title: Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters.
abstract: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone.
  
  
  
  We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg·kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens.
  
  
  
  In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity.
  
  
  
  Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
authors.affiliation: Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.
authors.forename: F P
authors.initials: FP
authors.lastname: Mayer
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Wimmer
authors.affiliation: Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: O
authors.initials: O
authors.lastname: Dillon-Carter
authors.affiliation: Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.
authors.forename: N V
authors.initials: NV
authors.lastname: Burchardt
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria.
authors.forename: M D
authors.initials: MD
authors.lastname: Mihovilovic
authors.affiliation: Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.|Center for Addiction Research and Science, Medical University Vienna, Vienna, Austria.
authors.forename: H H
authors.initials: HH
authors.lastname: Sitte
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008694:Methamphetamine; C548233:mephedrone