This study examined the influence of N-methyl-D-aspartate (NMDA) receptors upon the activity of serotoninergic neurones projecting from the rat dorsal raphe nucleus (DRN) to the striatum of rats. The channel blocker (+)-MK 801 (0.04-0.63 mg/kg, s.c.) augmented striatal accumulation of the serotonin (5-HT) precursor, 5-hydroxytryptophan (5-HTP), in rats treated with the inhibitor of decarboxylase, NSD 1015: the maximal effect of (+)-MK 801 was 164% relative to vehicle values (= 100%). In analogy, (+)-MK 801 (0.01-0.5 mg/kg, i.v.) increased the firing rate of DRN neurones with a maximal effect of 204%. This action was stereospecific in that (-)-MK 801, which shows lower affinity at NMDA receptors, enhanced firing only at higher doses. The selective, competitive antagonist at the NMDA recognition site, CPP (0.5-8.0 mg/kg, i.v.), also facilitated the firing rate of DRN neurones, though with a maximal effect (137%) less than that of (+)-MK 801. Further, CPP (40.0 mg/kg, s.c.) did not significantly modify striatal 5-HT synthesis. While NMDA did not significantly modify DRN firing alone, it abolished the facilitatory action of CPP, consistent with a competitive interaction at the NMDA recognition site. In conclusion, blockade of NMDA receptors specifically facilitates the activity of ascending serotoninergic neurones.