The time course of alteration in neuronal nitric oxide synthase (nNOS) and the influence of glutamate receptor antagonists on immunoreactivity of nNOS were investigated immunohistochemically in rat hippocampus during penicillin-induced epilepsy. It was found that nNOS-like immunoreactivity in hippocampus increased at 4 h after initiation of seizure and reached a peak at 24 h. When MK-801 (6 micrograms) and DNQX (4 micrograms) were injected respectively into hippocampus 20 min before administration of penicillin, seizure was reduced in strength. Meanwhile, the nNOS-like immunoreactivity in hippocampus was decreased, compared with the group which were administered penicillin alone. These results suggest that the increase of nitric oxide may be related to the injury of neurons during and after epilepsy; the changes' of nNOS may be related to the activity of NMDA and non-NMDA receptors. Neuron protective effect of MK-801 and DNQX may be in part mediated by nNOS.