Chronic olanzapine treatment leads to increased opioid receptor expression and changes in feeding regulating neurons in the rat hypothalamus

Abstract Opioid receptor antagonists have in recent years shown increasing promise as adjunct therapy to psychotropic medication. The goal is to reduce the weight gain and metabolic adverse effects that are associated with certain second generation antipsychotics, such as olanzapine (OLZ) and clozapine. In this study, female rats were treated for 4 weeks with a long-acting injectable formulation of OLZ at a dose that produced clinically relevant plasma levels to access effects on feeding regulation regions of the hypothalamus. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the mu, kappa and delta opioid receptors were defined in the five hypothalamic areas: paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamus (LH). In addition, hypothalamic neuron number and size were estimated using the optical fractionator and spatial rotator. Hyperphagia was observed after only 24 hours of OLZ treatment, with continued weight gain throughout the duration of the study. In contrast, the observed food intake reversed to control levels after 2 weeks of OLZ treatment. Blood samples from day 28 revealed no changes in metabolic markers compared to controls. Chronic OLZ treatment led to increased expression of kappa opioid receptor mRNA and receptor availability in the PVN, as well as increased mu opioid receptor availability in the PVN, ARC and VMN. These changes were accompanied by a decreased number of anorexigenic POMC neurons of the ARC and CRH neurons of the PVN. In conclusion, this study supports a connection between OLZ driven adverse metabolic effects and increased opioid receptor expression in the hypothalamus, thus providing a rationale for the positive effects of using opioid receptor antagonist to relieve OLZ adverse effects.