Crosstalk Between ATP-P 2X7 and Adenosine A 2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P receptors (P R) and adenosine A receptors (A R) 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 P R and A R. 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 P R (mRNA) and A R (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, .), which affords neuroprotection through A R blockade. Notably, BBG attenuated A R upregulation and caffeine attenuated P R upregulation. In microglial N9 cells, the P R agonist BzATP (100 μM) or the A R agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P R antagonist JNJ47965567 (1 μM) and by the A R 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 P R and A R 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.