The impact of the P2X7 receptor antagonist A-804598 on neuroimmune and behavioral consequences of stress

Stress leads to neuroinflammatory and behavioral consequences through upregulation of inflammatory-related cytokines within the central nervous system such as interleukin-1β (IL-1β), which may be indicative of microglial priming/activation. Evidence suggests that the P2X7 receptor (P2X7R) may play an important role in the synthesis and conversion of IL-1β. In a series of six experiments, adult male rats were intubated with a highly selective P2X7R antagonist (A-804598) before footshock exposure. As expected, footshock increased IL-1β and CD14 mRNA in the paraventricular nucleus, and A-804598 (25mg/kg) partially attenuated these effects. Footshock also increased hypothalamic IL-1 protein in whole hypothalamic blocks, but no effect was observed on the formation of pro-IL-1β or IL-1β in the paraventricular nucleus as assessed using western blotting. A-804598 also did not reverse the suppression in exploration produced by stress exposure. The present findings support the use of the footshock paradigm as a method for inducing stress-related neuroimmune and behavioral changes, but the evidence to support the role of A-804598 as a potential tool to reverse such changes remains modest. This study is the first to examine the role of P2X7R in vivo following footshock exposure. Further characterization of P2X7R may have implications for understanding the relationship between stress and inflammation.