Among the several classes of drugs currently studied as neuroprotective agents, glutamate release blockers have been indicated as being rather effective. In particular, lamotrigine and riluzole have shown promise in the treatment of either acutely developing cellular damages (stroke, posttraumatic lesions) or slowly progressing neurodegenerative diseases as amyotrophic lateral sclerosis. These drugs are supposed to interfere with the release of endogenous glutamate in situ, yet the mechanisms underlying this effect are not fully defined. One possibility is that lamotrigine and riluzole act by inhibiting voltage-dependent inward conductances active in the soma and/or in the axon terminal region. Therefore, we have investigated the effects of lamotrigine and riluzole on the voltage-gated sodium and calcium currents of acutely isolated neurons from the adult rat neocortex. In addition, since phenytoin is a well-known blocker of the sodium channel, we have compared lamotrigine and riluzole responses with the peak current inhibition produced by phenytoin in the same cells. Lamotrigine produced a large reduction of the high-voltage-activated calcium currents and a smaller; use-dependent inhibition of the sodium conductance. Riluzole inhibited significantly the sodium current at surprisingly low concentrations (nanomolar range) and by up to 80% at saturating doses (1-10 microM). Furthermore, riluzole inhibited both high- and low-voltage-activated calcium currents in neocortical neurons isolated from adult and young animals. By contrast, phenytoin caused only a slight reduction of high-voltage-activated calcium currents even at supratherapeutic doses (by < 12% at 10 microM). Taken together, the different pharmacological profiles of the tested agents might indicate that glutamate release blockers do not represent a homogenous class of drugs. Conversely, our findings could support their selective utilization in different disease status.