TY - JOUR T1 - AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.248393 SP - jpet.118.248393 AU - Natasha D Bush AU - Logan K Townsend AU - David C Wright Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/03/26/jpet.118.248393.abstract N2 - Olanzapine (OLZ) is an antipsychotic drug used in the treatment of schizophrenia. While effective in reducing psychoses, OLZ causes acute increases in blood glucose. The acute effects of OLZ on hyperglycaemia are likely caused by reductions in insulin secretion, insulin resistance and increased hepatic glucose production. 5'AMP-activated protein kinase (AMPK) is an energy sensor activated during exercise that can increase insulin sensitivity and insulin-independent glucose uptake in muscle. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) is a pharmacological agent that, among other effects, can activate AMPK in vivo. Conversely, hypothalamic activation of AMPK has been suggested to mediate the hyperglycemic effects of olanzapine. The purpose of this investigation was to determine if co-treatment with AICAR could prevent acute OLZ-induced hyperglycaemia in lean and obese C57BL6/J mice. OLZ (5 mg/kg; IP) caused rapid increases in blood glucose, a blunted insulin response and pyruvate intolerance, all of which were prevented with AICAR co-treatment in both lean and obese mice. AICAR did not affect OLZ-induced changes in whole body substrate oxidation or energy expenditure. Peripheral injection of AICAR, but not OLZ, activated AMPK signalling in the hypothalamus. The results of the current study provide evidence that AICAR prevents OLZ-induced hyperglycemia, despite increasing hypothalamic AMPK signaling. These protective effects were associated with the preservation of whole body insulin action and reductions in markers of liver glucose production. ER -