Dopaminergic Effects of Major Bath Salt Constituents 3,4-Methylenedioxypyrovalerone (MDPV), Mephedrone, and Methylone Are Enhanced Following Co-exposure
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Designer drug mixtures popularized as “bath salts” often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in various combinations. However, most preclinical investigations have only assessed the effects of individual bath salt constituents, and little is known about whether co-exposure to MDPV, mephedrone, and methylone produces significant neuropharmacological interactions. This study evaluated and compared how MDPV, mephedrone, and methylone influence discrete brain tissue dopamine (DA) levels and motor stimulant responses in mice when administered alone and as a ternary mixture. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline or 1 or 10 mg/kg doses of MDPV, mephedrone, or methylone, or a cocktail of all three cathinones at doses of 1, 3.3, or 10 mg/kg each. The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure using HPLC-ECD. Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. MDPV, mephedrone, and methylone produced dose-related increases in mesolimbic and nigrostriatal DA levels that were significantly enhanced following their co-administration. In addition, mice treated with the cathinone cocktail displayed decreased locomotor activity on day 1 that was exacerbated by day 7 and not observed with any of the drugs alone. Our findings demonstrate a significant enhanced effect of MDPV, mephedrone, and methylone on both DA, and these effects on DA result in significant alterations in locomotor activity.
KeywordsSynthetic cathinones Mephedrone Methylenedioxypyrovalerone Methylone Locomotor activity Bath salts
The authors would like to thank Katherine Burgess for her technical assistance.
This work was supported by the East Tennessee State University Research Development Committee Major Grant Program and the National Institutes of Health grant C06RR0306551.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
Research Involving Animals
The experimental protocol was approved by the ETSU University committee on animal care (UCAC) and followed the National Institute of health guidelines for the care and use of laboratory animals.
- Allen SA, Rednour S, Shepard S, Pond BB (2017) A simple and sensitive high-performance liquid chromatography-electrochemical detection assay for the quantitative determination of monoamines and respective metabolites in six discrete brain regions of mice. Biomed Chromatogr 1(11). https://doi.org/10.1002/bmc.3998
- Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products. Neuropsychopharmacology 38:552–562CrossRefGoogle Scholar
- 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 Rep 60:624Google Scholar
- DEA (2011) Schedules of controlled substances: temporary placement of three synthetic cathinones in schedule I. Final order. Fed Regist 76:65371–65375Google Scholar
- DEA (2014) National Forensic Laboratory Information System Special Report: synthetic cannabinoids and synthetic cathinones reported in NFLIS, 2010–2013. US Drug Enforcement Administration, Springfield. URL: https://www.nflis.deadiversion.usdoj.gov/DesktopModules/ReportDownloads/Reports/NFLIS_SR_CathCan_508.pdf. Accessed 27 Jan 2018
- Deluca P, Davey Z, Corazza O, Di Furia L, Farre M, Flesland LH, Mannonen M, Majava A, Peltoniemi T, Pasinetti M, Pezzolesi C, Scherbaum N, Siemann H, Skutle A, Torrens M, van der Kreeft P, Iversen E, Schifano F (2012) Identifying emerging trends in recreational drug use; outcomes from the Psychonaut Web Mapping Project. Prog Neuro-Psychopharmacol Biol Psychiatry 39:221–226CrossRefGoogle Scholar
