For decades it has been known that brainl gut peptides are released during the ingestion of a meal. Although a multitude of actions have been attributed to these peptides acting in the brain, including the release or inhibition of a variety of pituitary hormones, the actual physiological roles of these substances in the brain have not been confirmed. For the first time, we have demonstrated that feeding-induced hypothalamic-pituitary-adrenal (HPA) secretion may involve the brainl gut peptide, vasoactive intestinal peptide (VIP), acting in the paraventricular nucleus (PVN) of the hypothalamus. The effects of 24 h fasting and refeeding on the release of plasma ACTH and CORT secretion in male rats were investigated. Blood samples were collected 5 min prior to PVN administration of saline or VIP antagonist, [Lsy(1),Pro(2,5),Arg(3,4),Tyr(6)]-VIP and 30 min after refeeding. Plasma ACTH and CORT concentrations were significantly increased by 43 and 485%, respectively, by 30 min ingestion of food. Pretreatment with the VIP antagonist (0.75 and 1.5 nmol/rat) significantly reduced the food-induced ACTH response by 69 and 76% and the CORT response by 58 and 65%, respectively. There were no significant differences in food-intake among groups. These results suggest that one potential role of hypothalamic VIP may involve activation of hypothalamic-releasing factors to regulate ACTH and CORT levels during or after a meal.