Several of the most effective antiepileptic drugs are believed to stop the paroxysmal neuronal activity acting as Na+ channel blockers. However, no single study comparing in parallel the potency and efficacy of the most commonly used antiepileptic drugs on brain Na+ channel-mediated responses is available. In the present study the effects of increasing concentrations of carbamazepine, phenytoin, lamotrigine, oxcarbazepine and topiramate, which are among the most frequently used antiepileptic drugs, and of the new putative antiepileptic drug, vinpocetine, on the release of glutamate (Glu) elicited by the Na+ channel opener, veratridine were investigated in hippocampal isolated nerve endings preloaded with the labeled excitatory amino acid neurotransmitter. The present results show that carbamazepine, phenytoin, lamotrigine and oxcarbazepine, in the range from 150 to 1500 μM, progressively inhibit [3H]Glu release induced by veratridine. Also vinpocetine progressively inhibits the veratridine-induced response, but in a much lower range of concentrations (from 1.5 to 15 μM), whereas topiramate only exerts a modest inhibition (20%) of Glu release to veratridine at the highest dose tested (1500 μM). These results indicate that the mechanism of action of several of the most widely used antiepileptic drugs involves reduction in cerebral presynaptic voltage sensitive Na+ channels permeability. Considering that the high doses of antiepileptic drugs required to control seizures are frequently accompanied by adverse secondary effects, the higher potency of vinpocetine to reduce Na+ channels permeability might be advantageous.