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.
Highlights
Various illegal and/or restricted “designer drugs” have been created by modifying amphetamines
The effect of methylone on the transport of monoamines was examined in Chinese hamster ovary (CHO) cells stably expressing the rat monoamine transporters, rat DAT (rDAT), rNET and rSERT, in comparison with that on the mouse GABA transporter, mouse GABA transporter-1 (mGAT1)
Simultaneous incubation with [3H]DA, [3H]NE, or [3H]5HT and methylone caused a decrease in the uptake of [3H]substrate in a concentration-dependent fashion, the effects differed between transporters in contrast to the effects of methamphetamine (Fig. 1)
Summary
Various illegal and/or restricted “designer drugs” have been created by modifying amphetamines. Methylone (2methylamino-1-[3,4-methylenedioxy- phenyl]propane-1-one) is one such synthetic hallucinogenic amphetamine analogue, which resembles MDMA (3,4-methylenedioxymethamphetamine) but differs structurally by the presence of a ketone at the benzylic position [1, 2]. This compound has been newly placed under legal control as a drug of abuse in Japan [3]. In studies of its pharmacology in vitro methylone was threefold less potent than MDMA at inhibiting platelet serotonin transporter (SERT) and as potent as MDMA in inhibiting transporters for dopamine (DAT) and norepinephrine (NET), but only weakly inhibited the vesicular monoamine transporter [5, 6]. There have been few pharmacological investigations of methylone in animal models, or studies about its mechanism of action
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