Nicorandil reverses the behavioral changes and brain oxidative stress in a model of schizophrenia induced by ketamine in mice

We examined the effect of the K ATP channel opener nicorandil and the K ATP channel blocker glibenclamide on the behavioral and biochemical responses to ketamine in mice. Ketamine was injected at 30 mg/kg intraperitoneally (i.p.) daily for 2 weeks, and mice were then treated with either saline, glibenclamide (5 mg/kg), nicorandil (1 or 5 mg/kg), sucrose 1 g/kg, or glibenclamide + sucrose 1 g/kg, i.p. daily for another 8 days. The control group received only saline. Data indicated that (i) ketamine increased locomotion, rearing, and grooming behaviors. Locomotor activity increased in the center while rearing activity increased in the periphery and center of the open field. Social interaction was markedly decreased by ketamine. Nicorandil at 1 mg/kg increased and at 5 mg/kg produced marked depression in ambulation in the center of the field and in rearing in the field periphery. Locomotor activity and rearing of ketamine-treated mice were not affected by glibenclamide. Meanwhile, either agent reversed the increase in grooming and the inhibition of social interaction caused by ketamine. Sucrose had no significant effect on grooming or social interaction of mice given ketamine but increased ambulation and rearing activity in the field center. (ii) Ketamine caused a significantly elevated brain lipid peroxidation (malondialdehyde) while decreasing reduced glutathione, nitric oxide, and paraoxonase-1 activity. These biochemical alterations were markedly alleviated by nicorandil or glibenclamide. The study suggests a potential therapeutic value for the K ATP channel opener nicorandil in the ketamine model of schizophrenia.