title: The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter.
abstract: 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 [(3)H]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 [(3)H]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 [(3)H]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.
authors.affiliation: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. Electronic address: christian.pifl@meduniwien.ac.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Pifl
authors.affiliation: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Reither
authors.affiliation: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: Oleh
authors.initials: O
authors.lastname: Hornykiewicz
mesh_terms: D045744:Cell Line, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493452:SLC18A2 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; C548233:mephedrone; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: Amphetamines; Dopamine transporter; Noradrenaline transporter; Serotonin transporter; Synaptic vesicles; Vesicular monoamine transporter