Acute inhibition of serotonergic (5-HT) neurons in the medullary raphé (MR) using a 5-HT(1A) receptor agonist had an age-dependent impact on the "CO(2) response" of piglets (33). Our present study explored the effect of chronic 5-HT neuron lesions in the MR and extra-raphé on the ventilatory response to hypercapnia and hypoxia in piglets, with possible implications on the role of 5-HT in the sudden infant death syndrome. We established four experimental groups. Group 1 (n = 11) did not undergo any treatment. Groups 2, 3, and 4 were injected with either vehicle or the neurotoxin 5,7-dihydroxytryptamine in the cisterna magna during the first week of life (group 2, n = 9; group 4, n = 11) or second week of life (group 3, n = 10). Ventilation was recorded in response to 5% CO(2) (all groups) and 12% O(2) (group 2) during wakefulness and sleep up to postnatal day 25. Surprisingly, the piglets did not reveal changes in their CO(2) sensitivity during early postnatal development. Overall, considerable lesions of 5-HT neurons (up to 65% decrease) in the MR and extra-raphé had no impact on the CO(2) response, regardless of injection time. Postlesion raphé plasticity could explain why we observed no effect. 5,7-Dihydroxytryptamine-treated males, however, did present a lower CO(2) response during sleep. Hypoxia significantly altered the frequency during sleep in lesioned piglets. Further studies are necessary to elucidate the role of plasticity, sex, and 5-HT abnormalities in sudden infant death syndrome.

Malnutrition during pregnancy adversely affects postnatal forebrain development; its effect upon brain stem development is less certain. To evaluate the role of tryptophan [critical for serotonin (5-HT) synthesis] on brain stem 5-HT and the development of cardiorespiratory function, we fed dams a diet ∼45% deficient in tryptophan during gestation and early postnatal life and studied cardiorespiratory variables in the developing pups. Deficient pups were of normal weight at postnatal day (P)5 but weighed less than control pups at P15 and P25 (P < 0.001) and had lower body temperatures at P15 (P < 0.001) and P25 (P < 0.05; females only). Oxygen consumption (Vo(2)) was unaffected. At P15, deficient pups had an altered breathing pattern and slower heart rates. At P25, they had significantly lower ventilation (Ve) and Ve-to-Vo(2) ratios in both air and 7% CO(2). The ventilatory response to CO(2) (% increase in Ve/Vo(2)) was significantly increased at P5 (males) and reduced at P15 and P25 (males and females). Deficient pups had 41-56% less medullary 5-HT (P < 0.01) compared with control pups, without a difference in 5-HT neuronal number. These data indicate important interactions between nutrition, brain stem physiology, and age that are potentially relevant to understanding 5-HT deficiency in the sudden infant death syndrome.

In Wild Type (WT) and serotonin transporter (5HTT) null mice, we studied oxygen consumption, ventilation and heart rate in air and 5% CO2 at postnatal (P) days P5, P15, and P25 using either a head-out (younger mice) or whole body plethysmograph (older mice). Body weight and temperature did not differ between the groups. Oxygen consumption differed significantly only in females at P15 when it was reduced in 5HTT nulls (P < 0.01). Heart rate similarly differed only in female 5HTT nulls at P15 being decreased in both air and CO2 (P < 0.01). Ventilation in air and 5% CO2 was significant reduced via an effect on tidal volume at P15 (P < 0.02) and P25 (P < 0.05) but only in males. Ventilation in air and 5% CO2 was greater in 5HTT null females at P25. We conclude that the gender specific effect (male predominant) on the CO2 response reported in 5HTT null adult mice (Li and Nattie, 2008, J. Physiol. 586.9, 2321–2329, 2008) appears to have origins in early postnatal life (P15) when ventilation in both air and 5% CO2 is reduced.

Many cases of sudden infant death syndrome (SIDS) are associated with an altered brainstem serotonergic (5‐HT) system, which may affect cardiorespiratory function and contribute to sudden death. High SIDS rates are associated with poverty, raising the possibility that nutritional deficits in tryptophan (TP), a key determinant of 5‐HT synthesis, contribute to the altered 5‐HT system. We hypothesized that exposure of rats during pre‐ and early postnatal life to a diet deficient in TP would result in detrimental physiological effects. Sprague‐Dawley dams were fed either an amino acid based diet (control) or a TP 50% deficient diet (treated) from before mating until the end of the study. We measured ventilation and heart rate (HR) in pups at postnatal days (P) 5, 15 and 25 exposed to air or to 7% CO2. Treated pups weighed 38.4% less than control ones at P25 (P<0.001) although their weight was similar at P5. The CO2 response, represented by the percent increase of minute‐ventilation (V̇E) normalized to oxygen consumption (V̇O2), was reduced (P<0.001) in treated males by 17% at P15 and 18% at P25 compared to controls. HR in treated pups of both genders was lower in air at P15 only (P<0.001). These findings raise the possibility that dietary TP alterations contribute to abnormal development of the brainstem 5‐HT system and thus to SIDS, particularly in males who are affected by SIDS in a 2:1 ratio. (NICHD HD36379)