title: Olanzapine-induced hyperglycemia: possible involvement of histaminergic, dopaminergic and adrenergic functions in the central nervous system.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 L-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-HT2A 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), L-sulpiride (10 μg) and prazosin (3 μg) significantly increased phosphorylated AMPK in the hypothalamus of mice.
  
  
  CONCLUSIONS
  These results suggest that olanzapine activates hypothalamic AMPK by antagonizing histamine H1 receptors, dopamine D2 receptors and α1-adrenoceptors, which induces hyperglycemia.
authors.affiliation: Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Ikegami
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohashi
authors.forename: Misa
authors.initials: M
authors.lastname: Kai
authors.forename: Mamiko
authors.initials: M
authors.lastname: Osada
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kamei
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D001569:Benzodiazepines / Q000633:toxicity*; D001786:Blood Glucose / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D065127:Dopamine D2 Receptor Antagonists; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D000077152:Olanzapine; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D011969:Receptors, Histamine H1 / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D065127:Dopamine D2 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D011969:Receptors, Histamine H1; D001569:Benzodiazepines; D000077152:Olanzapine