Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801.