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The Effect of Clozapine on Central Insulin Response in Rats  

Kim, Se Hyun (Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University)
Yu, Hyun Sook (Biomedical Research Institute, Seoul National University Hospital)
Park, So Young (Biomedical Research Institute, Seoul National University Hospital)
Kim, Min Kyung (Department of Biomedical Sciences, Seoul National University College of Medicine)
Park, Hong Geun (Biomedical Research Institute, Seoul National University Hospital)
Kim, Yong Sik (Department of Neuropsychiatry, Dongguk University Ilsan Hospital)
Publication Information
Korean Journal of Biological Psychiatry / v.19, no.4, 2012 , pp. 187-192 More about this Journal
Abstract
Objectives Although antipsychotic drug clozapine has superior efficacy, this is hampered by metabolic side effects such as weight gain and diabetes. Recent studies demonstrate that clozapine induces insulin resistance. However, the identity and location of insulin resistance induced by clozapine has not been clarified. In this study, the effect of clozapine on central insulin response was investigated in rats. Methods Male Sprague-Dawley rats received intraperitoneal injection of clozapine or vehicle, which was followed by intracerebroventricular injection of insulin or its vehicle. The effects of clozapine on insulin-induced changes in blood glucose level and Akt phosphorylation in hypothalamus were investigated. Results Intraperitoneal injection of clozapine (20 mg/kg) increased blood glucose in rats. Intracerebroventricular injection of insulin reduced blood glucose in rats, which was blunted by pretreatment of clozapine. Accompanied with the antagonistic effect of clozapine to central insulin action in terms of blood glucose, clozapine inhibited the insulin-induced phosphorylation of Akt at Ser473 in rat hypothalamus. Conclusion Administration of clozapine inhibited the central insulin-induced changes in blood glucose and Akt phosphorylation in rat hypothalamus. These findings suggest that hypothalamus could be the site of action for the clozapine-induced insulin resistance.
Keywords
Atypical antipsychotics; Insulin resistance; Blood glucose; Hypothalamus; Akt;
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