Metabolic peptides such as orexin and neuropeptide Y (NPY) exert profound effects on feeding but also act centrally to stimulate the hypothalamo-pituitary-adrenal (HPA) axis. In late pregnancy the HPA axis is hyporesponsive to centrally administered orexin-A, which signals to the HPA axis, in part, via arcuate NPY neurones. We investigated whether reduced HPA axis responses to orexin may be a consequence of down-regulated NPY signaling to the paraventricular nucleus (PVN) in pregnancy. Pregnant (d 21) and virgin rats were blood sampled for ACTH, corticosterone, and oxytocin (also a stress hormone in rats) before and after intracerebroventricular NPY or vehicle. Behavior was monitored. Rats were killed 4 h after NPY and brains removed for in situ hybridization. In another experiment rats were given vehicle or NPY, perfuse fixed 90 min later, and brain sections processed for Fos and oxytocin immunocytochemistry. NPY significantly increased ACTH, corticosterone and oxytocin secretion in the virgins but had no such effect on ACTH or oxytocin in the pregnant rats; the corticosterone response to NPY was markedly attenuated in pregnant rats. NPY increased CRH and vasopressin mRNA expression in the parvocellular PVN and stimulated Fos expression in magnocellular supraoptic and PVN oxytocin neurones of virgin but not pregnant rats. NPY increased food intake and drinking similarly in virgin and pregnant rats. Thus, neuroendocrine stress responses to central NPY are absent in late pregnancy, whereas ingestive behavioral responses are intact. These changes may explain the similarly attenuated HPA response to centrally administered orexin-A and will favor anabolic adaptations in pregnancy.