The activity of hypothalamic pro-opiomelanocortin (POMC) neurons is known to display a circadian cycle. We hypothesized that the existence of a c-Fos responsive element (AP-1 site) within the POMC gene sequence might reflect the ability of POMC neurons to express c-fos proto-oncogene during circadian increase of their neuronal activity. To this aim, adult male rats previously kept under a controlled 12 h light/12 h dark schedule were sacrificed every 4 h throughout the 24 h cycle and their brains processed for Fos and/or POMC immunocytochemistry. Here we show that, specifically during the dark period of the cycle, the mediobasal hypothalamic area spontaneously exhibits a strong Fos immunoreactivity, whereas very low Fos labelling was detected during the light period. As postulated, the simultaneous visualisation of both Fos and POMC antigens allowed us to show that this nocturnal induction of Fos occurs almost exclusively at the nuclear level of POMC-producing neurons. These results not only highlight the mechanisms underlying the physiological functioning of the hypothalamic POMC system, but also demonstrate the feasibility of using c-fos expression as a useful tool to assess the pharmacological effect of drugs on the activity of POMC neurons as is the case for many other neuronal systems. Such drugs might be relevant in the treatment of psychosis since an alteration of POMC-related peptide transmission has been reported in the brains of both schizophrenic and depressive patients.