Prenatal nicotine exposure increases hyperventilation in α4-knock-out mice during mild asphyxia

- The role of α4-containing nAChRs in neonatal respiratory control in vivo has never been explored.
- At P1-2, nicotine reduces V˙E and V˙O2 but not the hyperventilatory response to mild asphyxia.
- At P7-8, nicotine exaggerates the hyperventilatory response to mild asphyxia of α4 KO but not WT mice.
- α4-containing nAChRs may be involved in modulating inhibitory control of ventilation such that in their absence nicotine's stimulatory effects are enhanced.

Prenatal nicotine exposure alters breathing and ventilatory responses to stress through stimulation of nicotine acetylcholine receptors (nAChRs). We tested the hypothesis that α4-containing nAChRs are involved in mediating the effects of prenatal nicotine exposure on ventilatory and metabolic responses to intermittent mild asphyxia (MA). Using open-flow plethysmography, we measured ventilation (V˙E) and rate of O2 consumption (V˙O2) of wild-type (WT) and α4-knock-out (KO) mice, at postnatal (P) days 1-2 and 7-8, with and without prenatal nicotine exposure (6 mg kg−1 day−1 beginning on embryonic day 14). Mice were exposed to seven 2 min cycles of mild asphyxia (10% O2 and 5% CO2), each interspersed with 2 min of air. Compared to WT, α4 KO mice had increased air V˙E and V˙O2 at P7-8, but not P1-2. Irrespective of age, genotype had no effect on the hyperventilatory response (increase in V˙E/V˙O2) to MA. At P1-2, nicotine suppressed air V˙E and V˙O2 in both genotypes but did not affect the hyperventilatory response to MA. At P7-8 nicotine suppressed air V˙E and V˙O2 of only α4 KO's but also significantly enhanced V˙E during MA (nearly double that of WT; p < 0.001). This study has revealed complex effects of α4 nAChR deficiency and prenatal nicotine exposure on ventilatory and metabolic interactions and responses to stress.