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Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
AuthorSitte, H. H. ; Baumann, M. H. ; Mihovilovic, M. D. ; Burchardt, N. V. ; Partilla, J. S. ; Dillon-Carter, O. ; Wimmer, L. ; Mayer, F. P.
Published in
British Journal of Pharmacology, hoboken, 2016, Vol. 173, Issue 17, page 2657-2668
Publishedhoboken : Wiley-Blackwell, 2016
Document typeJournal Article
Keywords (EN)human serotonin transporter / psychoactive substances / 3,4-methylenedioxymethamphetamine mdma / 4-methylmethcathinone mephedrone / pharmacological characterization / mediated efflux / designer drugs / concise guide / bath salts / dopamine
Project-/ReportnumberW 1232-B24
URNurn:nbn:at:at-ubmuw:3-1803 Persistent Identifier (URN)
 The work is publicly available
Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters [4.79 mb]
Abstract (English)

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY RESULTS 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. CONCLUSIONS AND IMPLICATIONS 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.

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