Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture

Rat neocortical neurons in culture were subjected to the whole cell mode of voltage clamping under experimental conditions designed to study Na+, Ca2+ and K+ currents in isolation. Following pharmacological blockade of most of the Ca2+ and K+ channels, depolarizing commands which brought the membrane potential from -80 to +10 mV elicited an inward current. This current was sensitive to tetrodotoxin (TTX) and was therefore caused by the opening of voltage-dependent channels permeable to Na+. Extracellular application of the antiepileptic drug valproic acid (VPA, 0.2-2mM) reduced in a dose-related, reversible way this Na+ current. VPA also evoked an increase of the voltage-dependent inward current recorded in the presence of TTX and thus presumably carried by Ca2+; this effect was seen in the presence of doses of VPA larger than 0.5 mM and was not reversible. Two types of outward K+ currents evoked by depolarizing steps in the presence of Na+ and Ca2+ channels blockers were not affected by VPA (up to 5 mM). Our data indicate that doses of VPA that are within the range present when it is used as an anticonvulsant, can influence inward currents generated by rat neocortical cells in culture. The reduction of the Na+, inward current is in line with findings obtained in mouse neurons by using standard intracellular recording techniques. This effect might represent an important mechanism of action for VPA in neocortex.