Rats were exposed to a diet containing 100 ppm cadmium chloride or a control diet. At 52 days of exposure, rats were trained to discriminate between saline and 5 mg/kg cocaine injections. After acquisition training, successive substitution tests were conducted using cocaine, the indirect dopamine agonist d-amphetamine, the mixed D1-D2 agonist apomorphine, SKF 38393 and SKF 82958 (both preferential D1 agonists), quinpirole (a preferential D2 agonist), GBR 12909 (a dopamine reuptake inhibitor), procaine (a local anesthetic), and morphine (an opiate). The results showed that cadmium-exposed rats were slower to acquire the saline–cocaine discrimination than controls. Moreover, cadmium contamination reduced substitution when apomorphine, SKF 82958, and GBR 12909 were presented during generalization testing. Also, cadmium exposure blocked tolerance to cocaine that was evident in control rats following 14 days of exposure to 60 mg/kg/day cocaine.