Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P receptors (PR) and adenosine A receptors (AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between PR and AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia "activation") and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of PR (mRNA) and AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the PR-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, .), which affords neuroprotection through AR blockade. Notably, BBG attenuated AR upregulation and caffeine attenuated PR upregulation. In microglial N9 cells, the PR agonist BzATP (100 μM) or the AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the PR antagonist JNJ47965567 (1 μM) and by the AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between PR and AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.