The central nervous system (CNS) is an important target for the effects of convulsants in mammals. In neurons, an increase in calcium levels after and external signal represents the initial step in many signalling pathways. To study if mechanisms related to calcium mobilization might be involved in the mechanism of action of different convulsants we planned a series o studies to determine the possible role of L-type voltage sensitive calcium channels (VSCC) and the calcium binding protein, calmodulin (CaM), in the induction of c-fos expression following administration of different convulsant drugs. As calcium agonists we used two antagonists of the GABA_A receptor (picrotoxinin (PTX) and pentylenetetrazole (PTZ)), two agonists of the L-Type VSCC ((BAY-K-8644 (BK) and lindane the γ isomer of hesachlorocyclohexane (γ-HCH)), N-methyl-D-aspartate acid (NMDA) and kainic acid (KA) as agonist of receptor operated channels (ROC). The inhibition of c-fos induction elicited by these drugs was studied using the L-type VSCC antagonist nifedipine, and the CaM antagonist N-(6-aminohexyl)-5chloro-1-naphthalene sulfonamide hydrochloride (W-7). We also determined the inhibitory effect of the nervous system depressor δ-hexachlorocyclohexane (δ-HCH). Primary cortical neurons, were used in different studies. c-fos protein and mRNA were detected by means of immunocytochemistry and  Northern Blot. Approximately 30% of the neurons displayed c-fos nuclear immunoreactivity under basal condition in culture. This value was increased to about 55% after treatment with any convulsant used. Nifedipine and δ-HCH acted in similar way reducing c-fos induction due to BK, γ-HCH and PTZ to basal or below levels. However, they were not able to inhibit the proto-oncogen induction elicited by BK, γ-HCH, PTZ and KA. The CaM antagonist did not affect NMDA or PTX-mediated increases in c-fos expression in neurons. The results obtained with δ-HCH, nifedipine and W-7 suggest that PTX and NMDA activate c-fos expression through calcium-dependent intracellular mechanisms, that are different from those activated by other convulsants, which at least part, act via L-type VSCC and CaM. These differences agree with the hypothesis that the dissociation in the mechanisms transducing calcium signals is due to the fact that the sites of calcium entry into neurons are spatially distinct, resulting in activation of different enzymes located at distinct sites in the cell.