Complement C5a exhibits anxiolytic-like activity via the prostaglandin D2−DP1 receptor system coupled to adenosine A2A and GABAA receptors

We have recently found that central PGD2 exhibits anxiolytic-like activity. Here we show that complement C5a exhibits anxiolytic-like activity via the PGD2 system. Centrally administered C5a had anxiolytic-like activity at a dose of 0.3 pmol/mouse in the elevated plus-maze test in mice. C5a-induced anxiolytic-like activity was inhibited by indomethacin, a cyclooxygenase inhibitor, or BWA868C, an antagonist of DP1 receptor for PGD2, respectively. The anxiolytic effect of C5a was also blocked by SCH58261 or bicuculline, antagonists of adenosine A2A and GABAA receptors, respectively, which were activated downstream of PGD2–DP1 receptor. These results suggest that C5a exhibits anxiolytic-like activity via the PGD2–DP1 receptor system coupled to the activation of adenosine A2A and GABAA receptors.

► Complement C5a exhibits anxiolytic activity after central administration. ► C5a-induced anxiolytic activity was blocked by a COX inhibitor or an antagonist of DP1 receptor for prostaglandin (PG) D2. ► This was also blocked by antagonists of adenosine A2A and GABAA receptors, which were activated downstream of the PGD2–DP1 receptor system. ► Thus, C5a exhibits anxiolytic activity via the PGD2–DP1 system coupled to A2A and GABAA receptors.