Depression has been associated with glial dysfunction, but the underlying mechanisms have remained elusive. Here, mice that developed depression-like behaviour after chronic social defeat stress had reduced ATP levels in the prefrontal cortex (PFC) and hippocampus compared with non-depressed and control mice. Central or peripheral ATP administration reduced depression-like behaviour in these mice. Transgenic mice with reduced or enhanced astrocytic ATP release showed higher and lower levels of depression-like behaviour, respectively. Infusion of purinergic P2X receptor antagonists into the medial PFC blocked antidepressant effects of ATP administration in socially defeated mice. These data suggest that deficient astrocytic ATP release and P2X receptor activation have a role in depression.