The effects of [+/-]-2,5-dimethoxy-4-iodoaminophentamine, a serotonin(2A/2C) receptor agonist, on pharyngeal airflow mechanics were examined in isoflurane-anesthetized lean and obese Zucker rats. The pharyngeal pressure associated with flow limitation, maximum inspiratory flow, oronasal resistance, genioglossus muscle activity, and arterial blood pressure (BP) were measured before and after the intravenous administration of the agonist. A robust activation of the genioglossus muscle in all lean and obese rats was associated with decreased upper airway (UA) collapsibility (p < 0.05), unchanged maximum flow, and increased oronasal resistance (p < 0.05) in both groups. The changes in UA mechanics and BP after the drug were similar in lean and obese rats. The serotonin agonist had no effect on UA mechanics in a group of paralyzed (pancuronium bromide) rats, despite similar elevations in BP. There was a smaller decrease (p < 0.05) in UA collapsibility that was also associated with increased upstream resistance when the drug was administered after bilateral hypoglossal nerve transection. We conclude that systemic administration of a serotonin(2A/2C) receptor agonist improves UA collapsibility predominantly, but not exclusively, via stimulation of the hypoglossal nerves and also increases upstream resistance, at least in part, through activation of nonhypoglossal motoneuronal pools innervating the UA muscles.