The implications of increased calpain-mediated proteolysis during epileptic seizures are still unclear, and in this study we investigate the effect of the continuous perfusion of calpain inhibitor I on picrotoxin-induced seizures in chronic freely moving rats. Continuous intrahippocampal microperfusion of 500 microM calpain inhibitor I had no effect on basal EEG, but doubled (P < 0.05) average seizure duration, and increased more than five-fold (P < 0.01) the total seizure time and three-fold (P < 0.01) the seizure offset time compared to picrotoxin alone, in each individual rat. However, seizure type and onset time were not modified by calpain inhibitor I. These results indicate that a calpain-mediated mechanism may be responsible for seizure offset, probably through AMPA glutamate receptors internalization and further degradation.