Arousal effect of caffeine depends on adenosine A_2A receptors in the shell of the nucleus accumbens

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosineA_2A receptors (A_2ARs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A_2ARs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that theA_2ARs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness. Caffeine-induced arousal was not affected in rats when A_2ARs were focally removed from the NAc core or other A_2AR-positive areas of the basal ganglia. Our observations suggest that caffeine promotes arousal by activating pathways that traditionally have been associated with motivational and motor responses in the brain.