Chronic Intermittent Hypoxia Elicits Serotonin-Dependent Plasticity in the Central Neural Control of Breathing

Abstract

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< 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< 0.05). Serotonin-dependent long-term facilitation (LTF) of ∫Phr was enhanced after CIH at 15, 30, and 60 min after episodic hypoxia (p< 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 post-hypoxia 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 serotonin-dependent 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.