- Original Article
- Published:
The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue
- Michael H Baumann1,
- Mario A Ayestas Jr1,
- John S Partilla1,
- Jacqueline R Sink1,
- Alexander T Shulgin2,
- Paul F Daley2,
- Simon D Brandt3,
- Richard B Rothman1,
- Arnold E Ruoho4 &
- …
- Nicholas V Cozzi5
Neuropsychopharmacologyvolume 37, pages1192–1203 (2012)Cite this article
16kAccesses
398Citations
60Altmetric
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 employedin vitro andin 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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more onnature.com
or
References
Battaglia G, Yeh SY, De Souza EB (1988). MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons.Pharmacol Biochem Behav29: 269–274.
Baumann MH, Ayestas MA, Sharpe LG, Lewis DB, Rice KC, Rothman RB (2002). Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate.J Pharmacol Exp Ther301: 1190–1197.
Baumann MH, Clark RD, Franken FH, Rutter JJ, Rothman RB (2008). Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges.Neuroscience152: 773–784.
Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB (2011).In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat.J Pharmacol Exp Ther337: 218–225.
Bossong MG, Van Dijk JP, Niesink RJ (2005). Methylone and mCPP, two new drugs of abuse?Addict Biol10: 321–323.
Brandt SD, Sumnall HR, Measham F, Cole J (2010). Analyses of second-generation ‘legal highs’ in the UK: initial findings.Drug Test Anal2: 377–382.
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJet al (2010). Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.J Med Chem53: 2204–2214.
CDC (2011). Emergency department visits after use of a drug sold as ‘bath salts’---Michigan, November 13, 2010--March 31, 2011.MMWR Morb Mortal Wkly Rep60: 624–627.
Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987). Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.J Pharmacol Exp Ther241: 338–345.
Cozzi NV, Foley KF (2003). Methcathinone is a substrate for the serotonin uptake transporter.Pharmacol Toxicol93: 219–225.
Cozzi NV, Sievert MK, Shulgin AT, Jacob III P, Ruoho AE (1999). Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines.Eur J Pharmacol381: 63–69.
Dal Cason TA, Young R, Glennon RA (1997). Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs.Pharmacol Biochem Behav58: 1109–1116.
Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza Set al (2004). Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors.Mol Pharmacol66: 675–682.
de la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura Met al (2004). Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition.Ther Drug Monit26: 137–144.
Dickson AJ, Vorce SP, Levine B, Past MR (2010). Multiple-drug toxicity caused by the coadministration of 4-methylmethcathinone (mephedrone) and heroin.J Anal Toxicol34: 162–168.
EMCDDA (2010).Annual Report on the sSate of Drug Problems in Europe. European Monitoring Centre for Drugs and Drug Addiction: Lisbon.
Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007). New insights into the mechanism of action of amphetamines.Annu Rev Pharmacol Toxicol47: 681–698.
Green AR, O’Shea E, Colado MI (2004). A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response.Eur J Pharmacol500: 3–13.
Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SCet al (2011). 4-Methylmethcathinone(mephedrone): neuropharmacological effects of a designer stimulant of abuse.J Pharmacol Exp Ther339: 530–536.
James D, Adams RD, Spears R, Cooper G, Lupton DJ, Thompson JPet al (2010). Clinical characteristics of mephedrone toxicity reported to the UK National Poisons Information Service.Emerg Med J28: 686–689.
Kamata HT, Shima N, Zaitsu K, Kamata T, Miki A, Nishikawa Met al (2006). Metabolism of the recently encountered designer drug, methylone, in humans and rats.Xenobiotica36: 709–723.
Karila L, Reynaud M (2010). GHB and synthetic cathinones: clinical effects and potential consequences.Drug Test Anal; e-pub ahead of print 2 December 2010.
Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg Fet al (2011). Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and serotonin levels in nucleus accumbens of awake rats.Br J Pharmacol; e-pub ahead of print 21 November 2011.
Lusthof KJ, Oosting R, Maes A, Verschraagen M, Dijkhuizen A, Sprong AG (2011). A case of extreme agitation and death after the use of mephedrone in the Netherlands.Forensic Sci Int206: e93–e95.
Malberg JE, Seiden LS (1998). Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat.J Neurosci18: 5086–5094.
Maskell PD, De Paoli G, Seneviratne C, Pounder DJ (2011). Mephedrone (4-methylmethcathinone)-related deaths.J Anal Toxicol35: 188–191.
Meltzer PC, Butler D, Deschamps JR, Madras BK (2006). 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors.J Med Chem49: 1420–1432.
Meyer MR, Wilhelm J, Peters FT, Maurer HH (2010). Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry.Anal Bioanal Chem397: 1225–1233.
Nagai F, Nonaka R, Satoh Hisashi Kamimura K (2007). The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain.Eur J Pharmacol559: 132–137.
O’Shea E, Granados R, Esteban B, Colado MI, Green AR (1998). The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (‘ecstasy’).Neuropharmacology37: 919–926.
Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FIet al (2001). Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.Synapse39: 32–41.
Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BAet al (2003).In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates.J Pharmacol Exp Ther307: 138–145.
