When considering possible targets for regulation of IL-1β, the purinergic receptor, P2X7, has received attention for several reasons. The processing and release of IL-1β in microglia, as well as peripheral macrophages, are stimulated by ATP-activation of the P2X7 receptor (Block et al., 2012; Ferrari et al., 1997b). The P2X7 receptor is a cell surface K+ ionophore that, when stimulated leads to activation of the NLRP3 inflammasome and release of IL-1β (Fig. 2) (Ferrari et al., 1997b). Moreover, there is a P2X7 receptor gene polymorphism that is associated with major depression (Lucae et al., 2006). P2X7 receptor knockout mice also exhibit an antidepressant- like profile in behavioral models, including the tail suspension and forced swim tests (Basso et al., 2009), and are resistant to stress in certain models of depression (Boucher et al., 2011). Preliminary results from our laboratory demonstrate that a selective, high affinity P2X7 receptor antagonist, A-804598 (Donnelly-Roberts et al., 2009), blocks the down-regulation of neurogenesis caused by acute stress (Iwata et al., 2012). Moreover, we have found that chronic administration of this P2X7 receptor antagonist reverses the depressive behavior caused by chronic unpredictable stress (unpublished observations).
