The nonmedical use of 'designer'
cathinone analogs, such as
4-methylmethcathinone (
mephedrone) and 3,4-methylenedioxymethcathinone (
methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of
mephedrone and
methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (
MDMA) and
methamphetamine. In vitro release assays using rat brain synaptosomes revealed that
mephedrone and
methylone are nonselective substrates for plasma membrane monoamine transporters, similar to
MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of
mephedrone or
methylone produces dose-related increases in extracellular
dopamine and
serotonin (5-HT), with the magnitude of effect on
5-HT being greater. Both
methcathinone analogs were weak motor stimulants when compared with
methamphetamine. Repeated administrations of
mephedrone or
methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused
hyperthermia but no long-term change in cortical or striatal
amines, whereas similar treatment with
MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust
hyperthermia and persistent depletion of cortical and striatal
5-HT. Our data demonstrate that designer
methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to
MDMA.
Dopaminergic effects of
mephedrone and
methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of
mephedrone and
methylone, determining the consequences of repeated
drug exposure warrants further study.