Chen Yang, Zhang Libo, Ding Zengbo, Wu Xianwen, Wang Guibin, Shi Jie
National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Front Mol Neurosci. 2022 Jul 22;15:975820. doi: 10.3389/fnmol.2022.975820. eCollection 2022.
3-Methylmethcathinone (3-MMC), a drug belonging to synthetic cathinones family, raised public attention due to its harmful health effects and abuse potential. Although it has similar properties to other cathinone derivatives, the behavioral effects of 3-MMC remain largely unknown. In the present research, we evaluated the rewarding effect of 3-MMC using conditioned place preference (CPP) paradigm and its effect on anxiety-like behavior using elevated plus maze (EPM) and compared with methamphetamine (METH). Then, we performed a whole-brain c-Fos mapping to identify the specific brain regions in response to 3-MMC exposure and explored the changes of synaptic transmission in nucleus accumbens (NAc) using patch-clamp recording after chronic 3-MMC and METH exposure. 3-MMC induced CPP at higher doses of 3 or 10 mg/kg in rats and acute exposure of 3 mg/kg 3-MMC to rats produced anxiolytic-like effect, while anxiety-like behavior was increased after 7 days of injection with 3-MMC. Whole-brain immunostaining revealed increased c-Fos expression in anterior cingulate cortex (ACC), NAc and ventral tegmental area (VTA) after chronic 3-MMC injection compared with saline, which was similar to METH. Especially, 3-MMC induced more neural activation of VTA compared with METH. Finally, we found that amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in NAc was decreased after chronic 3-MMC injection, while frequency of sIPSCs and spontaneous excitatory postsynaptic currents (sEPSCs) were not affected. Taken together, our results revealed the addictive potential of 3-MMC and its effect on anxiety-like behavior, which warn the risks of 3-MMC abuse and justify the control of synthetic cathinones. And 3-MMC selectively inhibit inhibitory but not excitatory transmission onto neurons in NAc, which may contribute to its effects.
3-甲基甲卡西酮（3-MMC）是一种属于合成卡西酮类的药物，因其对健康的有害影响和滥用潜力而引起了公众的关注。尽管它与其他卡西酮衍生物具有相似的特性，但3-MMC的行为效应在很大程度上仍不清楚。在本研究中，我们使用条件性位置偏爱（CPP）范式评估了3-MMC的奖赏效应，并使用高架十字迷宫（EPM）评估了其对焦虑样行为的影响，并与甲基苯丙胺（METH）进行了比较。然后，我们进行了全脑c-Fos映射，以确定对3-MMC暴露有反应的特定脑区，并在慢性3-MMC和METH暴露后使用膜片钳记录探索伏隔核（NAc）中突触传递的变化。3-MMC在大鼠中以3或10mg/kg的较高剂量诱导CPP，急性给予大鼠3mg/kg的3-MMC产生抗焦虑样效应，而在注射3-MMC7天后焦虑样行为增加。全脑免疫染色显示，与生理盐水相比，慢性注射3-MMC后前扣带回皮质（ACC）、NAc和腹侧被盖区（VTA）中的c-Fos表达增加，这与METH相似。特别是，与METH相比，3-MMC诱导VTA的神经激活更多。最后，我们发现慢性注射3-MMC后NAc中自发抑制性突触后电流（sIPSCs）的幅度降低，而sIPSCs的频率和自发兴奋性突触后电流（sEPSCs）不受影响。综上所述，我们的结果揭示了3-MMC的成瘾潜力及其对焦虑样行为的影响，这警示了3-MMC滥用的风险，并证明了对合成卡西酮进行管控的合理性。并且3-MMC选择性抑制NAc中神经元上的抑制性而非兴奋性传递，这可能是其产生作用的原因。
