The role of the L-arginine-NO pathway on the formation of PGE2 by human cultured astroglial cells incubated with NMDA has been investigated. Preincubation of T 67 astroglial cell line with NMDA (10-600 microM) produced a significant dose-dependent increase of both nitrite (the breakdown product of NO), PGE2 and cGMP levels in cell supernatant. This effect was inhibited by coincubation of cells with L-NAME (20-300 microM), an inhibitor of NO synthase showing that the release of PGE2 subsequent to NMDA receptor stimulation was driven by NO. The release of PGE2 but not elevation of nitrite and cGMP levels was affected by indomethacin (10 microM), an inhibitor of cyclooxygenase. The inhibitory effect of L-NAME on PGE2 release by NMDA-pretreated astroglial cells was reverted by arachidonic acid, showing that the effect of NO on PGE2 release occurred at the cyclo-oxygenase level. Thus, the present experiments demonstrate that the release of PGE2 by astroglial cells pretreated with NMDA is driven by activation of the L-arginine-NO pathway, and this may be relevant in the pathophysiological mechanisms where glutamatergic neurotransmission is involved.