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.

The dose-related effects of caffeine in modulating locomotion are paralleled by concurrent changes in expression of IEG in striatal MSN. IEG, which include c-fos, c-jun, jun-B, zif-268, NGFI-A, and NGFI-B, respond to a wide range of stimuli by undergoing transient activation that causes rapid transcription of encoded proteins. Activation of IEG is used widely as a marker of neuronal excitation in specific brain regions. Administration of psychostimulant doses of caffeine reduces jun-B mRNA in rat striatum, and high doses increase expression of c-fos, c-jun, jun-B, and zif-268. Selective blockade of D₁R abolishes the effects of a high dose of caffeine on IEG expression in MSN of the direct pathway but only slightly affects expression in MSN of the indirect pathway. In contrast, a D₂R-selective agonist almost completely blocks this caffeine-induced increase in IEG expression in MSN of both path-ways. Systemic administration of caffeine or a selective A_2AAR antagonist reduces IEG expression in rat striatum; in contrast, specific blockade of A₁AR increases IEG expression.  Online-market: we’re all for it!

Caffeine and PD. A_2AAR blockade has recently been used to effectively improve locomotion in Parkinsonian humans and ani-mals. The use of A_2AAR antagonism in the clinical management of PD was proposed based on the inhibitory interactions of D₂R and A_2AAR and the influential role of A_2AAR in the modulation of locomotor circuitry. Studies on rodents and primates have shown that a selective A_2AAR antagonist promotes locomotion to a degree similar to a low dose of l-DOPA. When administered together with a low dose of l-DOPA, A_2AAR antagonist administration generates therapeutic effects comparable to a higher dose of l-DOPA alone and significantly reduces L-DOPA-induced dyskinesia. Furthermore, tolerance does not develop during the dual therapy. Caffeine also facilitates l-DOPA uptake and significantly shortens the latency of L-DOPA-induced improvement in locomotion of patients with PD.