Combination of adenosine A1 and A2A receptor blocking agents induces caffeine-like locomotor stimulation in mice

The spontaneous locomotor activity of C57BL/6J mice was examined, using an automated detection system based on infra-red beams, after administration of caffeine (3-30 mg/kg, i.p.), the adenosine A(2A) receptor selective antagonist SCH 58261 (0.312-2.5 mg/kg, i.p.) and the A(1) selective antagonist DPCPX (1.25-5 mg/kg, i.p.). SCH 58261 failed to influence motor activity in mice habituated to the test environment. DPCPX produced a small increase in motility and locomotion (significant at the dose of 5.0 mg/kg), much weaker than that produced by caffeine. Combined administration of DPCPX (1.2 mg/kg, i.p.) and SCH 58261 (1.2 mg/kg, i.p.) produced stimulation of motility and locomotion comparable with the effect of caffeine (15 mg/kg, i.p.). In contrast to motility and locomotion, rearing counts were not significantly influenced by DPCPX, SCH 58261, their combination, or by caffeine. Caffeine (15 mg/kg, i.p.) caused an increase in NGFI-A mRNA (an immediate early gene was chosen as an index of neuronal activation) in the piriform cortex 4 h after injection. This effect was reproduced by the combination of A(1) and A(2A) receptor antagonist. It is hypothesised that the stimulatory effect of low doses of caffeine in C57BL/6J mice is due to concomitant blockade of both A(1) and A(2A) adenosine receptors.