Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors.
Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors.
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哌甲酯对谷氨酸受体和行为产生剂量依赖性影响。
DOI：
10.1016/j.biopsych.2014.04.003
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发表时间：
2014-12-15
影响因子：
10.6
通讯作者：
Yan Z
中科院分区：
文献类型：
--
作者：
Cheng J;Xiong Z;Duffney LJ;Wei J;Liu A;Liu S;Chen GJ;Yan Z
哌醋甲酯（MPH）是一种用于治疗注意力缺陷多动障碍（ADHD）的精神兴奋剂药物，可以提高警觉性和注意力，但滥用哌醋甲酯会增加攻击性和精神病的风险。在这项研究中，我们试图确定MPH复杂作用的分子机制。给青春期（4周龄）大鼠注射不同剂量的MPH。测定了MPH对前额皮质锥体神经元谷氨酸能信号传导的影响。mph诱导的行为改变也被平行检查。我们发现，低剂量（0.5 mg/kg） MPH通过肾上腺素能受体激活选择性地增强了NMDAR介导的兴奋性突触电流（EPSCs），而高剂量（10 mg/kg） MPH同时抑制了NMDAR-和AMPAR-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。行为学测试还显示，低剂量MPH促进了pfc介导的时间顺序识别记忆（TORM）和注意，而高剂量MPH注射的动物表现出显著提高的机车活动。抑制参与NMDAR胞吐的关键SNARE蛋白SNAP-25的功能，可以阻断低剂量MPH对NMDAR- epsc的增加。在反复应激的动物中，低剂量MPH通过依赖于SNAP-25的机制有效地恢复了NMDAR功能和TORM。我们的研究结果为低剂量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的机制。
Methylphenidate (MPH), a psychostimulant drug for the treatment of attention-deficit hyperactivity disorder (ADHD), produces the effects of increasing alertness and improving attention, while its misuse has been associated with an increased risk of aggression and psychosis. In this study, 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 (PFC) was measured. MPH-induced behavioral changes were also examined in parallel. We found that administration of low-dose (0.5 mg/kg) MPH selectively potentiated NMDAR-mediated excitatory synaptic currents (EPSCs) via adrenergic receptor activation, while the high-dose (10 mg/kg) MPH suppressed both NMDAR- and AMPAR-EPSCs. The dual effects of MPH on EPSCs were associated with bi-directional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated the PFC-mediated temporal order recognition memory (TORM) and attention, while animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of SNAP-25, a key SNARE proteins involved in NMDAR exocytosis, blocked the increase of NMDAR-EPSC by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and TORM via a mechanism dependent on SNAP-25. Our results have provided a potential mechanism underlying the cognitive enhancing effects of low-dose MPH, as well as the psychosis-inducing effects of high-dose MPH.
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影响因子：
11
作者：
Etain, B.;Dumaine, A.;Jamain, S.
通讯作者：
Jamain, S.
影响因子：
10.6
作者：
Fernandez, Alberto;Quintero, Javier;Ortiz, Tomas
通讯作者：
Ortiz, Tomas
影响因子：
5.5
作者：
Cheng, Jia;Liu, Wenhua;Yan, Zhen
通讯作者：
Yan, Zhen
影响因子：
3.4
作者：
Elliott, R;Sahakian, BJ;Robbins, TW
通讯作者：
Robbins, TW
影响因子：
2.8
作者：
ALBURGES, ME;HUNT, ME;WAMSLEY, JK
通讯作者：
WAMSLEY, JK