Previous studies demonstrate that cholecystokinin type-1 (CCK(1)) and serotonin type-3 (5-HT(3)) dependent pathways are independently involved in intestinal nutrient-induced meal termination. In the current study, we employed selective antagonists to investigate the relative contribution of CCK(1) and 5-HT(3) receptors in mediating the anorexia produced by duodenal infusion of Polycose or Intralipid in rats. Combined administration of 1 mg/kg ondansetron (Ond) and 1 mg/kg devazepide (Dev) reversed 132 mM Polycose-induced suppression to the level of control intake and significantly attenuated 263 mM Polycose-induced suppression greater than either antagonist alone. Similar results were observed when subthreshold doses of Ond (500 microg/kg) and Dev (5 microg/kg) were co-administered prior to 263 mM Polycose infusion. Suppression of intake resulting from 130 mM Intralipid was reversed to the level of control when Ond and Dev were co-administered at both independent effective doses (1 mg/kg each) and subthreshold doses (500 microg/kg and 5 microg/kg, respectively). Finally, combined administration of the antagonists increased sucrose intakes beyond intakes following control or treatment with either antagonist alone when rats were infused with saline. These data demonstrate that intestinal carbohydrates and lipids inhibit food intake through simultaneous CCK(1) and 5-HT(3) receptor activation and that these receptors appear to completely mediate the Intralipid-induced suppression of intake.