Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats
3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called “bath salts” products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT).
We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV.
To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats.
MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT.
Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans.
Keywords3,4-Methylenedioxypyrovalerone (MDPV) Methylone Cocaine Self-administration Microdialysis Rats
This research was supported by the Intramural Research Program of NIH, NIDA. The authors have no conflicts of interest to report. We dedicate this paper to our colleague and friend Steven R. Goldberg who passed away suddenly on November 25, 2014.
- 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 37:1192–203CrossRefPubMedPubMedCentralGoogle Scholar
- 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 38:552–62CrossRefPubMedPubMedCentralGoogle Scholar
- Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology (Berl) 231:199–207CrossRefGoogle Scholar
- Drug Enforcement Administration (2011) Schedules of controlled substances: temporary placement of three synthetic cathinones in schedule I. Final order. Fed Regist 76:65371–65375Google Scholar
- Drug Enforcement Administration (2013) Establishment of drug codes for 26 substances. Final rule. Fed Regist 78:664–666Google Scholar
- Drug Enforcement Administration (2014) National Forensic Laboratory Information System Special Report: Synthetic Cannabinoids and Synthetic Cathinones Reported in NFLIS, 2010–2013. U.S. Drug Enforcement Administration, Springfield, VA URL: https://www.nflis.deadiversion.usdoj.gov/DesktopModules/ReportDownloads/Reports/NFLIS_SR_CathCan_508.pdf
- Panlilio LV, Katz JL, Pickens RW, Schindler CW (2003) Variability of drug self-administration in rats. Psychopharmacology (Berl) 167:9–19Google Scholar
- Seely KA, Patton AL, Moran CL, Womack ML, Prather PL, Fantegrossi WE, Radominska-Pandya A, Endres GW, Channell KB, Smith NH, McCain KR, James LP, Moran JH (2013) Forensic investigation of K2, Spice, and “bath salt” commercial preparations: a three-year study of new designer drug products containing synthetic cannabinoid, stimulant, and hallucinogenic compounds. Forensic Sci Int 233:416–22CrossRefPubMedGoogle Scholar
- Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT, Wegner S, Blough BE, Marusich JA, Olive MF (2012) The reinforcing and rewarding effects of methylone, a synthetic cathinone commonly found in “bath salts”. J Addict Res Ther S9:002Google Scholar
- World Health Organization (2015). WHO expert committee on drug dependence: thirty-sixth report. WHO Technical Report Series no. 991. Geneva, Switzerland . URL: http://apps.who.int/iris/bitstream/10665/153834/1/WHO_TRS_991_eng.pdf?ua=1
- Wright MJ Jr, Angrish D, Aarde SM, Barlow DJ, Buczynski MW, Creehan KM, Vandewater SA, Parsons LH, Houseknecht KL, Dickerson TJ, Taffe MA (2012) Effect of ambient temperature on the thermoregulatory and locomotor stimulant effects of 4-methylmethcathinone in Wistar and Sprague-Dawley rats. PLoS One 7:e44652CrossRefPubMedPubMedCentralGoogle Scholar