Rationale and objectives The 5-HT.sub.2A and 5-HT.sub.2C receptors have been shown to be differentially involved in modulating cocaine-induced behaviors. In this study we investigated the effects of the 5-HT.sub.2A antagonist MDL100907 (0.3 mg/kg, i.p.) and the 5-HT.sub.2C antagonist SB242084 (0.5 mg/kg, i.p.) on development, expression, and recall of cocaine-induced conditioned place preference (CPP) in high- (HR) and low-responder (LR) rats to novelty. Results First, we examined the effects of MDL100907 and SB242084 on development of cocaine-induced CPP. Our results indicated that LR, but not HR, animals conditioned with SB242084 + cocaine showed a significantly higher CPP response than controls. This effect was long lasting, as it was still present 30 days after the last conditioning session. Second, we investigated the acute effects of MDL100907 and SB242084 on CPP expression 24 h after cocaine conditioning. Again, our data showed that SB242084 significantly enhanced the expression of cocaine CPP in LR, but not HR animals. Finally, we studied the acute effects of MDL100907 and SB242084 on CPP recall 30 days after cocaine conditioning. Neither MDL100907 nor SB242084 significantly affected the CPP response regardless of the rats' behavioral phenotype. Conclusions This is the first study investigating the contribution of 5-HT.sub.2A and 5-HT.sub.2C receptors on development, expression, and recall of cocaine-induced CPP in the HR-LR model of individual vulnerability to drug abuse. Our results show that SB242084 differentially modulates development and expression of CPP in HR vs. LR rats and suggest that 5-HT.sub.2C receptors play a key role in individual differences on cocaine reward-related learning/memory processes. Keywords Phenotype * Conditioning * Cocaine * Serotonin receptor * Learning and memory