Olanzapine Administration Reduces Chemotherapy-Induced Nausea Behavior in Rats

Abstract

Nausea and vomiting are consistently identified among the most distressing side effects of chemotherapy. In recent years, Olanzapine (OLZ) treatment was added to anti-emetic guidelines as a treatment for chemotherapy-induced nausea and vomiting (CINV), despite little available data supporting a mechanism behind the positive benefits of the drug. Here, we examine whether OLZ reduces cisplatin chemotherapy-induced side effects on food intake and pica behavior in rats (i.e., kaolin intake, a proxy for nausea/emesis). Behavioral experiments tested whether systemic or hindbrain administration of OLZ ameliorated cisplatin-induced pica, anorexia, and body weight loss in rats. We also tested whether systemic OLZ reduces cisplatin-induced neuronal activation in the dorsal vagal complex (DVC), a hindbrain region controlling emesis. Lastly, given their role in regulating feeding and emesis, circulating ghrelin levels and central mRNA expression levels of serotonin (HT) receptor subunits, including 5-HT2C, were measured in brain regions that regulate CINV and energy balance in an exploratory analysis to investigate potential mediators of OLZ action. Our results show that both systemic and hindbrain administration of OLZ attenuated cisplatin-induced kaolin intake and body weight loss, but not anorexia. Systemic OLZ decreased cisplatin-induced c-Fos immunofluorescence in the DVC and prevented cisplatin-induced reductions in circulating ghrelin levels. IP OLZ also blocked cisplatin-induced increases in Htr2c expression in DVC and hypothalamic micropunches. These data suggest hindbrain exposure to OLZ is sufficient to induce reductions in cisplatin-induced pica and that central serotonergic signaling, via 5-HT2C, and changes in circulating ghrelin may be potential mediators of olanzapine anti-emetic action.