Olanzapine-Induced Hyperglycemia: Possible Involvement of Histaminergic, Dopaminergic and Adrenergic Functions in the Central Nervous System

<b><i>Background/Aims:</i></b> Atypical antipsychotic drugs such as olanzapine are known to induce metabolic disturbance. We have already shown that olanzapine induces hepatic glucose production through the activation of hypothalamic adenosine 5′-monophosphate-activated protein kinase (AMPK). However, it is unclear how olanzapine activates hypothalamic AMPK. Since olanzapine is known to antagonize several receptors, including histaminergic, muscarinic, serotonergic, dopaminergic and adrenergic receptors, we examined the effect of each receptor antagonist on blood glucose levels in mice. Moreover, we also investigated whether these antagonists activate hypothalamic AMPK. <b><i>Methods:</i></b> Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. AMPK expression was measured by Western blotting. <b><i>Results:</i></b> Central administration of olanzapine (5-15 nmol i.c.v.) dose-dependently increased blood glucose levels in mice, whereas olanzapine did not change blood insulin levels. Histamine H₁ receptor antagonist chlorpheniramine (1-10 μg i.c.v.), dopamine D₂ receptor antagonist <smlcap>L</smlcap><i>-</i>sulpiride (1-10 μg i.c.v.) and α₁-adrenoceptor antagonist prazosin (0.3-3 μg i.c.v.) also significantly increased blood glucose levels in mice. In contrast, the blood glucose levels were not affected by muscarinic M₁ receptor antagonist dicyclomine (1-10 μg i.c.v.) or serotonin 5-HT_2A receptor antagonist M100907 (1-10 ng i.c.v.). Olanzapine-induced hyperglycemia was inhibited by the AMPK inhibitor compound C, and AMPK activator AICAR (10 ng to 1 μg i.c.v.) significantly increased blood glucose levels. Olanzapine (15 nmol), chlorpheniramine (10 μg), <smlcap>L</smlcap><i>-</i>sulpiride (10 μg) and prazosin (3 μg) significantly increased phosphorylated AMPK in the hypothalamus of mice. <b><i>Conclusion:</i></b> These results suggest that olanzapine activates hypothalamic AMPK by antagonizing histamine H₁ receptors, dopamine D₂ receptors and α₁-adrenoceptors, which induces hyperglycemia.