The effect of the serotonin (5-HT) reuptake inhibitor, fluoxetine (FLU), on nutrient intake was examined in rats given free access to three pure macronutrient diets (protein, carbohydrate and fat). Fluoxetine was administered either peripherally or directly into the hypothalamic paraventricular nucleus (PVN) at three different times of the rats' nocturnal cycle. Using a range of doses for IP (0.6-10 mg/kg) and PVN injection (3.2-100 nmol), FLU exerted a selective, dose-dependent suppression (-20% to -60%) of carbohydrate intake only during the first hour of the dark. No change in the consumption of protein or fat was observed. This suppressive effect in the early dark period was not observed during the late dark phase, after either IP or PVN administration. In animals with brain cannulae aimed at different hypothalamic nuclei, the nutrient-suppressive effect of FLU was found to be localized to the medial hypothalamic nuclei, namely, the ventromedial, dorsomedial and suprachiasmatic nuclei, in addition to the PVN. These results, along with other published work, support a role for hypothalamic 5-HT systems in the control of nutrient intake in a circadian-related manner and in mediating the central action of the anorectic compound FLU.