1. Neuropeptide Y (NPY) is one of the most potent stimulants of food intake. It has been debated which receptor subtype mediates this response. Initially Y(1) was proposed, but later Y(5) was announced as a 'feeding' receptor in rats and mice. Very little is known regarding other mammals. The present study attempts to characterize the role of NPY in feeding behaviour in the distantly related guinea-pig. When infused intracerebroventricularly, NPY dose-dependently increased food intake. 2. PYY, (Leu(31),Pro(34))NPY and NPY(2 - 36) stimulated feeding, whereas NPY(13 - 36) had no effect. These data suggest that either Y(1) or Y(5) receptors or both may mediate NPY induced food intake in guinea-pigs. 3. The Y(1) receptor antagonists, BIBO 3304 and H 409/22 displayed nanomolar affinity for the Y(1) receptor (K(i) values 1.1+/-0.2 nM and 5.6+/-0.9 nM, respectively), but low affinity for the Y(2) or Y(5) receptors. When guinea-pigs were pretreated with BIBO 3304 and H 409/22, the response to NPY was inhibited. 4. The Y(5) antagonist, CGP 71683A had high affinity for the Y(5) receptor (K(i) 1.3+/-0.05 nM) without having any significant activities at the Y(1) and Y(2) receptors. When CGP 71683A was infused into brain ventricles, the feeding response to NPY was attenuated. 5. The present study shows that NPY stimulates feeding in guinea-pigs through Y(1) and Y(5) receptors. As the guinea-pig is very distantly related to the rat and mouse, this suggests that both Y(1) and Y(5) receptors may mediate NPY-induced hyperphagia also in other orders of mammals.