Chronic intermittent hypoxia elicits serotonin-dependent plasticity in thecentral neural control of breathing

We tested the hypothesis that chronic intermittent hypoxia (CIH) elicits pl asticity in the central neural control of breathing via serotonin-dependent effects on the integration of carotid chemoafferent inputs. Adult rats wer e 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, vagot omized, 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 (integral Phr) responses du ring hypoxia were greater after CIH at arterial oxygen pressures (PaO2) bet ween 25 and 45 mmHg (p < 0.05), but not at higher PaO2 levels. CIH did not affect hypoxic phrenic burst frequency responses, although the post-hypoxia frequency decline that is typical in rats was abolished. <integral>Phr and frequency responses to electrical stimulation of the carotid sinus nerve w ere enhanced by CIH (p<0.005). Serotonin-dependent long-term facilitation ( LTF) of <integral>Phr was enhanced after CIH at 15, 30, and 60 min after ep isodic hypoxia (p < 0.05). Pretreatment with the serotonin receptor antagon ists methysergide (4 mg/kg, i.v.) and ketanserin (2 mg/kg, i.v.) reversed C IH-induced augmentation of the short-term hypoxic phrenic response and rest ored the post-hypoxia frequency decline in CIH rats. Whereas methysergide a bolished CIH-enhanced phrenic LTF, the selective 5-HT2 antagonist ketanseri n only partially reversed this effect. The results suggest that CIH elicits unique forms of serotonin-dependent plasticity in the central neural contr ol of breathing. Enhanced LTF after CIH may involve an upregulation of a no n-5-HT2 serotonin receptor subtype or subtypes.