Mephedrone (4-Methylmethcathinone): Acute Behavioral Effects, Hyperthermic, and Pharmacokinetic Profile in Rats

Abstract

Mephedrone (MEPH) is a synthetic cathinone derivative with effects that mimic MDMA and/or cocaine. Our study in male Wistar rats provides detailed investigations of MEPH's and its primary metabolite nor-mephedrone's (nor-MEPH) pharmacokinetics and bio-distribution to four different substrates (serum, brain, lungs, and liver), as well as comparative analysis of their effects on locomotion [open field test (OFT)] and sensorimotor gating [prepulse inhibition of acoustic startle reaction (PPI ASR)]. Furthermore, in order to mimic the crowded condition where MEPH is typically taken (e.g., clubs), the acute effect of MEPH on thermoregulation in singly- and group-housed rats was evaluated. Pharmacokinetics of MEPH and nor-MEPH after MEPH (5 mg/kg, sc.) were analyzed over 8 h using liquid chromatography with mass spectrometry. MEPH (2.5, 5, or 20 mg/kg, sc.) and nor-MEPH (5 mg/kg, sc.) were administered 5 or 40 min before the behavioral testing in the OFT and PPI ASR; locomotion and its spatial distribution, ASR, habituation and PPI itself were quantified. The effect of MEPH on rectal temperature was measured after 5 and 20 mg/kg, sc. Both MEPH and nor-MEPH were detected in all substrates, with the highest levels detected in lungs. Mean brain: serum ratios were 1:1.19 (MEPH) and 1:1.91 (nor-MEPH), maximum concentrations were observed at 30 min; at 2 and 4 h after administration, nor-MEPH concentrations were higher compared to the parent drug. While neither of the drugs disrupted PPI, both increased locomotion and affected its spatial distribution. The effects of MEPH were dose dependent, rapid, and short-lasting, and the intensity of locomotor stimulant effects was comparable between MEPH and nor-MEPH. Despite the disappearance of behavioral effects within 40 min after administration, MEPH induced rectal temperature elevations that persisted for 3 h even in singly housed rats. To conclude, we observed a robust, short-lasting, and most likely synergistic stimulatory effect of both drugs which corresponded to brain pharmacokinetics. The dissociation between the duration of behavioral and hyperthermic effects is indicative of the possible contribution of nor-MEPH or other biologically active metabolites. This temporal dissociation may be related to the risk of prolonged somatic toxicity when stimulatory effects are no longer present.

Keywords: 4-methylmethcathinone; Wistar rat; mephedrone; nor-mephedrone; open field; pharmacokinetics; prepulse inhibition; thermoregulation.

Figure 1

Mean mephedrone (MEPH) (A) and its metabolite nor-mephedrone (B) levels in serum, brain, lungs, and liver over 6 h after application of MEPH 5 mg/kg sc. Error bars display ±1 SEM.

Figure 2

Open field test (OFT): mean trajectory length (divided into 5-min blocks) by testing-onsets [5 and 40 min; (A) and (B), respectively] and drug treatments [vehicle controls (VEH), mephedrone (MEPH) 2.5, 5, and 20 mg/kg and nor-mephedrone (nor-MEPH 5 mg/kg)]. Compared to VEH, significant hyperactivity (p < 0.001 for all drug groups and in all time blocks) was present at the 5-min testing-onset (A), however the treatment effects were no longer significant at the 40 min testing-onset (B). Error bars display ±1 SEM. Picture inserts below (C) show typical trajectory patterns induced by the treatment in animals with 5-min testing-onset.

Figure 3

Mean time spent in the arena center [T_center, (A)] and mean probability of appearance in peripheral zones [thigmotaxis, (B)] after vehicle controls (VEH), mephedrone (MEPH) 2.5, 5, and 20 mg/kg, and nor-mephedrone (nor-MEPH) 5 mg/kg administered at the 5-min testing-onset. MEPH 2.5 and 5 mg/kg-treated rats spent significantly more time in the central zones compared to VEH, and thigmotaxis was decreased by MEPH 5 mg/kg and nor-MEPH 5 mg/kg, and increased by MEPH 20 mg/kg. Error bars display ±1 SEM. ***p < 0.001 compared to VEH.

Figure 4

Mean rectal temperature (°C) over 10 h after vehicle control (VEH), and mephedrone (MEPH) 5 and 20 mg/kg treatments for rats housed singly (A) or in groups of five (B). Substances were administered at 09:00 h. Temperatures of rats treated by 5 mg/kg did not differ from VEH, except for the short-term elevation in the first 30 min after the administration in group-housed rats. The increase induced by 20 kg/kg was maintained from 10:00 to 12:00 h in singly housed rats and from 09:30 to 11:00 h in group-housed rats. Error bars display ±1 SEM. *p < 0.05, ***p < 0.001 compared to VEH.