Šíchová Klára, Pinterová Nikola, Židková Monika, Horsley Rachel R, Lhotková Eva, Štefková Kristýna, Vejmola Čestmír, Uttl Libor, Balíková Marie, Kuchař Martin, Páleníček Tomáš
Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic.
Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Front Psychiatry. 2018 Jan 10;8:306. doi: 10.3389/fpsyt.2017.00306. eCollection 2017.
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.
4-甲基甲卡西酮（MEPH）是一种合成卡西酮衍生物，其作用类似于摇头丸和/或可卡因。我们对雄性Wistar大鼠进行的研究详细调查了MEPH及其主要代谢物去甲-4-甲基甲卡西酮（nor-MEPH）在四种不同底物（血清、脑、肺和肝）中的药代动力学和生物分布，以及它们对运动[旷场试验（OFT）]和感觉运动门控[惊吓反应前脉冲抑制（PPI ASR）]影响的比较分析。此外，为了模拟通常服用MEPH的拥挤环境（如俱乐部），评估了MEPH对单笼饲养和群居大鼠体温调节的急性影响。采用液相色谱-质谱联用技术分析了腹腔注射MEPH（5mg/kg）后8小时内MEPH和nor-MEPH的药代动力学。在OFT和PPI ASR行为测试前5或40分钟，分别腹腔注射MEPH（2.5、5或20mg/kg）和nor-MEPH（5mg/kg）；对运动及其空间分布、ASR、习惯化和PPI本身进行定量。腹腔注射5和20mg/kg MEPH后，测量其对直肠温度的影响。在所有底物中均检测到MEPH和nor-MEPH，其中肺中的含量最高。脑与血清的平均比值分别为1:1.19（MEPH）和1:1.91（nor-MEPH），给药后30分钟观察到最大浓度；给药后2和4小时，nor-MEPH的浓度高于母体药物。两种药物均未破坏PPI，但均增加了运动并影响其空间分布。MEPH的作用具有剂量依赖性、起效快且持续时间短，MEPH和nor-MEPH的运动刺激作用强度相当。尽管给药后40分钟内行为效应消失，但即使是单笼饲养的大鼠，MEPH诱导的直肠温度升高仍持续3小时。总之，我们观察到两种药物均具有强烈、短暂且很可能是协同的刺激作用，这与脑药代动力学情况相符。行为效应和体温过高效应持续时间的分离表明nor-MEPH或其他生物活性代谢物可能起了作用。当刺激效应不再存在时，这种时间上的分离可能与长期躯体毒性风险有关。
