Department of Pharmacodynamics, Medical University of Lodz, 90-151, Lodz, Poland.
Neurotox Res. 2020 Aug;38(2):536-551. doi: 10.1007/s12640-020-00227-8. Epub 2020 Jun 6.
Two chloromethcathinones, 3-chloromethcathinone (3-CMC) and 4-chloromethcathinone (4-CMC), and two para-substituted α-pyrrolidinophenones, 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-PVP) and 4-fluoro-α-pyrrolidinopentiophenone (4-F-PVP), represent synthetic cathinones, the second most frequently abused group of new psychoactive substances (NPSs), which has aroused a worldwide health concern in the last decade. Synthetic cathinones act as psychostimulants by elevating extracellular levels of monoaminergic neurotransmitters. This study investigates effects of 3-CMC, 4-CMC, 4-MeO-PVP, and 4-F-PVP on the spontaneous locomotor activity and motor performance of mice. Additionally, neurotoxicity of substituted methcathinones against SH-SY5Y neuroblastoma cells was evaluated. All test cathinones stimulate in a dose-dependent manner horizontal locomotor activity of mice. Consistently to our prior findings, pyrrovalerones, but not methcathinone derivatives, produce dose-dependent elevation of vertical locomotor activity (rearing behavior). None of the tested compounds decreases the time spent on the accelerating rotarod, pointing to the lack of considerable motor disability in mice after acute exposition. Only 4-MeO-PVP at the high tested dose (20 mg/kg) increases motor performance of mice. Considering that α-pyrrolidinophenones are highly potent and selective DA uptake inhibitors, while chloromethcathinones enhance non-selective DA/5-HT release, we suggest that the increase of vertical locomotor activity and performance on rotarod in mice may serve as a behavioral indicator of the monoaminergic profile of synthetic cathinones. Finally, this study gives first insights into cytotoxicity of both 3-CMC and 4-CMC displayed against SH-SY5Y cells, which emerges and intensifies after prolonged incubation, suggesting the indirect mechanism of action, unrelated to interactions with monoamine transporters.
两种氯甲卡西酮，即 3-氯甲卡西酮（3-CMC）和 4-氯甲卡西酮（4-CMC），以及两种对取代的α-吡咯烷苯丙酮，即 4-甲氧基-α-吡咯烷戊基苯丙酮（4-MeO-PVP）和 4-氟-α-吡咯烷戊基苯丙酮（4-F-PVP），代表合成卡西酮，这是新精神活性物质（NPS）中第二大滥用群体，在过去十年中引起了全球健康关注。合成卡西酮通过提高单胺能神经递质的细胞外水平而起作用。本研究调查了 3-CMC、4-CMC、4-MeO-PVP 和 4-F-PVP 对小鼠自发运动活动和运动表现的影响。此外，还评估了取代的甲卡西酮对 SH-SY5Y 神经母细胞瘤细胞的神经毒性。所有测试的卡西酮均以剂量依赖性方式刺激小鼠的水平运动活动。与我们之前的发现一致，吡咯烷酮，但不是甲卡西酮衍生物，会导致垂直运动活动（竖起行为）呈剂量依赖性增加。在加速旋转棒上花费的时间没有减少，这表明在急性暴露后，小鼠没有明显的运动障碍。只有 4-MeO-PVP 在测试的高剂量（20mg/kg）下会增加小鼠的运动表现。考虑到α-吡咯烷苯丙酮是高度有效和选择性的 DA 摄取抑制剂，而氯甲卡西酮增强非选择性 DA/5-HT 释放，我们认为，在小鼠中增加垂直运动活动和在旋转棒上的表现可以作为合成卡西酮单胺能谱的行为指标。最后，本研究首次揭示了 3-CMC 和 4-CMC 对 SH-SY5Y 细胞的细胞毒性，这种毒性在延长孵育后出现并加剧，表明其作用机制是间接的，与单胺转运体无关。
