Ghrelin, a peptide isolated from the rat stomach, is the endogenous ligand of the growth hormone-secretagogue receptor and also known to have orexigenic effect. We examined the influence of intraperitoneal (i.p.) injection of ghrelin on food intake and brain neuronal activity in freely fed mice. Ghrelin (3, 10 or 30 microg/mouse) dose-dependently increased food intake by 0.8-, 1.6- and 2.6-fold, respectively, at 30 min post injection. Ghrelin (10 microg/mouse) induces Fos expression selectively in the ventromedial part of the hypothalamic arcuate nucleus (Arc). No change in Fos expression was observed in other hypothalamic and hindbrain nuclei. About 90% of the Fos-positive neurons in the Arc expressed neuropeptide Y (NPY) messenger RNA. These data indicate that NPY neurons in the Arc are likely the primary target mediating i.p. ghrelin induced orexigenic effect.