Depolarizing shift in the GABA-induced current reversal potential by lidocaine hydrochloride

Lidocaine hydrochloride (LC-HCl) is widely used as a local anesthetic, while various adverse effects of LC-HCl, such as seizures have also been reported. Lidocaine is reported to inhibit various channels and receptors including GABAA receptors. Although the GABAA receptor-mediated response depends on Cl− equilibrium potential (ECl), little is known about the effect of LC-HCl on ECl. In the present study, we investigated the effect of LC-HCl on GABA-induced currents in cultured rat hippocampal neurons with gramicidin-perforated patch–clamp recording which is known to keep the intracellular Cl− concentration intact. LC-HCl inhibited outward GABA-induced currents with depolarizing shift of the GABA reversal potential (EGABA). The LC-HCl-induced positive EGABA shift was not observed with conventional whole-cell patch–clamp method which cannot retain intact intracellular Cl− concentration. The LC-HCl action on EGABA was inhibited by either furosemide, a blocker of both Na+-K+-Cl− cotransporter (NKCC) and K+-Cl− cotransporter (KCC), or an increase in extracellular K+ concentrations. Neither bumetanide, a specific inhibitor of NKCC, nor Na+-free external solution had any effect on the LC-HCl-induced EGABA shift. QX-314, a membrane impermeable lidocaine derivative, failed to shift EGABA to positive potential. Furthermore, LC-HCl caused a depolarizing shift of EGABA in cultured GT1-7 cells expressing KCC2 but failed to change EGABA in GT1-7 cells without expression of KCC2. These results suggest that the LC-HCl-induced positive EGABA shift is due to a blockade of KCC2. Together with the direct LC-HCl action to GABAA receptors, the positive EGABA shift induced by LC-HCl reduces the GABAergic inhibition in the central nervous system.