Advertisement

Psychopharmacology

, Volume 227, Issue 3, pp 493–499 | Cite as

Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of “bath salts,” produce opposite effects at the human dopamine transporter

  • Krasnodara Cameron
  • Renata Kolanos
  • Rakesh Verkariya
  • Louis De FeliceEmail author
  • Richard A. GlennonEmail author
Original Investigation

Abstract

Rationale

Psychoactive “bath salts” represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated.

Materials and methods

Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes.

Results

Whereas mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine.

Conclusions

Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in bath salts) might produce effects similar to a combination of methamphetamine and cocaine.

Keywords

Synthetic cathinones Cocaine Dopamine transporter hDAT Mephedrone Methamphetamine Methcathinone Methylenedioxypyrovalerone Drug abuse 

Notes

Acknowledgments

This work was supported, in part, by PHS grant DA033930 and DA02694702.

References

  1. Balint EE, Falkay G, Balint GA (2009) Khat—a controversial plant. Wein Klin Wochenschr 121:604–614CrossRefGoogle Scholar
  2. Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37:1192–1203PubMedCrossRefGoogle Scholar
  3. Dal Cason TA, Young R, Glennon RA (1997) Cathinone: an investigation of several N-alkyl and methylenedioxy analogs. Pharmacol Biochem Behav 58:1109–1116PubMedCrossRefGoogle Scholar
  4. de Durnaga S, Sanchez J (1929) A homolog of ephedrine. Bull Soc Chim Fr 45:284–286Google Scholar
  5. DeFelice LJ, Goswami T (2007) Transporters as channels. Annu Rev Physiol 69:87–112PubMedCrossRefGoogle Scholar
  6. Federal Register (2011) Schedules of controlled substances: temporary placement of three synthetic cathinones into Schedule I. Fed Regist 76:65371–65375, October 21Google Scholar
  7. Fuwa T, Fukumori N, Tanaka T, Kubo Y, Ogata A, Uehara S, Honda Y, Kodama T (2007) Microdialysis study of drug effects on central nervous system: changes of dopamine levels in mice striatum after oral administration of methylenedioxypyrovalerone. Ann Rep Tokyo Metr Inst P H 58:287–292Google Scholar
  8. Glennon RA, Showalter D (1981) The effect of cathinone and several related derivatives on locomotor activity. Res Commun Subst Abuse 2:186–192Google Scholar
  9. Glennon RA, Young R (2011) Drug discrimination: application to medicinal chemistry and drug studies. Wiley, HobokenCrossRefGoogle Scholar
  10. Glennon RA, Young R, Martin BR, Dal Cason TA (1995) Methcathinone (“CAT”): an enantiomeric potency comparison. Pharmacol Biochem Behav 50:601–606PubMedCrossRefGoogle Scholar
  11. Glennon RA, Yousif M, Naiman NA, Kalix P (1987) Methcathinone: a new and potent amphetamine-like agent. Pharmacol Biochem Behav 26:547–551PubMedCrossRefGoogle Scholar
  12. Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM, Vieira-Brock PL, German CL, Conrad KM, Hoonakker AJ, Gibb JW, Wilkins DG, Hanson GR, Fleckenstein AE (2011) 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther 339:530–536PubMedCrossRefGoogle Scholar
  13. Iversen LE (2010) Consideration of the cathinones. Advisory Council on the Misuse of Drugs. A report submitted to the Home Secretary of the UK (March 31, 2010)Google Scholar
  14. Iwamoto H, Blakely L, De Felice LJ (2006) Na+, Cl, and pH dependence of the human choline transporter (hCHT) in Xenopus oocytes: the proton inactivation hypothesis of hCHT in synaptic vesicles. J Neurosci 26:9851–9859PubMedCrossRefGoogle Scholar
  15. Kalix P (1980) A constituent of khat leaves with amphetamine-like releasing properties. Eur J Pharmacol 68:213–215PubMedCrossRefGoogle Scholar
  16. Kalix P (1984) The pharmacology of khat. Gen Pharmacol 15:179–187PubMedCrossRefGoogle Scholar
  17. Kalix P (1996) Catha edulis, a plant that has amphetamine effects. Pharm World Sci 18:69–73PubMedCrossRefGoogle Scholar
  18. Kalix P (1992) Cathinone, a natural amphetamine. Pharmacol Toxicol 70:77–86PubMedCrossRefGoogle Scholar
  19. Kalix P, Braeden O (1985) Pharmacological aspects of the chewing of khat leaves. Pharmacol Rev 37:149–164PubMedGoogle Scholar
  20. Kalix P, Glennon RA (1986) Further evidence for an amphetamine-like mechanism of action of the alkaloid cathinone. Biochem Pharmacol 35:3015–3019PubMedCrossRefGoogle Scholar
  21. Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, Yoshitake T (2011) Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and serotonin levels in nucleus accumbens of awake rats. Br J Pharmacol 164:1949–1958PubMedCrossRefGoogle Scholar
  22. Kennedy JG, Teague J, Fairbanks L (1980) Qat use in North Yemen and the problem of addiction: A study in medical anthroplology. Cult Med Psychiat 4:311–344CrossRefGoogle Scholar
  23. Köppe H, Ludwig G, Holstein W, Zile L (1969) 1-(3’,4’-Methylenedioxy-phenyl-2-pyrrlidino-alkanones-(1). US Patent 3,478,050, November 11, 1969.Google Scholar
  24. Martínez-Clemente J, Escubedo E, Pubill D, Camarasa J (2012) Interaction of mephedrone with dopamine and serotonin targets in rats. Eur Neuropsychopharmacol 22:231–236PubMedCrossRefGoogle Scholar
  25. 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 Chem 49:1420–1432PubMedCrossRefGoogle Scholar
  26. Ramsey S, De Felice LJ (2002) Serotonin transporter function and pharmacology are sensitive to expression level: evidence for an endogenous regulatory factor. J Biol Chem 277:14475–14482PubMedGoogle Scholar
  27. Rodriguez-Menchaca AA, Solis E Jr, Cameron K, De Felice LJ (2012) (+)Amphetamine induces a persistent leak in the human dopamine transporter: Molecular stent hypothesis. Br J Pharmacol 156:2749–2757CrossRefGoogle Scholar
  28. Simmler LD, Buser TA, Donzelli M, Schramm Y, Diue LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2012) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. doi: 10.1111/j.1476-5381.2012.02145.x
  29. Sonders MS, Zhu SJ, Zahniser NR, Kavanaugh MP, Amara SG (1997) Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J Neurosci 17:960–174PubMedGoogle Scholar
  30. Spiller HA, Ryan ML, Weston RG, Jansen J (2011) Clinical experience with and analytical confirmation of 'bath salts' and 'legal highs' (synthetic cathinones) in the United States. Clin Toxicol 49:499–505CrossRefGoogle Scholar
  31. United Nations (1979) The botany and chemistry of khat. United Nations Narcotics Laboratory Report of an Expert Group, Antananarivo, Madagascar, November 27–December 1, 1978, MNAR Document 3/1979Google Scholar
  32. Young R, Glennon RA (1998) Discriminative stimulus effects of S(−)-methcathinone (MCAT): a potent stimulant drug of abuse. Psychopharmacol (Berl) 140:250–256CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Physiology and Biophysics, School of MedicineVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of Medicinal Chemistry, School of PharmacyVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations