| Methylphenidate (MPH) is widely used as a therapeutic drug for Attention Deficit Hyperactivity Disorder. Extensive behavioral and pharmacological studies have shown that MPH improves cognitive functions in ADHD patients. Such beneficial effects can be also seen in normal humans and animals. The therapeutic effect of MPH is produced via blocking dopamine reuptake transporters and increasing the concentration of dopamine in synaptic cleft. However, little is known about the cellular mechanism underlying MPH enhancement of cognitive functions. The present study employed behavioral pharmacological and Western blot techniques to investigate the cellular mechanism underlying MPH improvement of PFC-dependent working memory in rats.1. Working memory capacity is correlated with prefrontal cortical NMDAR and AMPAR surface levels. MPH treatment enhanced working memory, which was accompanied by increased surface expression of NMDAR and AMPAR in the mPFC.2. MPH enhancement of working memory requires increased surface expression of NMDAR in the mPFC. Inhibition of MPH up-regulation of NMDAR surface expression abolished working-memory enhancement. Pharmacological up-regulation of NMDAR and AMPAR surface expression enhanced working memory.3. Surface expression of NR2B but not GluRl in the mPFC mediate MPH improvement of working memory. Intra-mPFC infusion of a behaviorally subeffective dose of NR2B antagonist blocked the enhancing effects of MPH on working memory, while a behaviorally subeffective dose of GluRl antagonist did not.4. MPH up-regulates surface expression of prefrontal cortical NMDAR through dopamine Dl receptor activation, thereby enhancing working memory. Co-administration of Dl receptor antagonist inhibited MPH-induced up-regulation of NMDAR surface expression and abolished MPH enhancement of working memory.In conclusion, MPH up-regulates the surface expression of prefrontal cortical NMDAR, thereby improving working memory. This process requires dopamine D1 receptor involvement. |
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