Identification of central circuitry components mediating anorexigenic properties of oxytocin

Recent years have brought exciting discoveries showing that a neurohormone, oxytocin (OT), acts as an appetite suppressant. Importantly, OT decreases energy needs-driven consumption of high-calorie foods by promoting early satiation, and it terminates intake motivated by palatability related to sweet taste. OT’s anorexigenic effects on both aspects of ingestive behavior are mediated by the OT receptor (OTr) expressed broadly in the brain, however, our understanding of which specific sites relay anorexigenic actions of OT is limited. Thus far, only the nucleus accumbens and ventral tegmental area of the mesolimbic system, and the brainstem’s dorsal vagal complex, have been directly implicated in relaying OT-induced hypophagia. Thus, the overarching goal of this thesis was to examine which discrete components of circuitry expressing the OTr mediate OT’s anorexigenic effects on energy- versus reward-driven feeding. The research approaches included intracranial drug administration, analyses of region-specific expression of genes, neuronal activation mapping, and feeding behavior testing in rats. The first set of studies explored whether extreme overeating induced by a powerful orexigen, butorphanol tartrate (BT), can be alleviated by pharmacologically stimulating the OT receptor in the forebrain versus the hindbrain (via lateral (LV) and fourth ventricular (4V) OT injections, respectively). I established effective doses of BT and LV / 4V OT. Then, I determined doses of LV and 4V OT that reduce hyperphagia produced by BT in sated and deprived rats. Finally, I assessed whether OT’s effects on BT-induced feeding can be suppressed by an OTr antagonist. 4 mg/kg BT increased intake in fed and in deprived rats, whereas LV and 4V OT at 1μg caused a decrease in deprived rats. BT-induced chow intake in hungry and sated animals was suppressed by a very low, 0.1-μg dose of 4V OT, whereas 1μg OT was effective LV. The effect of OT was attenuated by OTr antagonist. The data strongly suggest that while both the forebrain and hindbrain populations of the OTr promote hypophagia, the hindbrain component of the circuitry is particularly sensitive to appetite reducing properties of OT in animals motivated to eat by a potent orexigen, BT. In the second set of studies, I examined whether either of the two populations of the hypothalamic OTr, in the medial preoptic area (MPOA) or the ventromedial hypothalamic nucleus (VMH), mediates OT-driven hypophagia in energy- and reward-related ingestive behaviors. I provide insights into mechanisms underlying OT-driven anorexia mediated by the hypothalamus by (a) defining whether OT MPOA or VMH administration affects feeding for energy versus palatability; (b) identifying feeding-related sites activated by VMH OT injection; (c) measuring VMH OTr mRNA changes in response to hunger and palatability; and (d) examining how VMH OT affects sweet solution intake in rats. MPOA had no effect on intake of energy-dense chow in deprived rats nor did it decrease intake of calorie-dilute palatable solutions. VMH OT decreased chow intake and the effect was reversed by the antagonist. OT did not affect intakes of saccharin and sucrose solutions. Fos immunoreactivity, a marker of neuronal activation, was elevated in the VMH and energy balance-related paraventricular and arcuate nuclei, but not reward areas. VMH OT receptor expression was higher in hungry than sated rats; saccharin intake had no effect. In sum, MPOA OTr is not involved in OT-driven hypophagia mediated by hypothalamic networks. VMH OT decreases intake driven by energy not by palatability. Finally, I assessed whether the OTr present in the basolateral (BLA) and central amygdala (CNA), sites implicated in emotional/pleasure processing of food intake, is involved in appetite control by OT. I injected OT in the BLA or CNA and assessed intake of chow induced by energy deprivation and intake of sweet solutions in nondeprived rats. I examined whether these effects are reversible by OTr blockade. I determined the effect of energy deprivation and exposure to saccharin on BLA and CNA expression of OTr mRNA. BLA OT at 0.3 μg and CNA OT at 1 μg reduced chow intake after deprivation. Only BLA OT was effective at suppressing consumption of sucrose and saccharin. The anorexigenic effects of BLA and CNA OT were attenuated by an OTr antagonist. BLA OTr mRNA expression was affected by exposure to saccharin, whereas that of CNA OTr, by energy deprivation. The relationship between amygdalar OT and energy- vs palatability-driven intake depends on the discrete localization of the OTr in this complex structure. Overall, these findings shed light on the specific elements of brain circuitry mediating anorexigenic properties of OT. Both the forebrain and hindbrain OTr populations are relevant to feeding control. OT’s inhibitory effects on feeding for energy are mediated by a broader network of sites that includes, aside from the previously reported nucleus accumbens and dorsal vagal complex, the VMH, BLA, and CNA. Only the BLA OT modifies eating for reward. Surprisingly, the OTr in the MPOA is not involved in feeding regulation