Methylone and Monoamine Transporters: Correlation with Toxicity

Methylone, a synthetic hallucinogenic amphetamine analog similar to MDMA, inhibits the activity of dopamine, norepinephrine, and serotonin transporters in a concentration-dependent manner, with the strongest effect on the norepinephrine transporter, followed by dopamine and then serotonin transporters. Compared to methamphetamine, methylone is less effective at blocking dopamine and norepinephrine transporters but more effective at blocking the serotonin transporter. Methylone alone is not toxic to cells except at high concentrations, but when combined with methamphetamine, it produces a synergistic toxic effect in cells that express monoamine transporters, likely because methylone acts as a transportable substrate that inhibits transporter function.

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Abstract

Methylone (2-methylamino-1-[3,4-methylenedioxyphenyl]propane-1-one) is a synthetic hallucinogenic amphetamine analog, like MDMA (3,4-methylenedioxy- methamphetamine), considered to act on monoaminergic systems. However, the psychopharmacological profile of its cytotoxicity as a consequence of monoaminergic deficits remains unclear. We examined here the effects of methylone on the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using a heterologous expression system in CHO cells, in association with its cytotoxicity. Methylone inhibited the activities of DAT, NET, and SERT, but not GABA transporter-1 (GAT1), in a concentration-dependent fashion with a rank order of NET > DAT > SERT. Methylone was less effective at inhibiting DAT and NET, but more effective against SERT, than was methamphetamine. Methylone alone was not toxic to cells except at high concentrations, but in combination with methamphetamine had a synergistic effect in CHO cells expressing the monoamine transporters but not in control CHO cells or cells expressing GAT1. The ability of methylone to inhibit monoamine transporter function, probably by acting as a transportable substrate, underlies the synergistic effect of methylone and methamphetamine.