CAFFEINE CROSS-TOLERANCE TO SELECTIVE DOPAMINE D-1 AND D-2 RECEPTOR AGONISTS BUT NOT TO THEIR SYNERGISTIC INTERACTION

This study examined the role of dopamine systems in tolerance to caffeine-induced stimulation of motor activity in the rat. Selective dopamine D-1 and D-2 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 D-1 receptor agonist SKF-77434 (1.0-30 mg/kg, s.c.) and the dopamine D-2 receptor agonists quinpirole (0.03-10 mg/kg, s.c.) and R(-)-propylnorapomorphine (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 D-1 and D-2 receptor agonists. The concurrent administration of the partial dopamine D-1 receptor agonist SKF-38393 (10 mg/kg, s.c.) with the dopamine D-2 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 D-1 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 D-1 and D-2 receptor agonists. It appears that tolerance to the locomotor stimulant effect of caffeine is mediated by both dopamine D-1 and D-2 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.