The adenosine A 1 receptor contributes to the stimulatory, but not the inhibitory effect of caffeine on locomotion: a study in mice lacking adenosine A 1 and/or A 2A receptors

Abstract

Caffeine has biphasic effects on locomotion, and blockade of the adenosine A 2A receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A 1 receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type mice (A1R WT), mice heterozygous for (A1R HET), and mice lacking the adenosine A 1 receptor (A1R KO). Caffeine had the typical biphasic dose–effect relationship in all three genotypes, but the stimulatory action of caffeine was facilitated in the A1R KO mice. In order to investigate the interaction between blockade of A1Rs and A2ARs, mice lacking both receptors (A1R KO/A2AR KO) were tested. Regardless of A1R genotype, animals lacking A2AR were not stimulated by caffeine, whereas animals heterozygous for A2AR were. As expected, the A1R is not crucial for the stimulatory effect of caffeine, but seems to modulate the effect of caffeine exerted via A2AR blockade. Furthermore, these results suggest that the inhibitory effect of high doses of caffeine is due neither to blockade of the A1R, nor of the A2AR, and an effect independent of these adenosine receptors is likely.