TL neuro

January 9, 2015

Mephedrone is more reinforcing than methylone or MDMA in female rats

Filed under: 4-MMC/Mephedrone, Cathinones, IVSA, MDMA, Methylone — mtaffe @ 9:27 am

A paper from the laboratory on the self-administration of MDMA-like cathinone drugs has been recently accepted for publication published online.

Creehan, K.M., Vandewater, S.A. and Taffe, M.A. Intravenous self-administration of mephedrone, methylone and MDMA in female rats. Neuropharmacology, 2015, 92:90-97. DOI: 10.1016/j.neuropharm.2015.01.003 [Publisher Link, PubMed]


This paper is the result of our “Open Experiment in Open Experimenting” which is chronicled on the linked page.
StructureFig-MDMA-Methylone-MephedroneBackground 1: Cathinones, aka “bathsalts”
There are a number of synthetic cathinone stimulants that are in reasonably substantial and continued use in the US, as well as elsewhere worldwide. Cathinone, the core molecule differs from amphetamine in the addition of a ketone in the beta position. In the figure, 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) can be contrasted with its cathinone cousing Methylone, which might otherwise be called 3,4-methylenedioxymethcathinone. If you see Methylone referred to as “bk-MDMA”, as it sometimes is with users, you will now be able to recognize what “beta-keto-MDMA” means. Mephedrone more or less led the emergence of substituted cathinones with one death noted in Sweden in 2008 and a major increase in prevalence in the UK throughout 2009 and 2010. To my view there has never been a major place in the recreational pharmacopeia for 4-methylmethamphetamine, the amphetamine cousin of mephedrone.

Background 2: Empathogenic or MDMA-like neuropharmacology
We have described in prior posts how mephedrone exhibits an MDMA-like trait of preferentially increasing serotonin versus dopamine overflow in the nucleus accumbens of rats; this is different from the dopamine-dominant response to methamphetamine or amphetamine. This pattern has been proposed to be intimately related to the fact that MDMA is only an uncertain reinforcer in rodent IVSA compared with the more typical amphetamines. Mephedrone is much more readily self-administered than MDMA and a single prior report seemed to indict that methylone likewise is an effective reinforcer in IVSA.

Background 3: Female animals
The NIH has recently issue a policy position which reinforces the critical importance of conducting sex-difference comparisons across biomedical domains (Clayton and Collins 2014). It has been shown that female rats will self-administer more cocaine (Roth and Carroll 2004b; Smith et al. 2011) and more methamphetamine (Reichel et al. 2012; Roth and Carroll 2004a) than males; these sex differences can be more pronounced under long-access escalation and/or Progressive Ratio procedures. Little is known about any possible sex differences in the self-administration of atypical stimulants like MDMA or the recently emerging MDMA-like designer cathinones. In short, we couldn’t find a single report of IVSA of any of these compounds in female rats (although Oakly et al, 2014 fails to specify the sex). Thus, the present study was conducted in female rats to expand understanding of the comparative reinforcing properties of these compounds.

Creehan15-Fig2-infusionsThis figure from the paper (click to enlarge) illustrates the number of infusions of drug obtained by three groups of female Wistar rats during the acquisition phase of intravenous self-administration (IVSA). Each group was trained on a different drug. The take-away messages is in the upper panel. At equal training doses the rats trained on mephedrone (4-methylmethcathinone, 4-MMC) take more infusions across the training interval. [Significant difference from the first session within group by *, Between mephedrone and both other groups by #, versus methylone by ‡ and versus MDMA by †.].
The bottom two panels of the figure split the groups into the upper and lower halves based on average drug intake during the acquisition interval. The point of doing so is that the Schenk lab studies (here, here) have shown that ~40-50 percent of (male, normal or wild-type) rats will fail to meet their acquisition criteria for MDMA IVSA. This is unusual for stimulant IVSA- something like 80-100% would be more typical for cocaine. Instead of creating arbitrary “acquisition” criteria, we chose to report subgroup analyses (the paper also contains drug-associated lever discrimination ratio information). Mephedrone was still preferred by the lower-preference animals and we illuminated a small advantage for methylone IVSA in the more-preferring Upper Half compared with the MDMA trained animals.

This direct comparison paper verifies a picture which has been emerging with the nascent IVSA literature on mephedrone- i.e., that it is clearly more effective as a reinforcer compared with MDMA. This points back to the neuropharmacological effects outlined above (enhanced serotonin response in nucleus accumbens of rats) and raises new questions about the relevance of such properties in predicting abuse liability. Together, these behavioral findings oppose a claim advanced by Bonano and colleagues (2014) on the basis of intracranial self-stimulation reward data that mephedrone has decreased abuse liability relative to methylone and MDMA.

There is only the single other paper on methylone IVSA and our results do not concur with the findings of Watterson et al (2012). Obviously there are methodological differences so additional experiments will be needed to gain better clarity on the propensity of methylone to support IVSA compared with MDMA and mephedrone. There was a hint in our data that for the more-preferring animals methylone might be slightly superior to MDMA as a reinforcer. So it isn’t impossible that some methodological issues might uncover a larger methylone/MDMA difference.


Relevant Literature
Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA. The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology. 2013 Aug;71:130-40. doi: 10.1016/j.neuropharm.2013.04.003. Epub 2013 Apr 15. [PMC (free) Link]

Aarde SM, Angrish D, Barlow DJ, Wright MJ Jr, Vandewater SA, Creehan KM, Houseknecht KL, Dickerson TJ, Taffe MA. Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats. Addict Biol. 2013 Sep;18(5):786-99. doi: 10.1111/adb.12038. Epub 2013 Jan 30.[PMC (free) Link]

Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509: 282-3

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. The Journal of pharmacology and experimental therapeutics, 339 (2), 530-6 PMID: 21810934

Motbey CP1, Clemens KJ, Apetz N, Winstock AR, Ramsey J, Li KM, Wyatt N, Callaghan PD, Bowen MT, Cornish JL, McGregor IS.High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine.J Psychopharmacol. 2013 Sep;27(9):823-36. doi: 10.1177/0269881113490325. Epub 2013 Jun 5.

Roth ME, Carroll ME (2004a) Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology 172: 443-449

Roth ME, Carroll ME (2004b) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78: 199-207

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 S9:002: 1-8


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