Caffeine and the Regulation of Locomotor Activity / Summary

In addition to modulating dopaminergic processes, caffeine shows neuroprotective efficacy in animal models of PD. In mice with neurotoxin-induced damage, caffeine acts in a dose-dependent manner to reduce the loss of endogenous dopamine and the dopamine transporter in mouse striatum. Striatal A_2AAR has been proposed to promote glutamate release and glia-mediated inflammation, which contribute to the pathogenesis of PD. Studies showing a significant reduction in risk of PD in populations with regular caffeine intake support a neuroprotective effect of caffeine against the development or exacerbation of PD. In an animal model, the neuroprotective effects of caffeine were mimicked by A_2AAR but not A₁AR antagonists, suggesting that A_2AAR blockade predominates in the antiPD effect of caffeine.

Caffeine and the Regulation of Locomotor Activity / Caffeine and PD

The influence of caffeine on locomotion is dose-dependent. High doses of caffeine (100 mg/kg) are either ineffective or reduce locomotor activity in both rats and mice; this effect has been attributed to rapid development of tolerance. A₁AR blockade promotes D₁R-mediated enhancement of locomotion in rats, and this effect is attenuated by prior chronic treatment with caffeine but not with a selective A_2AAR antagonist. Furthermore, long-term administration of a specific A_2AAR antagonist did not induce tolerance to caffeine. These findings led to the proposal that tolerance to caffeine is associated with chronic occupancy of A₁AR and that A₁AR activity is reduced and A_2AAR function is retained during the generation of caffeine tolerance.

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.

Caffeine and the Regulation of Locomotor Activity / part 1

The methylxanthine drug caffeine is a well-known psychostimulant chemical that promotes behaviors such as vigilance, attention, arousal, and locomotor activity. Caffeine is a competitive inhibitor of cyclic nucleotide phosphodiesterase (an enzyme that catalyzes cAMP degradation). However, caffeine's major mechanism of action in brain is nonselective blockade of adenosine re-ceptors.³⁰ Caffeine blocks postsynaptic A₁AR and A_2AAR, causing attenuation of adenosinergic neurotransmission and relative amplification of dopaminergic neurotransmission. These effects enhance both D₁R-mediated inhibition (via the direct pathway) and D₂R-mediated attenuation in stimulation (via the indirect pathway) on GPi-SNr-mediated inhibition of thalamus, thereby increasing thalamic stimulation of cortex and promoting locomotion.