Early Onset of Ventilatory and Airway Response to Hypercapnia is Mediated by Medullary 5-HT_1A Receptors in Infant Rats

抄録

Medullary 5-hydroxytryptamine (5-HT) neurons are involved in ventilatory responses to hypercapnia. Underdeveloped medullary 5-HT neurons and reduced 5-HT_1A receptor binding activity in the dorsomedial medulla oblongata (DMM) have been found in infants with sudden infant death syndrome (SIDS). The DMM includes the solitary tract nucleus, which receives primary afferent inputs from the lung, and the hypoglossal nucleus, which affects genioglossal muscle tone. We hypothesized that hypercapnia would elicit 5-HT release in the DMM and that local 5-HT_1A receptors would affect ventilatory and airway responses to hypercapnia. This hypothesis was investigated in unanesthetized infant Wistar rats by microdialysis of the DMM coupled with double-chamber plethysmography. After microdialysis probe placement, the rats were acclimatized to the chamber for over 5h, and artificial cerebrospinal fluid (aCSF) or a 5-HT_1A receptor antagonist, WAY-100635, was then perfused into the DMM, and extracellular fluid was collected. Respiratory flow curves were recorded while the rats inhaled five concentrations of CO₂ in O₂ for 10 min each (0% [100% O₂], 5%, 7%, 9%, and 0% again). 5-HT concentration was measured using high-performance liquid chromatography with electrochemical detection. 5-HT release in the DMM and hypercapnic ventilatory and airway responses increased dose dependently with CO₂ concentration during both aCSF and WAY-100635 perfusion, with no difference between groups. However, early-onset ventilatory and airway responses to hypercapnia were significantly delayed or reduced by WAY-100635 perfusion in the DMM. These results suggest that 5-HT release in the DMM is dependent on hypercapnia, while early ventilatory and airway responses to hypercapnia are mediated by 5-HT_1A receptors in the DMM. Blunted early onset of hypercapnic ventilatory and airway responses may be one cause of SIDS.