Chronic administration of cocaine (50 mg/kg/day for 7 days, s.c. via an osmotic minipump) produced tolerance to inhibition of [3H]dopamine uptake by cocaine in rat striatum but did not produce cross-tolerance to inhibition of [3H]dopamine uptake by nicotine. Chronic nicotinic treatment (6 mg/kg/day for 7 days, s.c. via an osmotic minipump), however, produced tolerance to the inhibition of [3H]dopamine uptake by nicotine and cross-tolerance to inhibition of uptake by cocaine in rat striatum. Nicotine did not inhibit uptake of [3H]dopamine in the nucleus accumbens of saline-treated animals. In this tissue, both cocaine and nicotine treatments produced tolerance to cocaine, as in striatum. Unlike the effects on [3H]dopamine uptake, chronic cocaine infusion did not have any effect on the ability of cocaine to inhibit [3H]serotonin uptake in either brain region.