Several lines of evidence substantiate the important role of the central nervous system melanocortin 3- and 4-receptor (MC3/4-R) system in the control of food intake and energy balance. Agouti-related peptide (AgRP), an endogenous antagonist of these receptors, produces a robust and unique pattern of increased food intake that lasts up to 7 days after a single injection. Little is known about brain regions that may mediate this powerful effect of AgRP on food intake. To this end we compared c-Fos-like immunoreactivity (c-FLI) in several brain sites of rats injected intracerebroventricularly with 1 nmol AgRP-(83-132) 2 and 24 h before death and compared c-FLI patterns to those induced by another potent orexigenic peptide, neuropeptide Y (NPY). Although both NPY and AgRP induced c-FLI in hypothalamic areas, AgRP also produced increased c-FLI in the accumbens shell and lateral septum. Although NPY elicited no changes in c-FLI 24 h after administration, AgRP induced c-FLI in the accumbens shell, nucleus of the solitary tract, central amygdala, and lateral hypothalamus. These results indicate that an NPY-like hypothalamic circuit mediates the short-term effects of AgRP, but that the unique sustained effect of AgRP on food intake involves a complex circuit of key extrahypothalamic reward and feeding regulatory nuclei.