To assess the role of NMDA receptors in modulating neurotransmitter release in the myenteric plexus, we studied the effects of L-glutamic acid and NMDA on endogenous acetylcholine and noradrenaline overflow (assayed by HPLC) from the guinea pig isolated distal colon. L-Glutamic acid and NMDA enhanced electrically evoked acetylcholine and noradrenaline overflow and these effects were reversed by selective NMDA receptor antagonists. The possible functional significance of these findings was studied by measuring the efficiency of the colonic peristaltic reflex in the presence of NMDA receptor agonists. NMDA inhibited propulsion velocity at all concentrations tested, this effect being antagonized by (+/-)-2-amino-5-phosphonopentanoic acid and virtually abolished in sympathetically denervated animals. In conclusion, the inhibitory effect of NMDA on peristalsis, being almost entirely dependent on the integrity of sympathetic pathways, could be, at least in part, due to NMDA-induced noradrenaline release.