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

Opioid receptor antagonists have shown increasing promise as an 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 and clozapine. In this study, female rats were treated for 4 weeks with a long-acting injectable formulation of olanzapine to assess effects on hypothalamic feeding regulation. 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 unbiased optical fractionator and spatial rotator methods. Hyperphagia was observed after only 24 hours of olanzapine 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 olanzapine treatment. Chronic olanzapine treatment 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 fewer anorexigenic proopiomelanocortin-expressing neurons of the ARC and corticotropin-releasing hormone expressing neurons of the PVN. This study links olanzapine-driven metabolic effects to increased opioid receptor expression in the hypothalamus, thus providing a rationale for the positive effects of using opioid receptor antagonists to relieve olanzapine adverse effects.