Postnatal loss of brainstem serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia.

Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO 65211, USA.
The Journal of Physiology (Impact Factor: 4.38). 09/2011; 589(Pt 21):5247-56. DOI: 10.1113/jphysiol.2011.214445
Source: PubMed

ABSTRACT Pet-1(-/-) mice with a prenatal, genetically induced loss of 5-hydroxytryptamine (5-HT, serotonin) neurones are compromised in their ability to withstand episodic environmental anoxia via autoresuscitation. Given the prenatal role of 5-HT neurones in the development of neural networks, here we ask if a postnatal loss of 5-HT neurones also compromises autoresuscitation. We treated neonatal rat pups at postnatal day (P)2-3 with an intra-cisternal injection of 5,7-dihydroxytryptamine (5,7-DHT; ~40 μg; n = 8) to pharmacologically lesion the 5-HT system, or vehicle (control; n = 14). At P7-10 we exposed unanaesthetized treated and control pups to 15 episodes of environmental anoxia (97% N(2), 3% CO(2)). Medullary 5-HT content was reduced 80% by 5,7-DHT treatment (P < 0.001). Baseline ventilation (V(E)), metabolic rate (V(O(2))), ventilatory equivalent (V(E)/V(O(2))), heart rate (HR), heart rate variability (HRV) and arterial haemoglobin saturation (S(aO(2))) were no different in 5-HT-deficient pups compared to controls. However, only 25% of 5-HT-deficient pups survived all 15 episodes of environmental anoxia, compared to 79% of control littermates (P = 0.007). High mortality of 5,7-DHT-treated pups was associated with delayed onset of gasping (P < 0.001), delayed recovery of HR from hypoxic-induced bradycardia (P < 0.001), and delayed recovery of eupnoea from hypoxic-induced apnoea (P < 0.001). Treatment with 5,7-DHT affected neither the gasping pattern once initiated, nor HR, V(E)/V(O(2)) or S(aO(2)) during the intervening episodes of room air. A significant increase in HRV occurred in all animals with repeated exposure, and in 5-HT-deficient pups this increase occurred immediately prior to death. We conclude that a postnatal loss of brainstem 5-HT content compromises autoresuscitation in response to environmental anoxia. This report provides new evidence in rat pups that 5-HT neurones serve a physiological role in autoresuscitation. Our data may be relevant to understanding the aetiology of the sudden infant death syndrome (SIDS), in which there is medullary 5-HT deficiency and in some cases evidence of severe hypoxia and failed autoresuscitation.

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    ABSTRACT: In neonatal rodents, a loss of brainstem serotonin (5-hydroxytryptamine, 5-HT) in utero or at birth compromises anoxia-induced gasping and the recovery of heart rate (HR) and breathing with re-oxygenation (i.e. autoresuscitation). How arterial pressure (MAP) is influenced after an acute loss of brainstem 5-HT content is unknown. We hypothesized that a loss of 5-HT for ~1 day would compromise MAP during episodic anoxia. We injected 6-fluorotryptophan (20 mg/kg i.p.) into rat pups (P9-10 or P11-13, n=22 treated, 24 control), causing a ~70% loss of brainstem 5-HT. Pups were exposed to a maximum of 15 anoxic episodes, separated by 5 min of room air to allow autoresuscitation. In younger pups we measured breathing frequency (fB), and volume (VT) using "head-out" plethysmography and HR from the electrocardiogram. In older pups, we used whole-body plethysmography to detect gasping, while monitoring MAP. Gasp latency and the time required for respiratory, HR and MAP recovery following each episode were determined. Despite normal gasp latency, fB and a larger VT (P<0.001), 5-HT-deficient pups survived 1/2 the number of episodes as controls (P<0.001). The anoxia-induced decrease in MAP experienced by 5-HT-deficient pups was double that of controls (P=0.017), despite the same drop in HR (P=0.48). MAP recovery was delayed ~10 sec by 5-HT deficiency (P=0.001). Our data suggest a loss of brainstem 5-HT leads to a pronounced, premature loss of MAP in response to episodic anoxia. These data may help explain why some SIDS cases die from what appears to be cardiovascular collapse during apparent severe hypoxia.
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    ABSTRACT: In this study, we asked whether a “full term” prenatal nicotinic exposure (fPNE, 6 mg·kg−1·day−1 nicotinic delivery) over the full gestation, compared to a traditional PNE (tPNE) over the last two-thirds of the gestation, caused a higher mortality following a remarkable depressed hypoxic ventilatory response (dHVR) independent of brain and pulmonary edema and change in serum corticosterone. P12-14 pups pretreated with tPNE, fPNE or their vehicle (tCtrl and fCtrl) were exposed to 5% O2 for up to 60 min followed by harvesting the brain and lungs or anesthetized to collect blood for detecting arterial blood pH/gases and serum cotinine and corticosterone levels. We found that fPNE had little effect on baseline VE and heart rate, but consistently induced a dHVR and prolonged apnea that were rarely observed after tPNE. The severity of the dHVR in PNE pups were closely correlated to an earlier appearance of lethal ventilatory arrest (the hypoxia-induced mortality). PNE did not induce brain and pulmonary edema, but significantly increased serum corticosterone levels similarly in tPNE and fPNE pups. Moreover, the accumulated nicotinic dose given to the individual was significantly higher in fPNE than tPNE pups, though there was no difference in serum cotinine levels and arterial blood pH/gases between the two groups. Our results suggest that nicotinic exposure at the early stage of gestation achieved by fPNE, rather than tPNE, is critical in generating the dHVR and subsequent death occurring independently of brain/pulmonary edema and changes in arterial blood pH/gases and serum corticosterone.
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