OBJECTIVE To investigate whether there is a difference in sensitivity to a serotonin agonist, meta-chlorophenylpiperazine (mCPP), or cholecystokinin (CCK-8), an intestinal hormone that inhibits food intake, between the Osborne-Mendel (OM) rat, which becomes obese eating a high-fat diet, and the S5B/Pl (S5B) rat, which is resistant to dietary-induced obesity. METHODS OM and S5B rats were adapted to either a high-saturated-fat diet (56% energy as fat) or a low-fat diet (10% energy as fat) or to both for 14 days and then treated with several doses of mCPP or CCK-8. RESULTS Treatment with mCPP reduced food intake in both strains of rats. The dose-response curve showed that the OM rats had an increased sensitivity to the serotonergic agonist. Animals eating the high-fat diet had less response to mCPP; and in the S5B rats, the response was significantly reduced. After treatment with CCK-8, there was a similar dose-related suppression of food intake in both the OM and S5B rats. CONCLUSIONS These data are consistent with the hypothesis that the serotonin system in the S5B rat has a greater activity that could act to inhibit fat intake. The response to CCK was not significantly affected by strain or diet.