Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone
- 61 Downloads
The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused.
Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1–3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1–3 receptor antagonists were examined in both groups.
Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline.
In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates.
A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.
KeywordsDrug discrimination Ketanserin MDMA Mephedrone Methamphetamine Psychostimulants Rats SB242084 SCH23390 Sulpiride
The authors wish to thank Drs. Ellen Unterwald and Sara Jane Ward for their intellectual contributions and initial readings of this manuscript. Funding sources: R21DA032718, R01DA039139 and P30 DA013429-16.
- Aarde SM, Angrish D, Barlow DJ, Wright MJ Jr, Vandewater SA, Creehan KM et al (2013) Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats. Addict Biol. 2013 18:786–799Google Scholar
- 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. 37:1192–1203CrossRefGoogle Scholar
- Baumann MH, Walters HM, Niello M, Sitte HH (2018) Neuropharmacology of synthetic cathinones. Handb Exp Pharmacol Nov 8. https://doi.org/10.1007/164_2018_178
- Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS (2015) Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues. Br J Pharmacol 172(10):2433–2444. https://doi.org/10.1111/bph.13030 CrossRefGoogle Scholar
- Gregg RA, Baumann MH, Partilla JS, Bonano JS, Vouga A, Tallarida CS, Velvadapu V, Smith GR, Peet MM, Reitz AB, Negus SS, Rawls SM (2015) Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats. Brit J Pharmacol 72(3):883–894CrossRefGoogle Scholar
- Philogene-Khalid HL, Simmons SJ, Nayak S, Martorana RM, Su SH, Caro Y, Ranieri B, DiFurio K, Mo L, Gentile TA, Murad A, Reitz AB, Muschamp JW, Rawls SM (2017a) Stereoselective differences between the reinforcing and motivational effects of cathinone-derived 4-methylmethcathinone (Mephedrone) in self-administering rats. ACS Chem Neurosci 8(12):2648–2654. https://doi.org/10.1021/acschemneuro.7b00212 CrossRefGoogle Scholar
- Philogene-Khalid HL, Smith GR, Reitz AB, Liu-Chen L, Rawls SM (2017b) S enantiomer of the synthetic cathinone mephedrone reduces anxiety- and depressant-like effects caused by cocaine or MDPV withdrawal in rats. Drug Alcohol Depend 178:119–125. https://doi.org/10.1016/j.drugalcdep.2017.04.024 CrossRefGoogle Scholar
- Pigott A, Frescas S, McCorvy JD, Huang XP, Roth BL, Nichols DE (2012) Trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT(2) receptor family. Beilstein J Org Chem 8:1705–1709. https://doi.org/10.3762/bjoc.8.194 CrossRefGoogle Scholar
- Roth BL, Driscol J (2018) PDSP Ki database. Psychoactive drug screening program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 26 November 2018Google Scholar
- Schenk S, Highgate Q (2018) Dopamine and serotonin antagonists fail to alter the discriminative stimulus properties of ±methylenedioxymethamphetamine. Behav Pharmacol. https://doi.org/10.1097/FBP.0000000000000442
- Smith DA, Negus SS, Poklis JL, Blough BE, Banks ML (2016) Cocaine-like discriminative stimulus effects of alpha- pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys. Addict Biol 22:1169–1178. https://doi.org/10.1111/adb.12399 CrossRefGoogle Scholar
- Suyama JA, Sakloth F, Kolanos R, Glennon RA, Lazenka MF, Negus SS, Banks ML (2016) Abuse-related neurochemical effects of para-substituted methcathinone analogs in rats: microdialysis studies of nucleus accumbens dopamine and serotonin. J Pharmacol Exp Ther 36:182–190Google Scholar