Recent studies have shown excitatory effects of serotonin on upper airway motoneurons. This excitatory effect is normally present and arises from cells in the caudal raphe nuclei. The firing of these serotonergic neurons is reduced during sleep. To determine the importance of serotonin in the maintenance of patient airways and normal respiration in waking in obstructive sleep apnea, we studied the effects of two serotonin antagonists on upper airway dilator muscle activity, diaphragm activity, Sao2, and upper airway cross-sectional area in an animal model of sleep-disordered breathing, the English bulldog. Systemic administration of both antagonists resulted in significant reductions in the peak amplitudes of upper airway muscle respiratory bursts (range, 39 to 62% suppression; p < 0.05). Lesser reductions in diaphragm activity were noted (range, 10 to 33% suppression; p < 0.05). Oxyhemoglobin saturations also fell (p < 0.05), coinciding with suppressions in upper airway muscle activity. With reductions in dilator muscle activity, upper airway cross-sectional areas, as measured with cine CT, showed significant inspiratory collapse. These results support the hypothesis that serotonin is important in the maintenance of patent upper airways in obstructive sleep apnea.