MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, designated as Ecstasy if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing 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. Objectives: 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. Methods: We investigated the interaction of [H-3](+/-, RS)- (+, S)- and (-, R)-MDMA with the human SERT, dopamine (DA) transporter (DAT), and norepinephrine (NE) transporter (NET) in stably transfected human embryo kidney (HEK)-293 cells. Results: The human DAT, NET, and SERT actively transported [H-3]RS (+/-)-MDMA saturably, stereoselectively, and in a temperature-, concentration-, and transporter-dependent manner. MDMA exhibited the highest affinity for the NET >> SERT > DAT, the same rank order for MDMA inhibition of [H-3]DA, [H-3]NE, and [H-3]5-HT transport and stimulated release of the [H-3]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. Conclusions: The affmity of MDMA for the human SERT in transfected cells 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 MDMA effects in DAT-, SERT-, and NET-expressing neurons in the primate brain and the therapeutic potential of NET or DAT inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of NMMA.