Outbred Long-Evans rats exhibit wide variation in their locomotor response to cocaine. Here, we investigated the relationship between these individual differences and interoceptive effects of cocaine in low cocaine responder (LCR) and high cocaine responder (HCR) phenotypes. Rats were trained to discriminate cocaine (10.0 mg/kg, intraperitoneally) from saline by repeated pairings of injections with one of two response levers. In subsequent tests for stimulus generalization to other cocaine doses (1.25-15.0 mg/kg), LCRs exhibited partial-to-full generalization at 1.85 and 2.5 mg/kg cocaine, respectively, whereas HCRs did not. When the selective 5-HT reuptake inhibitor fluoxetine (5.0 mg/kg) was coadministered with saline or different cocaine doses, we observed similar upward shifts in dose-response in both phenotypes. In contrast, coadministration of the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.3 mg/kg) led to partial substitution of DOI for cocaine and enhancement of the stimulus properties of 1.25 mg/kg cocaine in LCRs only. Finally, a retest of cocaine-induced locomotion after discrimination testing revealed marked behavioral sensitization in LCRs and modest changes in behavior in HCRs. Taken together, these results suggest that initial sensitivity to the locomotor-stimulant effects of cocaine is inversely related to its interoceptive properties and that differences in 5-HT systems may contribute to the phenotypic differences observed.