Valproic acid intensifies epileptiform activity in the hippocampal pyramidal neurons

The effects of large concentrations of valproic acid (VPA) on veratridine-induced epileptiform activity (veratridine model) were investigated in rat hippocampal CA1 pyramidal neurons. Studies were performed on the veratridine model in rat brain slices using conventional electrophysiological intracellular techniques. Large concentrations of VPA (5 mM or more) enhanced rather than inhibited epileptiform activity induced by veratridine. During the proepileptic phase of VPA, a membrane depolarization accompanied by a decrease in membrane input resistance were evident. The voltage-dependent proepileptic effect of VPA was blocked by tetrodotoxin (TTX; 100 nM) but not by the calcium channel blockers, diltiazem (5 microM) or omega-conotoxin GVIA (5 microM). VPA did not induce a proepileptic effect when it was superfused at high concentration (0.5-10 mM) on sodium channel-independent models such as the bicuculline or magnesium-free artificial cerebrospinal fluid. Large concentrations of VPA had no significant effect on untreated neurons. The VPA-enhanced veratridine bursting is probably related to the reported proepileptic activities observed in patients taking high doses of this drug. These data also suggest the involvement of sodium channels in the proepileptic effect of VPA.