title: Central administration of an orexin receptor 1 antagonist prevents the stimulatory effect of Olanzapine on endogenous glucose production.
abstract: Atypical antipsychotic drugs such as Olanzapine (Olan) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. It has been shown that peripheral injections of Olan activate neurons in the lateral hypothalamus/perifornical area and that a large part of these neurons are orexin (Ox) A-positive. We investigated further the possible involvement of the central Ox system in the metabolic side-effects of Olan by comparing the hyperglycaemic effects of an intragastric (IG) Olan infusion between animals treated intracerebroventricularly (ICV) with an Ox-1 receptor antagonist (SB-408124) or vehicle. As observed in previous studies IG Olan caused an increase in blood glucose, endogenous glucose production and plasma glucagon levels. ICV pre-treatment with the Ox-1 receptor antagonist did not affect the Olan-induced hyperglycaemia or increased plasma glucagon concentrations, but the increased endogenous glucose production was blunted by the ICV SB-408124 treatment. From these results we conclude that the metabolic side-effects of Olan are partly mediated by the hypothalamic Ox system.
authors.affiliation: Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience-Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105BA Amsterdam, The Netherlands. e.girault@nin.knaw.nl
authors.forename: Elodie M
authors.initials: EM
authors.lastname: Girault
authors.forename: Ewout
authors.initials: E
authors.lastname: Foppen
authors.forename: Mariëtte T
authors.initials: MT
authors.lastname: Ackermans
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.forename: Andries
authors.initials: A
authors.lastname: Kalsbeek
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001786:Blood Glucose / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D000077152:Olanzapine; D000068796:Orexin Receptor Antagonists; D010671:Phenylurea Compounds / Q000008:administration & dosage; D051381:Rats; D015430:Weight Gain / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D000068796:Orexin Receptor Antagonists; D010671:Phenylurea Compounds; C542397:SB 408124; D001569:Benzodiazepines; D005947:Glucose; D000077152:Olanzapine
keywords: Corticosterone; EGP; Glucose metabolism; IG; Intracerebroventricular; Olan; Olanzapine; Orexin; Ox; Ox-1R; SB-408124; endogenous glucose production; intragastric; olanzapine; orexin; orexin-1 receptor