Pancreatic polypeptide (PP) inhibits pancreatic exocrine secretion by indirect mechanisms that may be centrally mediated. The central site of action of PP that results in inhibition of pancreatic secretion has not been identified. Using autoradiography to identify 125I-PP binding to frozen sections of rat brain, we have identified saturable, high-affinity PP receptors in high concentrations in the interpenduncular nucleus, area postrema (AP), nucleus tractus solitarius, and dorsal motor nucleus of the vagus. The PP receptor differs from neuropeptide Y and peptide YY receptors in its binding specificity and location. Because PP is not produced in the brain, and the blood-brain barrier (BBB) excludes circulating peptides from most areas in the brain, we employed an in vivo radioreceptor assay to determine whether circulating PP binds to areas such as the AP that has both an incomplete BBB and a high concentration of PP receptors. 125I-PP and 131I-bovine serum albumin were infused simultaneously into rats through a peripheral vein with or without excess unlabeled PP. After 10 min, rats were killed and the brains were removed and cut into eight regions based on the autoradiographic localization of PP receptors. There was a significant (P less than 0.02) increase in saturable radiolabeled PP accumulation in the region that included the AP, demonstrating that circulating PP can bind to this area of the brain in vivo. PP is released into the circulation after a meal via mechanisms that exhibit vagal and cholinergic dependence. We speculate that PP completes a feedback loop by binding to receptors in the AP and interacting with the adjacent vagal nuclei to inhibit vagal activity.