The atypical antidepressant bupropion has been shown to be an efficacious smoking cessation agent; however, its therapeutic mechanism of action is unknown. To further understand the mechanism by which bupropion reduces smoking, the present study determined the effect of repeated bupropion pretreatment on nicotine self-administration or sucrose-maintained responding. Rats were trained to self-administer intravenous nicotine (0.02 mg/kg/infusion; Experiment 1) or to respond for sucrose pellets (45 mg each; Experiment 2) on a fixed-ratio 5 schedule. Once rats reached stable responding, bupropion (70 mg/kg, subcutaneously) or vehicle was injected 15 min before the session for 14 consecutive sessions. Bupropion acutely decreased both nicotine self-administration and sucrose-maintained responding by approximately 60%-70%. With repeated bupropion pretreatment, however, responding for nicotine decreased completely. In contrast, the bupropion-induced decrease in responding for sucrose following acute administration did not change significantly with repeated bupropion administration. These results suggest that bupropion acquired some specificity with repeated use, decreasing the intake of nicotine and producing an extinction-like pattern in nicotine self-administration. Thus the present results parallel human clinical studies with bupropion demonstrating its smoking cessation properties following repeated treatment. These results indicate that the rat nicotine self-administration paradigm is a useful animal model for assessing smoking cessation pharmacotherapies.