In order to examine whether tolerance develops to the discriminative stimulus and reinforcing effects of ketamine, rats were trained either to discriminate ketamine (10 mg/kg) from saline or to self-administer ketamine (1.1 mg/kg/injection), and then treated with chronic ketamine (32 rag/kg), administered i.p. every 8 hours for 7 days. No shift in the dose-response curve for either paradigm was obtained following this chronic regimen. However, following a 2-week rest period in which animals had no exposure to ketamine, the dose-response curve was shifted two-fold to the left, indicating increased sensitivity to the drug. Reinstatement of training shifted the dose-response curve back to the right in both paradigms. These results suggest that tolerance to the discriminative stimulus and reinforcing effects of ketamine develops during training. Examination of the self-administration training data support this assumption, since inter-reinforcer time decreases, reflecting an increase in ketamine intake over training sessions.