Cheng Jia, Xiong Zhe, Duffney Lara J, Wei Jing, Liu Aiyi, Liu Sihang, Chen Guo-Jun, Yan Zhen
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Biol Psychiatry. 2014 Dec 15;76(12):953-62. doi: 10.1016/j.biopsych.2014.04.003. Epub 2014 Apr 12.
Methylphenidate (MPH), a psychostimulant drug used to treat attention-deficit/hyperactivity disorder, produces the effects of increasing alertness and improving attention. However, misuse of MPH has been associated with an increased risk of aggression and psychosis. We sought to determine the molecular mechanism underlying the complex actions of MPH.
Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex was measured. Behavioral changes induced by MPH were also examined in parallel.
Administration of low-dose (.5 mg/kg) MPH selectively potentiated N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) via adrenergic receptor activation, whereas high-dose (10 mg/kg) MPH suppressed both NMDAR-mediated and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated EPSCs. The dual effects of MPH on EPSCs were associated with bidirectional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated prefrontal cortex-mediated temporal order recognition memory and attention. Animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of synaptosomal-associated protein 25, a key SNARE protein involved in NMDAR exocytosis, blocked the increase of NMDAR-mediated EPSCs by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and temporal order recognition memory via a mechanism dependent on synaptosomal-associated protein 25.
These results provide a potential mechanism underlying the cognitive-enhancing effects of low-dose MPH as well as the psychosis-inducing effects of high-dose MPH.
哌甲酯（MPH）是一种用于治疗注意力缺陷/多动障碍的精神兴奋药物，具有提高警觉性和改善注意力的作用。然而，MPH的滥用与攻击行为和精神病风险增加有关。我们试图确定MPH复杂作用背后的分子机制。
给青春期（4周龄）大鼠注射不同剂量的MPH一次。测量MPH对前额叶皮层锥体神经元谷氨酸能信号传导的影响。同时也检测了MPH诱导的行为变化。
低剂量（0.5mg/kg）MPH通过肾上腺素能受体激活选择性增强N-甲基-D-天冬氨酸受体（NMDAR）介导的兴奋性突触后电流（EPSCs），而高剂量（10mg/kg）MPH则抑制NMDAR介导的和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的EPSCs。MPH对EPSCs的双重作用与谷氨酸受体亚基表面水平的双向变化有关。行为测试还表明，低剂量MPH促进前额叶皮层介导的时间顺序识别记忆和注意力。注射高剂量MPH的动物表现出明显升高的运动活性。抑制突触体相关蛋白25（一种参与NMDAR胞吐作用的关键SNARE蛋白）的功能，可阻断低剂量MPH引起的NMDAR介导的EPSCs增加。在反复应激的动物中，低剂量MPH给药通过依赖突触体相关蛋白25的机制有效恢复NMDAR功能和时间顺序识别记忆。
这些结果为低剂量MPH的认知增强作用以及高剂量MPH的精神病诱导作用提供了潜在机制。
