Both the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and electroconvulsive shock (ECS) have been reported to induce c-Fos in rat brain. However, the former has anticonvulsant and psychotomimetic effects and the latter has proconvulsant and antipsychotic effects. To understand the mode of action of these treatments, the authors examined the effect of MK-801 and the interaction between MK-801 and ECS on the induction of c-Fos in the rat hippocampus and frontal cortex. MK-801 induced c-Fos in these brain regions in a nonlinear dose-response relationship. Maximum effect was achieved with 1-2 mg/kg of MK-801. The level of c-Fos paralleled animal hyperkinetic behavior, suggesting the role of c-Fos in the induced psychotomimetic behaviors. Pretreatment with MK-801 dose-dependently attenuated both the seizures and c-Fos expression by ECS. However, at an MK-801 pretreatment dose of 8 mg/kg, which completely blocked ECS-induced seizure, the induction of c-Fos was not completely blocked, suggesting non-NMDA mediated pathways of the induction of c-Fos by ECS.