British Journal of Pharmacology p. 2657 - 2668 (2016)
Update date:2022-08-04
Topics:
Mayer
Wimmer
Dillon-Carter
Partilla
Burchardt
Mihovilovic
Baumann
Sitte
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.
View MoreAnhui Redstar Pharmaceutical Corp., Ltd
Contact:+86-563-5120837
Address:Jingxian Industrial Development Zone, Anhui , China
Shanghai KFSL Pharmaceutical Technology Co.,Ltd.
Contact:+86-21-39971718
Address:859 jiadingchengliu shanghai
Suzhou HeChuang Chemical Co.,Ltd.
Contact:+86-512-88800520
Address:No.9 Guanchao Rd,Changshu Advanced Materials Industy Park
Lianyungang Ningkang Chemical Co., Ltd
Contact:.+86-518-88588008
Address:http://www.chemnk.com
Jiangxi Hessence Chemicals Co., Ltd.
Contact:+86 796 3511924
Address:Chengxi Industrial Park, Jishui County, Jiangxi Province 331600 China.
Doi:10.1002/ejic.200300068
(2003)Doi:10.1021/ja01196a040
(1947)Doi:10.1021/ja01326a087
(1934)Doi:10.1002/jccs.200300129
(2003)Doi:10.1021/ja00496a055
(1979)Doi:10.1016/S0040-4020(01)96588-3
(1985)