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

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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.