It is known that the paraventricular hypothalamic nucleus is responsible for some of the stimulatory effects of neuropeptide Y, peptide YY and the pancreatic polypeptides on food intake. However, specific neuropeptide Y Y1 and Y2 receptors were not abundantly expressed in the hypothalamus. In contrast, specific [125I]human pancreatic polypeptide binding sites were detected in this hypothalamic nucleus as well as the medial preoptic area, interpeduncular nucleus, nucleus tractus solitarius, area postrema and dorsal vagal nucleus while cortical areas and the hippocampus contained negligible levels of labeling. The ligand binding profile of the various competitors suggests that the binding sites labeled by [125I]human pancreatic polypeptide are predominantly of the neuropeptide Y Y4 and/or Y5 subtypes. These newly cloned receptors may play a key role in the modulatory effects of neuropeptide Y and related peptides on appetite.