Melanin-concentrating hormone (MCH) and NPY are orexigenic peptides localized in the lateral hypothalamic area and arcuate nucleus, respectively. Although both NPY- and MCH-containing fibers innervate areas of the hypothalamus implicated in feeding, the extent to which the regulation of appetite is dependent on interactions between these peptides is unknown. Daytime feeding responses to 2 nmol MCH, 1 nmol NPY, or vehicle were investigated in male Sprague Dawley rats previously implanted with intracerebroventricular cannulas. The effects of prior administration of the Y(1)-receptor antagonists BIBO 3304 (20 nmol) or GR231118 (5 nmol) on these responses were examined. NPY and MCH stimulated food intake relative to vehicle (4 h intake, 5.9 +/- 0.7 and 3.6 +/- 0.2 g, respectively; P < 0.0001). BIBO 3304 and GR231118 significantly inhibited MCH- induced feeding by 73% (P < 0.01) and 86% (P < 0.01), respectively, at 2 h. Coadministration of NPY and MCH did not increase food intake above that in response to NPY alone; however, prior administration of BIBO 3304 resulted in a less marked inhibition of feeding (P < 0.05, 30 min only). Inhibition of MCH-induced feeding by two structurally different NPY Y(1)-receptor antagonists provides strong evidence that the orexigenic action of MCH involves the Y(1)-receptor.