Shankaran M, Gudelsky GA (1999). A neurotoxic regimen of MDMA suppresses behavioral, thermal and neurochemical responses to subsequent MDMA administration.Psychopharmacology (Berl)147: 66–72.
Sitte HH, Freissmuth M (2010). The reverse operation of Na(+)/Cl(−)-coupled neurotransmitter transporters--why amphetamines take two to tango.J Neurochem112: 340–355.
Sogawa C, Sogawa N, Ohyama K, Kikura-Hanajiri R, Goda Y, Sora Iet al (2011). Methylone and monoamine transporters: correlation with toxicity.Curr Neuropharmacology9: 58–62.
Spanos LJ, Yamamoto BK (1989). Acute and subchronic effects of methylenedioxymethamphetamine [(+/−)MDMA] on locomotion and serotonin syndrome behavior in the rat.Pharmacol Biochem Behav32: 835–840.
Sparago M, Wlos J, Yuan J, Hatzidimitriou G, Tolliver J, Dal Cason TAet al (1996). Neurotoxic and pharmacologic studies on enantiomers of the N-methylated analog of cathinone (methcathinone): a new drug of abuse.J Pharmacol Exp Ther279: 1043–1052.
Vardakou I, Pistos C, Spiliopoulou C (2011). Drugs for youth via Internet and the example of mephedrone.Toxicol Lett201: 191–195.
Willuhn I, Wanat MJ, Clark JJ, Phillips PE (2010). Dopamine signaling in the nucleus accumbens of animals self-administering drugs of abuse.Curr Top Behav Neurosci3: 29–71.
Winstock AR, Mitcheson LR, Deluca P, Davey Z, Corazza O, Schifano F (2011). Mephedrone, new kid for the chop?Addiction106: 154–161.
Wise RA (2008). Dopamine and reward: the anhedonia hypothesis 30 years on.Neurotox Res14: 169–183.
Wood DM, Davies S, Puchnarewicz M, Button J, Archer R, Ovaska Het al (2010). Recreational use of mephedrone (4-methylmethcathinone, 4-MMC) with associated sympathomimetic toxicity.J Med Toxicol6: 327–330.
Wood DM, Greene SL, Dargan PI (2011). Clinical pattern of toxicity associated with the novel synthetic cathinone mephedrone.Emerg Med J28: 280–282.
Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola Vet al (2009). Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil.J Pharmacol Exp Ther329: 738–746.
Acknowledgements
This work was generously supported by the National Institute on Drug Abuse (NIDA), Intramural Research Program (MHB, MAA, JSP, JRS and RBR), NIDA Grants DA017675 (NVC) and DA027191 (AER), and the Retina Research Foundation/UW Eye Research Institute Edwin and Dorothy Gamewell Professorship (AER). We thank Ava Cozzi and Lisa Ehrlicher for helpful discussions.
Author information
Authors and Affiliations
Translational Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
Michael H Baumann, Mario A Ayestas Jr, John S Partilla, Jacqueline R Sink & Richard B Rothman
Alexander Shulgin Research Institute, Lafayette, CA, USA
Alexander T Shulgin & Paul F Daley
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
Simon D Brandt
Department of Neuroscience and the UW Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Arnold E Ruoho
Department of Cell and Regenerative Biology, Neuropharmacology Laboratory, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Nicholas V Cozzi
- Michael H Baumann
Search author on:PubMed Google Scholar
- Mario A Ayestas Jr
Search author on:PubMed Google Scholar
- John S Partilla
Search author on:PubMed Google Scholar
- Jacqueline R Sink
Search author on:PubMed Google Scholar
- Alexander T Shulgin
Search author on:PubMed Google Scholar
- Paul F Daley
Search author on:PubMed Google Scholar
- Simon D Brandt
Search author on:PubMed Google Scholar
- Richard B Rothman
Search author on:PubMed Google Scholar
- Arnold E Ruoho
Search author on:PubMed Google Scholar
- Nicholas V Cozzi
Search author on:PubMed Google Scholar
Corresponding author
Correspondence toMichael H Baumann.
Ethics declarations
Competing interests
The authors declare no conflict to interest.
Rights and permissions
About this article
Cite this article
Baumann, M., Ayestas, M., Partilla, J.et al. The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue.Neuropsychopharmacol37, 1192–1203 (2012). https://doi.org/10.1038/npp.2011.304
Received:
Revised:
Accepted:
Published:
Issue date:
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
Keywords
This article is cited by
A systematic review and meta-analysis of synthetic cathinone use and psychosis
- Rishika R. Daswani
- Cassandra M. Choles
- Alasdair M. Barr
Psychopharmacology (2024)
Effects of congeners of amphetamine on the human heart
- Joachim Neumann
- Stefan Dhein
- Ulrich Gergs
Naunyn-Schmiedeberg's Archives of Pharmacology (2024)
Serotonin-releasing agents with reduced off-target effects
- Felix P. Mayer
- Marco Niello
- Harald H. Sitte
Molecular Psychiatry (2023)
Pharmacological affinity fingerprints derived from bioactivity data for the identification of designer drugs
- Kedan He
Journal of Cheminformatics (2022)
(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice
- Deborah Rudin
- John D. McCorvy
- Harald H. Sitte
Neuropsychopharmacology (2022)


