Severe spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brain stem 5-HT neurons

The medullary 5-HT system has potent effects on heart rate and breathing in adults. We asked whether this system mitigates the respiratory instability and bradycardias frequently occurring during the neonatal period. 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was administered to rat pups at postnatal day 2 (P2), and we then compared the magnitude of bradycardias occurring with disruptions to eupnea in treated and vehicle control littermates at P5-6 and P10-12. We then used a novel method that would allow accurate assessment of the ventilatory and heart rate responses to near square-wave challenges of hypoxia (10% O₂), hypercapnia (5 and 8% CO₂ in normoxia and hyperoxia), and asphyxia (8% CO₂-10% O₂), and to the induction of the Hering-Breuer inflation reflex (HBR), a potent, apnea-inducing reflex in newborns. The number of 5-HT-positive neurons was reduced ∼80% by drug treatment. At both ages, lesioned animals had considerably larger bradycardias during brief apnea; at P5-6, average and severe events were ∼50% and 70% greater, respectively, in lesioned animals (P = 0.002), whereas at P10-12, events were ∼ 23% and 50% greater (P = 0.018). However, lesioning had no effect on the HR responses to sudden gas challenge or the HBR. At P5-6, lesioned animals had reduced breathing frequency and ventilation (V̇E), but normal V̇E relative to metabolic rate (V̇E/V̇O₂). At P10-12, lesioned animals had a more unstable breathing pattern (P = 0.04) and an enhanced V̈E response to moderate hypercapnia (P = 0.007). Within the first two postnatal weeks, the medullary 5-HT system plays an important role in cardiorespiratory control, mitigating spontaneous bradycardia, stabilizing the breathing pattern, and dampening the hypercapnic V̇E response.