Adenosine A_2A Receptors Control the Mis-Localization of Aquaporin-4 in Rats Subject to Repeated Restraint Stress

Repeated stress triggers anxiety accompanied by a deregulation of cortical glucocorticoid receptors, which is relieved by blocking adenosine A_2A receptors (A_2AR). A_2AR 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_2AR 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_2AR 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_2AR controls AQP4 polarization upon restraint stress and prompt considering that A_2AR might control the impact of repeated stress on brain dysfunction through a control of the glymphatic system.