Klára Šíchová, Nikola Pinterová, Monika Židková, Rachel R. Horsley, Eva Lhotková, Kristýna Štefková, Čestmír Vejmola, Libor Uttl, Marie Balíková, Martin Kuchař, Tomáš Páleníček
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.
Pharmacology, Toxicology and Pharmaceutical Science
7
14%
Psychology
4
8%
Medicine and Dentistry
4
8%
Agricultural and Biological Sciences
3
6%
Other
6
12%
Unknown
14
27%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 January 2018.
All research outputs
#15,486,175
of 23,012,811 outputs
Outputs from Frontiers in Psychiatry
#5,836
of 10,145 outputs
Outputs of similar age
#270,753
of 443,273 outputs
Outputs of similar age from Frontiers in Psychiatry
#73
of 112 outputs
Altmetric has tracked 23,012,811 research outputs across all sources so far. This one is in the 22nd percentile – i.e., 22% of other outputs scored the same or lower than it.
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We're also able to compare this research output to 112 others from the same source and published within six weeks on either side of this one. This one is in the 30th percentile – i.e., 30% of its contemporaries scored the same or lower than it.
