We tested the hypothesis that chronic intermittent hypoxia (CIH) elicits plasticity in the central neural control of breathing via serotonin-dependent effects on the integration of carotid chemoafferent inputs. Adult rats were exposed to 1 week of nocturnal CIH (11-12% O 2 /air at 5 min intervals; 12 hr/night). CIH and untreated rats were then anesthetized, paralyzed, vagotomized, and artificially ventilated. Time-dependent hypoxic responses were assessed in the phrenic neurogram during and after three 5 min episodes of isocapnic hypoxia. Integrated phrenic amplitude (͐Phr) responses during hypoxia were greater after CIH at arterial oxygen pressures (PaO 2 ) between 25 and 45 mmHg ( p Ͻ 0.05), but not at higher PaO 2 levels. CIH did not affect hypoxic phrenic burst frequency responses, although the post-hypoxia frequency decline that is typical in rats was abolished. ͐Phr and frequency responses to electrical stimulation of the carotid sinus nerve were enhanced by CIH ( p Ͻ 0.05). Serotonin-dependent long-term facilitation (LTF) of ͐Phr was enhanced after CIH at 15, 30, and 60 min after episodic hypoxia ( p Ͻ 0.05). Pretreatment with the serotonin receptor antagonists methysergide (4 mg/kg, i.v.) and ketanserin (2 mg/kg, i.v.) reversed CIH-induced augmentation of the short-term hypoxic phrenic response and restored the posthypoxia frequency decline in CIH rats. Whereas methysergide abolished CIH-enhanced phrenic LTF, the selective 5-HT 2 antagonist ketanserin only partially reversed this effect. The results suggest that CIH elicits unique forms of serotonindependent plasticity in the central neural control of breathing. Enhanced LTF after CIH may involve an upregulation of a non-5-HT 2 serotonin receptor subtype or subtypes. Key words: control of breathing; serotonin; plasticity; hypoxia; phrenic motoneurons; ratsAlthough plasticity is a fundamental property of neural systems (Zigmond et al., 1999;Kandel et al., 2000), its significance in the central neural control of breathing in adult mammals has been appreciated only recently (Eldridge and Millhorn, 1986;Mitchell et al., 1990Mitchell et al., , 1993McCrimmon et al., 1995; Poon, 1996a,b;Powell et al., 1998). In this study, we demonstrate the existence of novel forms of serotonin-dependent plasticity in the hypoxic ventilatory control system elicited by chronic intermittent hypoxia.The hypoxic ventilatory response in mammals consists of several time-dependent facilitatory and inhibitory mechanisms that are revealed by different patterns and durations of hypoxia (Bisgard and Neubauer, 1995;Powell et al., 1998). In anesthetized rats, a single 5 min hypoxic episode increases phrenic nerve activity, an effect known as the short-term hypoxic phrenic response. When normoxia is restored, phrenic burst frequency decreases below the original baseline level and returns to baseline over several minutes (post-hypoxia frequency decline) (Coles and Dick, 1996;Bach et al., 1999).A unique form of serotonin-dependent respiratory plasticity, known as phrenic long-term facilitatio...