Inflammation is widely recognized as contributing to the pathology of acute and chronic neurodegenerative conditions. Microglial cells are pathologic sensors in the brain and activated microglia have been viewed as detrimental. Leukotriene, including cysteinyl leukotrienes (CysLTs) are suggested to be involved in brain inflammation and neurological diseases and ATP, by its receptors is a candidate for microglia activation. A23187 (10μM) stimulated microglia to co-release CysLTs and [³H]adenine based purines ([³H]ABPs), mainly ATP. The biosynthetic production of CysLTs was abolished by 10μM MK-886, an inhibitor of 5-lipoxygenase-activating protein activity. RT-PCR analysis showed that microglia expressed both CysLT₁/ CysLT₂receptors, P₂Y₁ATP-receptors and several members of the ATP binding cassette (ABC) transporters including MRP1, MRP4 and Pgp. The increase in [Ca²⁺]i elicited by LTD4 (0.1 μM) and 2MeSATP (100μM), agonists for CysLT- and P₂Y₁-receptors, was abolished by the respective antagonists, BAYu9773 (0.5 μM) and suramin (50 μM). The stimulation of both receptor subtypes, induced a concomitant increase in the release of both [³H]ABPs and CysLTs that was blocked by the antagonists and significantly reduced by a cocktail of ABC transporter inhibitors, BAPTA/AM (intracellular Ca²⁺chelator) and staurosporine (0.1 μM, PKC blocker). P2Y antagonist was unable to antagonise the effects of LTD₄and BAYu9773 did not reduce the effects of 2MeSATP. These data suggest that: i) the efflux of purines and cysteinyl-leukotrienes is specifically and independently controlled by the two receptor types, ii) calcium, PKC and the ABC transporter system can reasonably be considered common mechanisms underlying the release of ABPs and CysLTs from microglia. The blockade of P₂Y₁or CysLT₁/CysLT₂receptors by specific antagonists that abolished the raise in [Ca²⁺]i and drastically reduced the concomitant efflux of both compounds, as well as the effects of BAPTA and staurosporine support this hypothesis. In conclusion, the data of the present study suggest a cross talk between the purine and leukotriene systems in a possible autocrine/paracrine control of the microglia-mediated initiation and progression of an inflammatory response.