title: The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.
abstract: 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.
authors.affiliation: Translational Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. mbaumann@mail.nih.gov
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ayestas
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Sink
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Shulgin
authors.forename: Paul F
authors.initials: PF
authors.lastname: Daley
authors.forename: Simon D
authors.initials: SD
authors.lastname: Brandt
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Ruoho
authors.forename: Nicholas V
authors.initials: NV
authors.lastname: Cozzi
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D006213:Hallucinogens / Q000494:pharmacology; D066298:In Vitro Techniques; D008124:Locomotion / Q000187:drug effects; D008297:Male; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics; D013574:Synaptosomes / Q000187:drug effects; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D006213:Hallucinogens; D026901:Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D014316:Tritium; D012701:Serotonin; D008694:Methamphetamine; C548233:mephedrone; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C400939:methylone; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine