Methylone (2-methylamino-1-[3,4-methylenedioxy-phenyl]propan-1-one), an
amphetamine analog, has emerged as a popular
drug of abuse worldwide.
Methylone induces
hyperthermia, which is thought to contribute toward the lethal consequences of
methylone overdose.
Methylone has been assumed to induce hyperthermic effects through inhibition of
serotonin and/or
dopamine transporters (SERT and DAT, respectively). To examine the roles of each of these
proteins in
methylone-induced toxic effects, we used SERT and DAT knockout (KO) mice and assessed the hyperthermic and lethal effects caused by a single administration of
methylone.
Methylone produced higher rates of lethal toxicity compared with other
amphetamine analogs in wild-type mice. Compared with wild-type mice, lethality was significantly lower in DAT KO mice, but not in SERT KO mice. By contrast, only a slight diminution in the hyperthermic effects of
methylone was observed in DAT KO mice, whereas a slight enhancement of these effects was observed in SERT KO mice. Administration of the selective D1 receptor antagonist
SCH 23390 and the D2 receptor antagonist
raclopride reduced
methylone-
induced hyperthermia, but these drugs also had hypothermic effects in saline-treated mice, albeit to a smaller extent than the effects observed in
methylone-treated mice. In contradistinction to 3,4-methylenedioxymethamphetamine, which induces its toxicity through SERT and DAT, these data indicate that DAT, but not SERT, is strongly associated with the lethal toxicity produced by
methylone, which did not seem to be dependent on the hyperthermic effects of
methylone. DAT is therefore a strong candidate molecule for interventions aimed at preventing acute neurotoxic and lethal effects of
methylone.