Department of Pharmacology and Pharmacodynamics, Medical University, 20-093 Lublin, Poland.
Department of Drug Addiction Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland.
Int J Mol Sci. 2021 Jan 8;22(2):589. doi: 10.3390/ijms22020589.
A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71-84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone-but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.
一种合成卡西酮，即甲卡西酮，被青少年和年轻人广泛滥用。尽管它被广泛使用，但对于其对认知功能的长期影响知之甚少。因此，我们首次评估了以下两种情况：（A）青春期（PND40）期间重复使用甲卡西酮（30mg/kg，腹腔注射，每天一次，共 10 天）是否会导致成年（PND71-84）大鼠的空间记忆和反转学习（巴恩斯迷宫任务）受损；以及（B）这些影响是否与安非他命（2.5mg/kg，腹腔注射）相当。此外，还评估了这些药物对成年大鼠中 MMP-9、NMDA 受体亚基（GluN1、GluN2A/2B）和 PSD-95 蛋白表达的影响。这些药物的作用是在自身诱导大鼠产生奖励/强化作用的剂量下进行评估的。结果显示，在青春期接受甲卡西酮/安非他命的成年大鼠出现空间记忆缺陷（安非他命的延迟作用）和反转学习缺陷。然而，反转学习缺陷实际上可能是由于空间学习而不是认知灵活性受损所致。此外，甲卡西酮而非安非他命以延迟发作的方式增强了前额叶皮层和海马中的 MMP-9 水平。青春期给予甲卡西酮会导致年轻成年（PND63）和成年（PND87）大鼠前额叶皮层和海马中 MMP-9 水平改变和 GluN2B 包含的 NMDA 受体上调。最后，在成年大鼠中，前额叶皮层的 PSD-95 表达增加，而海马中的 PSD-95 表达减少。相比之下，在青春期暴露于安非他命的成年大鼠中，海马中的 GluN2A 亚基和 PSD-95 表达减少（下调）。因此，在甲卡西酮治疗的大鼠中，空间记忆的损伤与 MMP-9 水平的变化有关。由于含有 GluN2B 的 NMDA 受体在青春期占主导地位，因此与安非他命相比，甲卡西酮似乎在这段生命时期对认知产生更有害的影响。
