)monoamines, which differed from reports derived from rodent monoamine transporters. The extent of MDMA-induced release of 5-HT was higher compared with release of DA or NE. Discussion: The affinity of MDMA for the human SERT does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor. The findings highlight the need to investigate the therapeutic potential of NET inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of MDMA.