www.elsevier.com/locate/brainres Available online at www.sciencedirect.com Research Report Central administration of an orexin receptor 1 antagonist prevents the stimulatory effect of Olanzapine on endogenous glucose production Elodie M. Girault a,n , Ewout Foppen a,b , Marie ¨tte T. Ackermans c , Eric Fliers b , Andries Kalsbeek a,b a Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience—Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105BA Amsterdam, The Netherlands b Department of Endocrinology and Metabolism, Academic Medical Centre (AMC), Meibergdreef 9, 1105AZ Amsterdam, The Netherlands c Laboratory of Endocrinology, Department of Clinical Chemistry, Academic Medical Centre (AMC), University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands article info Article history: Accepted 25 June 2013 Available online 4 July 2013 Keywords: Olanzapine Orexin Glucose metabolism Intracerebroventricular Corticosterone SB-408124 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 hyperglycae- mia 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. & 2013 Elsevier B.V. All rights reserved. 1. Introduction Treatment with atypical antipsychotic drugs (AAPDs) is associated with significant weight gain and metabolic disturbances including hyperglycaemia and insulin resis- tance. Over the past decade, particular attention has been paid to one of the AAPDs that causes dramatic weight gain, Olanzapine (Olan). However, the exact mechanisms 0006-8993/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.brainres.2013.06.034 Abbreviations: Olan, olanzapine; Ox, orexin; IG, intragastric; Ox-1R, orexin-1 receptor; EGP, endogenous glucose production n Corresponding author. Fax: +31 206 17682. E-mail addresses: e.girault@nin.knaw.nl (E.M. Girault), e.foppen@nin.knaw.nl (E. Foppen), m.t.ackemans@amc.uva.nl (M.T. Ackermans), e.fliers@amc.uva.nl (E. Fliers), a.kalsbeek@nin.knaw.nl (A. Kalsbeek). brain research 1527 (2013) 238–245