The present microdialysis study evaluated the anticonvulsant activity of extracellular hippocampal dopamine (DA) and serotonin (5-HT) with concomitant assessment of the possible mutual interactions between these monoamines. The anticonvulsant effects of intrahippocampally applied DA and 5-HT concentrations were evaluated against pilocarpine-induced seizures in conscious rats. DA or 5-HT perfusions protected the rats from limbic seizures as long as extracellular DA or 5-HT concentrations ranged, respectively, between 70-400% and 80-350% increases compared with the baseline levels. Co-perfusion with the selective D(2) blocker remoxipride or the selective 5-HT(1A) blocker WAY-100635 clearly abolished all anticonvulsant effects. These anticonvulsant effects were mediated independently since no mutual 5-HT and DA interactions were observed as long as extracellular DA and 5-HT levels remained within these protective ranges. Simultaneous D(2) and 5-HT(1A) receptor blockade significantly aggravated pilocarpine-induced seizures. High extracellular DA (> 1000% increases) or 5-HT (> 900% increases) concentrations also worsened seizure outcome. The latter proconvulsive effects were associated with significant increases in extracellular glutamate (Glu) and mutual increases in extracellular monoamines. Our results suggest that, within a certain concentration range, DA and 5-HT contribute independently to the prevention of hippocampal epileptogenesis via, respectively, D(2) and 5-HT(1A) receptor activation.