Effect of MK-801 and ketamine on hydroxyl radical generation in the posterior cingulate and retrosplenial cortex of free-moving mice, as determined by in vivo microdialysis

This study investigated the effect of MK-801 and ketamine, N-methyl-d-aspartate (NMDA) receptor antagonists which can induce schizophrenic symptoms and have neurotoxicity in human and animals, on hydroxyl radical (·OH) generation in the posterior cingulate and retrosplenial (PC/RS) cortex of free-moving mice using the salicylic acid trapping technique. MK-801 (0.6 mg/kg) or ketamine (50 mg/kg) acute administration significantly increased ·OH levels in mouse PC/RS cortex. The basal ·OH levels after MK-801 and ketamine administrations for 7 consecutive days were significantly increased compared with the naive basal levels. MK-801 (0.6 mg/kg) or ketamine (50 mg/kg) challenge after chronic administration further significantly increased dialysate levels of ·OH. Our study also found that the release of ·OH was secondary to stereotyped behavior, and the intensity of stereotyped behavior induced by MK-801 was more than that induced by ketamine. The results suggested that NMDA receptor antagonists participate in the generation of ·OH in the PC/RS cortex of mouse, and oxidative stress, derived from the formation of free radicals, might play an important role in the pathophysiology of these two models of schizophrenia.