Five dogs with chronic doubly cannulated proximal jejunal Thiry-Vella loops were studied to evaluate the role of luminal and circulating serotonin on intestinal intraluminal pressure quantitated using computer-assisted planimetry. Luminal perfusion with serotonin (50 micrograms/min) for 60 min resulted in a significant increase in luminal pressure. Upon cessation of infusion, intraluminal pressures rapidly returned to basal. While 4% lidocaine had no effect on basal intraluminal pressure, the drug almost abolished the pressure response to luminal serotonin. In contrast, atropine lowered mean baseline intraluminal pressures and also markedly inhibited the response to subsequent perfusion with serotonin. These data suggest that the motility response to intraluminal serotonin is neurally mediated. Intravenous serotonin infusion (3.3 micrograms/kg/min), which raised circulating levels of the amine to those noted after a standard meal, increased intraluminal pressures to a maximum similar to those noted after luminal perfusion; after cessation of infusion, pressures rapidly returned to basal. These observations support a physiologic role for serotonin in the modulation of intestinal motility.