The antidepressant effect of a night without sleep is a well-known but poorly understood phenomenon. The authors showed that 12-hour sleep deprivation increased hippocampal extracellular adenosine levels and adenosine receptor A1 (A1R) signalling in mice. Conversely, impairing gliotransmission in astrocytes reduced the antidepressant-like effects of 12-hour sleep deprivation. Moreover, sleep deprivation had no effects in mice lacking A1Rs and central administration of an A1R agonist mimicked the antidepressant effect of sleep deprivation. These data point to astrocytic adenosine signalling as a possible therapeutic target for a novel class of antidepressants.