This study examined the role of dopamine systems in tolerance to caffeine-induced stimulation of motor activity in the rat. Selective dopamine D1 and D2 receptor agonists were tested alone and combined in rats receiving caffeine chronically by a method of scheduled access to a caffeine solution or in control rats receiving no caffeine. Rats treated chronically with oral caffeine were tolerant to the motor stimulant effects of caffeine (3.0-100 mg/kg, i.p.). The partial dopamine D1 receptor agonist SKF-77434 (1.0-30 mg/kg, s.c.) and the dopamine D2 receptor agonists quinpirole (0.03-10 mg/kg, s.c.) and R(-)-pro-pylnorapomorphine (NPA, 0.03-1.0 mg/kg, s.c.) dose-dependently increased activity in control rats. Caffeine-treated rats were cross-tolerant to the locomotor stimulant effect of these selective dopamine D1 and D2 receptor agonist. The concurrent administration of the partial dopamine D1 receptor agonist SKF-38393 (10 mg/kg, s.c.) with the dopamine D2 receptor agonists quinpirole and R(-)-propylnorapomorphine had a synergistic effect on locomotor activity in both control and caffeine-treated rats. This synergistic effect was also seen when the partial dopamine D1 receptor agonist SKF-77434 (1.0 and 10 mg/kg, s.c.) was given in combination with quinpirole. There was little or no cross-tolerance to the concurrent administration of selective dopamine D1 and D2 receptor agonists. It appears that tolerance to the locomotor stimulant effect of caffeine is mediated by both dopamine D1 and D2 receptor sub-types. Cross-tolerance occurs to drugs that activate a single type of dopamine receptor but not to drug combinations that concurrently activate more than one type of receptor.