The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A(2A) receptors

1 The locomotor stimulatory effects induced by caffeine (1,3,7-trimethylxan thine) in rodents have been attributed to antagonism of adenosine A(1) and A(2A) receptors. Little is known about its locomotor depressant effects see n when acutely administered at high doses. The roles of adenosine A(1) and A(2A) receptors in these activities were investigated using a Digiscan acti meter in experiments carried out in mice. Besides caffeine, the A(2A) antag onist SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1, 2,4-triazolo[1,5-c]pyrimidine), the A(1) antagonist DPCPX (8-cyclopentyl-1, 3-dipropylxanthine), the A(1) agonist CPA (N-6-cyclopentyladenosine) and A( 2A) receptor knockout mice were used. 2 Caffeine had a biphasic effect on locomotion of wild-type mice not habitu ated to the open field, stimulating locomotion at 6.25-25 mg kg(-1) i.p. do ses, while depressing it at 100 mg kg(-1). In sharp contrast, caffeine dose -dependently decreased locomotion in A(2A) receptor knockout mice over the whole range of tested doses. 3 The depressant effects induced by high doses of caffeine were lost in con trol CD1 mice habituated to the open held. 4 The A(1) agonist CPA depressed locomotion at 0.3-1 mg kg(-1) i.p, doses. 5 The A(1) antagonist DPCPX decreased locomotion of A(2A) receptor knockout s and CD1 mice at 5 mg kg(-1) i.p. and 25 mg kg(-1) i.p. respectively. 6 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. 7 These results suggest therefore that the stimulant effect of low doses of caffeine is mediated by A(2A) receptor blockade while the depressant effec t seen at higher doses under some conditions is explained by A, receptor bl ockade.