PRL-releasing peptide (PrRP) administered centrally inhibits food intake and body weight gain. To elucidate the role of PrRP, its actions were compared with those of a homeostatic regulator of food intake, the satiety factor, cholecystokinin (CCK), and a nonhomeostatic regulator, lithium chloride (LiCl), which reduces food intake due to visceral illness. Immunohistochemical analysis of the protein product of the c-fos gene, showed that central administration of PrRP activated some areas of the brain in common with both CCK and LiCl administered peripherally. However, PrRP was more similar to CCK than to LiCl in its behavioral effects. PrRP did not cause conditioned taste aversion, but instead enhanced the normal behavioral satiety sequence. Furthermore, brainstem PrRP neurons were strongly activated by CCK, but not by LiCl. These data provide evidence that pathways from the gut to the brain that are involved in signaling satiety and visceral illness may have some independent components and suggest that PrRP may mediate some of the central satiating actions of CCK.