Oxytocin (OT) elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates, and humans, in part, by reducing food intake. Chronic OT administration produces more sustained weight loss in high-fat diet (HFD)-fed DIO rodents relative to chow-fed controls, but the reasons for this effect remain unclear. We hypothesized that HFD-induced obesity is associated with elevated OT receptor (OXTR) binding in brain regions where OT is known to cause decreased food intake and that this sensitized neural system is one mechanism by which OT preferentially elicits weight loss in DIO rodents. We therefore determined the impact of diet (HFD vs chow) and drug treatment (chronic OT infusion vs vehicle) on (1) OXTR binding in hindbrain and forebrain sites where OT suppresses food intake relative to control sites that express OXTR and (2) forebrain vasopressin 1a receptor (AVPR1a) density to evaluate the specificity of any OT effects. Using quantitative receptor autoradiography, we found that (1) diet composition failed to alter OXTR or AVPR1a binding; (2) chronic OT treatment produced largely global reductions in forebrain OXTR and AVPR1a binding without significantly altering hindbrain OXTR binding. These findings suggest that forebrain OXTR and AVPR1a are down-regulated in response to chronic OT treatment. Given that chronic intranasal OT may be used as a therapeutic strategy to treat obesity, future studies should consider the potential downregulatory effect that chronic treatment can have across forebrain and hindbrain nonapeptide receptors and assess the potential contribution of both receptor subtypes to the outcome measures
