{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T17:40:16Z","timestamp":1793814016813,"version":"4.6.1"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P<jats:sub>2X7<\/jats:sub>receptors (P<jats:sub>2X7<\/jats:sub>R) and adenosine A<jats:sub>2A<\/jats:sub>receptors (A<jats:sub>2A<\/jats:sub>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<jats:sub>2X7<\/jats:sub>R and A<jats:sub>2A<\/jats:sub>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 \u201cactivation\u201d) and interleukin-1\u03b2 (IL1\u03b2) and tumor necrosis factor \u03b1 (TNF\u03b1; proinflammatory cytokines) and an up-regulation of P<jats:sub>2X7<\/jats:sub>R (mRNA) and A<jats:sub>2A<\/jats:sub>R (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P<jats:sub>2X7<\/jats:sub>R-preferring antagonist brilliant blue G (BBG, 45 mg\/kg, i.p.) or by caffeine (0.3 g\/L,<jats:italic>p.o<\/jats:italic>.), which affords neuroprotection through A<jats:sub>2A<\/jats:sub>R blockade. Notably, BBG attenuated A<jats:sub>2A<\/jats:sub>R upregulation and caffeine attenuated P<jats:sub>2X7<\/jats:sub>R upregulation. In microglial N9 cells, the P<jats:sub>2X7<\/jats:sub>R agonist BzATP (100 \u03bcM) or the A<jats:sub>2A<\/jats:sub>R agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P<jats:sub>2X7<\/jats:sub>R antagonist JNJ47965567 (1 \u03bcM) and by the A<jats:sub>2A<\/jats:sub>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<jats:sub>2X7<\/jats:sub>R and A<jats:sub>2A<\/jats:sub>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.<\/jats:p>","DOI":"10.3389\/fncel.2021.639322","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T05:50:42Z","timestamp":1614577842000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":41,"title":["Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress"],"prefix":"10.3389","volume":"15","author":[{"given":"Liliana","family":"Dias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e1tia R.","family":"Lopes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Q.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Nunes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Pochmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuno J.","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo R.","family":"Tom\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Agostinho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo A.","family":"Cunha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105253","DOI":"10.1016\/j.phrs.2020.105253","article-title":"Purinergic signaling orchestrating neuron-glia communication","volume":"162","author":"Agostinho","year":"2020","journal-title":"Pharmacol. 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