The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter

Mephedrone (4-methylmethcathinone, MMC) and 3,4-methylenedioxymethamphetamine (MDMA) are constituents of popular party drugs with psychoactive effects. Structurally they are amphetamine-like substances with monoamine neurotransmitter enhancing actions. We therefore compared their effects on the human monoamine transporters using human cell lines stably expressing the human noradrenaline, dopamine and serotonin transporter (NET, DAT and SERT); preparations of synaptic vesicles from human striatum in uptake experiments; and a superfusion system where releasing effects can be reliably measured. MMC and MDMA were equally potent in inhibiting noradrenaline uptake at NET, with IC50 values of 1.9 and 2.1 µM, respectively. Compared to their NET inhibition potency, both drugs were weaker uptake inhibitors at DAT and SERT, with MMC being more potent than MDMA at DAT (IC50: 5.9 vs 12.6 µM) and less potent than MDMA at SERT (IC50: 19.3 vs 7.6 µM). MMC and MDMA both induced concentration-dependently [3H]1-methyl-4-phenylpyridinium-release from NET-, DAT or SERT-expressing cells which was clearly transporter-mediated release as demonstrated by the selective inhibitory effects of nmolar to low µmolar concentrations of desipramine, GBR 12909 and fluoxetine, respectively. MMC and MDMA differed most in their inhibition of [3H]dopamine uptake by synaptic vesicles from human striatum with MDMA being 10-fold more potent than MMC (IC50: 20 vs 223 µM) and their ability to release [3H]dopamine from human vesicular monoamine transporter expressing SH-SY5Y neuroblastoma cells in which MDMA seems to have a stronger effect. Our findings give a molecular explanation to the lower long-term neurotoxicity of MMC compared to MDMA.