Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats

Abstract

Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact it was not criminalized until April of 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self-administer 4-MMC in one hour sessions. Per infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2–3 mg/kg/hr. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were employed to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found the T1/2 of 4-MMC was about an hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4-MMC in the traditional preclinical self-administration model.

Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone

“…These repeated injection studies also used a rectal probe to measure the response at 1 hour intervals so the observed hyperthermia may have resulted from an additive effect of repeated mephedrone injection combined with stress-induced hyperthermia associated with rectal measurement as evident in vehicle control animals (Baumann et al, 2012;Hadlock et al, 2011). The current study therefore used radiotelemetry to measure the temperature response following repeated mephedrone injection and showed it produced hypothermia as reported following a single injection (Aarde et al, 2013;Miller et al, 2012). In the current study, 5,7-DHT administration abolished the hypothermic response to mephedrone.…”

“…This is one of only a few studies to use radiotelemetry to obtain a high temporal resolution of changes appropriate for the shortduration responses (Aarde et al, 2013;Miller et al, 2012;Wright et al, 2012). The main findings were as follows; (1) while hyperactivity and increase in extracellular striatal dopamine seen after the first mephedrone injection were similar in magnitude and time course to those seen following the second and third injections, the hypothermia was attenuated with repeated dosing; (2) extracellular striatal 5-HT overflow was more variable but was enhanced when second and third injections were given when compared with the first response; (3) 6-OHDA did not affect hyperactivity but reduced the duration of the hypothermic response; (4) 5,7-DHT administration and 5-HT 1B receptor antagonism attenuated mephedrone-induced hyperactivity; (5) 5,7-DHT administration completely abolished, and 5-HT 1A receptor antagonism attenuated mephedrone-induced hypothermia.…”

“…Most studies show the acute effect of a single injection, or self-administration of mephedrone in the rat is hypothermia (Aarde et al, 2013;Miller et al, 2013;Shortall et al, 2013a), but hyperthermia has also been reported following rapid repeated dosing (Baumann et al, 2012;Hadlock et al, 2011). Given the established association of hyperthermia with life-threatening adverse effects of MDMA (Docherty and Green, 2010), it is essential to see if there might be a similar adverse risk with repeated mephedrone.…”

Mephedrone, Methylone and 3,4‐Methylenedioxypyrovalerone (MDPV) Induce Conditioned Place Preference in Mice

“…Mephedrone and MDPV have been shown to be self-administered when given to rats [22,23,26,45,46]. The information currently available about the human effects of these drugs of abuse is very limited.…”

“…However, in another study, methylone did not show an effect of dose on ICSS thresholds even if a trend was observed [25]. Studies have shown that mephedrone and methylone are locomotor stimulants [11,12,[26][27][28].…”