Within the dorsomedial hypothalamus (DMH), cholecystokinin (CCK) has been proposed to modulate neuropeptide Y (NPY) signaling to affect food intake. However, the neural circuitry underlying the actions of this CCK-NPY signaling system in the controls of food intake has yet to be determined. We sought to characterize the feeding inhibition and brain neural activation produced by CCK administration into the DMH of rats. We determined the time course of feeding inhibitory effects of exogenous DMH CCK, assessed NPY gene expression in the DMH in response to DMH CCK administration, and characterized c-Fos activation in the entire brain induced by CCK injection into the DMH using c-Fos like immunohistochemistry. We found that parenchymal injection of CCK into the DMH decreased food intake during the entire 22 h observation period, with a primary effect in the first 4 h, and down-regulated NPY gene expression in the DMH. c-Fos immunohistochemistry revealed that DMH CCK increased the number of c-Fos positive cells in the paraventricular nucleus (PVN), arcuate nucleus, suprachiasmatic nucleus and retrochiasmatic area as well as in the contralateral DMH. This pattern of activity is different from that produced by peripherally administered CCK which is short acting and primarily activates neurons in the nucleus of the solitary tract and area postrema, as well as the PVN and DMH. Together, these data suggest that DMH CCK plays an important role in the control of food intake, and does so by activating different pathways from those activated by peripheral CCK.