215 Perinatal Nicotine Exposure Disrupts Breathing Rhythm by Interfering with O2 (NOT CO2) – Sensitive Respiratory Stabilizing Mechanisms.

Abstract

There is a strong association between perinatal tobacco (especially nicotine) exposure and poor infant outcome, but the mechanisms linking the two are not well understood. Here we determined how perinatal nicotine exposure compromises neonatal respiratory control by comparing the effects of nicotine in normal (wild-type, WT) and knockout (KO) mice lacking nicotinic acetylcoline receptors (nAChRs) containing the b2 subunit. These nAChRs are a major component of high-affinity nicotine binding sites in the nervous system. Pregnant WT and KO mice were implanted with micro-osmotic minipumps on embryonic day 14. Pumps delivered either water or nicotine (6.0 mg.kg-1 day-1). Breathing was measured using dual-chamber plethysmograhy. Control WT and KO pups had comparable breathing rhythms at rest. Stress, however, unmasked important differences between genotypes. KO pups responded briskly to hypoxia, but breathing became highly irregular, with frequent pauses (apnoeas) during recovery from hypoxia. Irregular breathing and apnoeas were never seen in WT pups post-hypoxia. Control KO and WT pups responded similarly to CO2, with no evidence of breathing irregularity or apnoea in either genotype during recovery from bouts of intermittent hypercapnia. Nicotine-exposure augmented the response of the WT pups to hypoxia. WT pups also developed an irregular breathing rhythm due to frequent apnoeas between bouts of hypoxia. Nicotine-exposed WT pups consequently resembled the KO. Nicotine-exposure did not alter the hypoxic breathing pattern of KO pups. Moreover, perinatal nicotine exposure did not alter responses of either WT or KO pups to intermittent hypercapnia. Conclusion: Our findings suggest that nicotine increases the risk of neonatal apnoea by disrupting nAChR-dependent mechanisms that fine-tune breathing rhythm. These mechanisms are particularly sensitive to sudden changes in reflex drive from O2rather than CO2-sensitive chemoreflexes.