The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A2A receptors

The locomotor stimulatory effects induced by caffeine (1,3,7‐trimethylxanthine) in rodents have been attributed to antagonism of adenosine A1 and A2A receptors. Little is known about its locomotor depressant effects seen when acutely administered at high doses. The roles of adenosine A1 and A2A receptors in these activities were investigated using a Digiscan actimeter in experiments carried out in mice. Besides caffeine, the A2A antagonist SCH 58261 (5‐amino‐7‐(β‐phenylethyl)‐2‐(8‐furyl)pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine), the A1 antagonist DPCPX (8‐cyclopentyl‐1,3‐dipropylxanthine), the A1 agonist CPA (N6‐cyclopentyladenosine) and A2A receptor knockout mice were used. Caffeine had a biphasic effect on locomotion of wild‐type mice not habituated to the open field, stimulating locomotion at 6.25–25 mg kg−1 i.p. doses, while depressing it at 100 mg kg−1. In sharp contrast, caffeine dose‐dependently decreased locomotion in A2A receptor knockout mice over the whole range of tested doses. The depressant effects induced by high doses of caffeine were lost in control CD1 mice habituated to the open field. The A1 agonist CPA depressed locomotion at 0.3–1 mg kg−1 i.p. doses. The A1 antagonist DPCPX decreased locomotion of A2A receptor knockouts and CD1 mice at 5 mg kg−1 i.p. and 25 mg kg−1 i.p. respectively. DPCPX (0.2–1 mg kg−1 i.p.) left unaltered or even reduced the stimulant effect of SCH 58261 (1–3 mg kg−1 i.p.) on CD1 mice. These results suggest therefore that the stimulant effect of low doses of caffeine is mediated by A2A receptor blockade while the depressant effect seen at higher doses under some conditions is explained by A1 receptor blockade.