A Novel Mechanism For The Action Of Methylphenidate In The Medial Prefrontal Cortex Of Rats

Methylphenidate (MPH), commercially called Ritalin, is widely used as a therapeutic drug for Attention Deficit Hyperactivity Disorder (ADHD). Such therapeutic effect has been explained as its blockade of dopamine (DA) and norepinephrine (NE) transporters. Here, we report that MPH enhances, via sigma-1receptors, NMDA-receptor mediated synaptic transmission in pyramidal cells of the medial prefrontal cortex (mPFC) of rats.In the present study, we examined the effect of MPH on excitatory synaptic transmission in layer V-VI pyramidal cells of rat mPFC by using whole-cell patch-clamp recording. Our results show that bath application of MPH significantly enhanced NMDA-R mediated evoked excitatory postsynaptic currents (eEPSCs) and this enhancement still existed when catecholamine was depleted by reserpine, indicating a post-synaptic action. MPH significantly enhanced the currents induced by puff application of NMDA and this facilitation was blocked by sigma-1but not Dl/5and a2receptor antagonists. MPH-induced enhancement of NMDA-R current was blocked by inhibition of phospholipase C (PLC) or protein kinase C (PKC) but not protein kinase A (PKA). The facilitation effect of MPH required intracellular but not extracellular Ca2+, because it was blocked by chelation of intracellular Ca2+or suppression of IP3-induced release of intracellular Ca2+store, but not by inhibition of L-type Ca2+channel. On the other hand, MPH had no effect on non-NMDA-R mediated current induced by puff application of glutamate. Furthermore, our immunohistochemical staining and western blotting results showed that sigma-1receptors are widely distributed in the mPFC. Taken together, the present results demonstrate for the first time that MPH could facilitate NMDA-R mediated excitatory synaptic transmission in mPFC pyramidal cells through action at sigma-1receptors, probably via PLC/IP3/PKC signaling pathway. Our study reveals a novel mechanism for the action of methylphenidate in the medial prefrontal cortex of rats. In addition, we conducted receptor binding experiments and revealed that MPH could interact with sigma-1receptor in a competitive manner. Behavioral pharmacological study in mice showed that the sigma-1receptor selective antagonist BD1063attenuated the stimulant effect of MPH on locomotion. Pre-treatment with BD1063produced a significant shift to the right of the dose-response curve of MPH in stimulating locomotor activities. These data indicate that MPH could functionally interact with sigma-1receptors.