Abstract
Repeated stress triggers anxiety accompanied by a deregulation of cortical glucocorticoid receptors, which is relieved by blocking adenosine A(2A) receptors (A(2A)R). A(2A)R also controls the glymphatic system and the polarization of its key driver aquaporin-4 (AQP4). Since the glymphatic system is altered upon repeated stress, we now tested if A(2A)R blockade could alleviate AQP4 polarization in rats subject to repeated restraint stress (RRS). As expected, RRS enhanced anxiety in the elevated plus maze, decreased self-care behavior in the splash test, and decreased cortical glucocorticoid receptors levels; these alterations were prevented by daily treatment with the selective A(2A)R antagonist KW-6002 (3 mg/kg/day). KW-6002 treatment also prevented the RRS-induced decrease of AQP4 density in gliosomes, corresponding to astrocytic membrane endfeet, the perivascular AQP4 polarization in astrocytes, and both perivascular and cellular AQP4 coverage. These findings show that A(2A)R controls AQP4 polarization upon restraint stress and prompt considering that A(2A)R might control the impact of repeated stress on brain dysfunction through a control of the glymphatic system.