Caffeine and the Regulation of Locomotor Activity / part 2

Other mechanisms also contribute to the general behavioral stimulation induced by caffeine. Studies with adenosine receptor KO mice indicate that A_2AAR, but not A₁AR, are involved in the sleep-promoting effect of adenosine. Caffeine administration reduces the hypnotic effects of alcohol in mice by means of A_2AAR blockade,and caffeine-induced psychomotor stimulation is deficient in A_2AAR KO mice, supporting the contention that caffeine-induced psychomotor stimulation occurs through A_2AAR antagonism. Finally, by blocking A₁AR, caffeine attenuates adenosine-mediated inhibition of mesopontine cholinergic neurons in the brainstem, thereby increasing neuronal firing rate, stimulating prefrontal cortex, and promoting arousal.

Although both A₁AR and A_2AAR antagonists can promote locomotor activity, consensus has not been reached regarding the relative contributions of A₁AR and A_2AAR blockade to the effects of caffeine. Caffeine-mediated locomotor activation has been attributed to blockade of presynaptic A₁AR, because administration of both caffeine and selective A₁AR antagonists caused behavioral changes and increased release of dopamine and glutamate in rat striatum. Furthermore, A₁AR agonists reduce dopamine release. 
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However, genetic deletion of A_2AAR reduces dopamine levels in striatum, although A_2AAR are not present on striatal dopaminergic terminals. These data suggest that A_2AAR has a significant (although perhaps indirect) role in regulating dopamine levels in striatum and that caffeine acts presynaptically through A₁AR to modulate extracellular levels of both glutamate and dopamine. With regard to behavior, A₁AR agonists reduce locomotor activity and attenuate the psychomotor stimulant effect of caffeine to a greater extent than do selective A_2AAR ago-nists. However, the effects of both drugs are attenuated in A_2AAR KO mice, suggesting that the inhibitory effect of A₁AR on locomotion is dependent on A_2AAR. In rats, a selective A_2AAR antagonist increased locomotor activity to an extent comparable to caffeine, whereas a selective A₁AR agonist did not, further implying that psychomotor stimulant effects of caffeine are mediated mainly through A_2AAR blockade.