A regulatory pathway linking caffeine action, mood and the diurnal clock.

Depression is a leading cause of disability worldwide. Circadian abnormalities and mood changes are symptoms of depression. The psychostimulant caffeine alters wakefulness and alleviates other depression-related symptoms during chronic intake, but the underlying mechanisms are unclear. It is not known, whether and how acute caffeine administration affects mood. Molecular approaches, transgenic mouse models, pharmacological intervention and behavioral analysis were combined to uncover a regulatory pathway, which connects caffeine action with diurnal signaling via the key dopaminergic protein DARPP-32 and alters mood-related phenotypes in mice, which are often assessed in the context of antidepressant action. We observed that Thr75-DARPP-32 binds to the circadian regulator CLOCK and disrupts CLOCK:BMAL1 chromatin binding, thereby affecting gene expression. T75A-DARPP-32 mutant mice show reduced caffeine effects on CLOCK:BMAL1 and lack caffeine-induced effects on mood. This study provides a link between caffeine, diurnal signaling and mood-related behaviors, which may open new perspectives for our understanding of antidepressant mechanisms in the mouse brain.