Caffeine-mediated induction of c-fos, zif-268 and arc expression through A1 receptors in the striatum: different interactions with the dopaminergic system.

Adenosine and the adenosine receptor antagonist, caffeine, modulate locomotor activity and striatal neuropeptide expression through interactions with the dopaminergic system by mechanisms which remain partially undetermined. We addressed this question by using quantitative immunocytochemistry and in situ hybridization, combined with retrograde tracing of striatal neurons, to characterize the mechanism(s) leading to the striatal increase in the immediate early genes (IEG), c-fos, zif-268 and arc, following a single injection of caffeine or the A1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Caffeine and DPCPX induced c-fos, zif-268 and arc expression, both at mRNA and protein levels, in large proportions of striatonigral and striatopallidal neurons. The involvement of dopamine systems was evaluated by manipulations of the dopaminergic transmission. Quinpirole, a D2 agonist, almost completely blocked the caffeine-induced IEG increase in both striatopallidal and striatonigral neurons. Conversely, the lesion of the nigrostriatal pathway and the D1 antagonist SCH23390 abolished the caffeine effects in striatonigral neurons but had no or slight effect, respectively, on its action in striatopallidal neurons. These observations demonstrate that caffeine- and DPCPX-mediated IEG inductions involved different mechanisms in striatonigral and striatopallidal neurons through blockade of A1 receptors. Immediate early gene inductions result from a stimulation of dopamine release in striatonigral neurons and from activation of glutamate release and probably also acetylcholine release in striatopallidal neurons. These results also support the idea that, besides A2A receptors, adenosine acting at the A1 receptor plays pivotal functions in the basal ganglia physiology and that blockade of these receptors by specific or nonspecific antagonists, DPCPX and caffeine, may influence a broad range of neuronal functions in the striatum.