Some antidepressants are reported to have anti-inflammatory effects as well. We therefore studied the effects of various antidepressants, i.e., paroxetine (SSRI), fluvoxamine (SSRI), sertraline (SSRI), milnacipran (SNRI) and amitriptyline (TCA), on microglial activation in the LPS-inflammation model without cell death. Among antidepressants used, only paroxetine suppressed microglial activation as is shown by their morphology, CD11b expression level, and L-Glu release. We thus investigated the mechanisms which restricted the effects to paroxetine. Because we have shown that P2X4 receptor is important for acceleration of microglial activation in this inflammation model, we first examined the interaction between antidepressants described above and P2X4 receptor by comparing the effects of these drugs (0.1nM-10μM) on the P2X4-mediated Ca2+ influx to 1321N1 cells which stably express P2X4 receptors. We also confirmed the cell toxicity of the antidepressants in this concentration range. Unexpectedly, interactions with P2X4 receptors were observed for all antidepressants used here. Further, sertraline showed the most powerful inhibition and paroxetine showed the second-most powerful inhibition in a concentration-dependent manner. Our present results suggest that P2X4 does not restrict the suppressive effects to paroxetine. Currently we are investigating the other possible targets, i.e., ATP release from activated microglia or other subtypes of purinergic receptors.