- Gannon BM, Galindo KI, Mesmin MP, Rice KC, Collins GT (2018a) Reinforcing effects of binary mixtures of common bath salt constituents: studies with 3, 4-Methylenedioxypyrovalerone (MDPV), 3, 4-methylenedioxymethcathinone (methylone), and caffeine in rats. Neuropsychopharmacology 43:761–769CrossRefGoogle Scholar
- Graves SM, Xie Z, Zampese E, Stout KA, Tai RA, Schwarzschild SE, Burbulla LF, Krainc D, Schumacker PT, Surmeier DJ (2017) Methamphetamine-induced mitochondrial oxidant stress mediated by monoamine oxidase metabolism of dopamine. FASEB J 31:987–983Google Scholar
- Juraska JM, Sisk CM, DonCarlos, LL (2013) Sexual differentiation of the adolescent rodent brain: hormonal influences and developmental mechanisms. Horm Behav 64:203-210Google Scholar
- López-Arnau R, Buenrostro-Jáuregui M, Muñoz-Villegas P, Rodríguez-Morató J, Duart L, Camarasa J, De la Torre R, Pubill D, Escubedo E (2017) The combination of MDPV and ethanol results in decreased cathinone and increased alcohol levels. Study of such pharmacological interaction. Prog Neuro-Psychopharmacol Biol Psychiatry 76:19–28CrossRefGoogle Scholar
- López-Arnau R, Buenrostro-Jáuregui M, Camarasa J, Pubill D, Escubedo E (2018) Effect of the combination of mephedrone plus ethanol on serotonin and dopamine release in the nucleus accumbens and medial prefrontal cortex of awake rats. Naunyn Schmiedeberg's Arch Pharmacol 391(3):247–254Google Scholar
- Peters JR, Keasling R, Brown SD, Pond BB (2016) Quantification of synthetic cathinones in rat brain using HILIC-ESI-MS/MS. J Anal Toxicol 40:718–725Google Scholar
- Power M (2013) Drugs 2.0: the web revolution that’s changing how the world gets high. Granta Publications, LondonGoogle Scholar
- SAMHSA (2013) The DAWN report: bath salts were involved in over 20,000 drug-related emergency department visits in 2011. Center for Behavioral Health Statistics and QualityGoogle Scholar
- Schindler CW, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD, Baumann MH (2016) Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Psychopharmacology 233:1981–1990CrossRefGoogle Scholar
- Segal DS, Kuczenski R (1987) Individual differences in responsiveness to single and repeated amphetamine administration: behavioral characteristics and neurochemical correlates. J Pharmacol Exp Ther 242:917–926Google Scholar
- Shortall SE, Macerola AE, Swaby RTR, Jayson R, Korsah C, Pillidge KE, Wigmore PM, Ebling FJP, Green AR, Fone KCF (2013) Behavioural and neurochemical comparison of chronic intermittent cathinone, mephedrone and MDMA administration to the rat. Eur Neuropsychopharmacol 23:1085–1095CrossRefGoogle Scholar
- Smith RF, McDonald CG, Bergstrom HC, Ehlinger DG, Brielmaier JM (2015) Adolescent nicotine induces persisting changes in development of neural connectivity. Neurosci Biobehav Rev 55:432–443.Google Scholar
- Solis E (2016) Electrophysiological actions of synthetic cathinones on monoamine transporters. In: Baumann M, Glennon R, Wiley J (eds) Neuropharmacology of new psychoactive substances (NPS). Current Topics in Behavioral Neurosciences, vol 32. Springer, Cham pp 73–92Google Scholar
- Štefková K, Židková M, Horsley RR, Pinterová N, Šíchová K, Uttl L, Balíková M, Danda H, Kuchař M, Páleníček T (2017) Pharmacokinetic, ambulatory, and hyperthermic effects of 3, 4-methylenedioxy-N-methylcathinone (methylone) in rats. Front Psychiatry 8:232Google Scholar
- Vardakou I, Pistos C, Spiliopoulou CH (2011) Drugs for youth via Internet and the example of mephedrone. Toxicol Lett 201:191–195Google Scholar
- Warrick BJ, Hill M, Hekman K, Christensen R, Goetz R, Casavant MJ, Wahl M, Mowry JB, Spiller H, Anderson D, Aleguas A, Gummin D, Thomas R, Nezlek C, Smolinske S (2013) A 9-state analysis of designer stimulant, “bath salt,” hospital visits reported to poison control centers. Ann Emerg Med 62:244–251CrossRefGoogle Scholar