Low doses of 5-HT agonists have been shown to selectively suppress carbohydrate intake in rats given dietary choices. To investigate further the relationship between dietary macronutrient composition and 5-HT-induced anorexia, the present study examined the effects of three 5-HT agonists on rats fed single isocaloric diets containing varying proportions of carbohydrate (CHO) and protein (PRO). Rats were habituated to eat one of the three diets (73.5% CHO--10% PRO, 58.5% CHO--25% PRO or 43.5% CHO--40% PRO) during the dark period (1900-0700 h). Saline or 5-HT agonists (fluoxetine, RU 24969 and dexfenfluramine) were administered intraperitoneally at 1845 hours, 15 min prior to food access. At the doses used, food intake was significantly affected only during the first hour of eating. All 5-HT agonists caused dose-dependent decreases in food intake (P < 0.01). The magnitude of decrease, however, was significantly influenced by diet composition. Reduction in intake was greatest in rats fed the 73.5% CHO--10% PRO diet. Thus, rats chronically fed a diet high in carbohydrate content were more sensitive to the anorectic effect of 5-HT agonists than rats fed diets containing moderate to low levels of carbohydrate.