Prenatal nicotine exposure increases apnoea and attenuates nicotinic potentiation of hypoglossal output in mice
© BioMed Central Ltd 2001
Received: 2 August 2001
Published: 17 August 2001
Maternal smoking is associated with an increased risk of Sudden Infant Death Syndrome (SIDS) and nicotine is implicated as a causative agent due to adverse effects on central nervous system development . The consequences of these changes for respiration are uncertain, but there is growing consensus that altered respiratory control contributes to the reduced ability of nicotine-exposed animals to tolerate hypoxia [2,3]. Most studies have focussed on overall changes in ventilation, but paid minimal attention to breathing pattern. In addition, responses have rarely been examined in the earliest neonatal periods when immature control mechanisms are more likely to contribute to unstable breathing, frequent apnoeas and hypoxic episodes. We therefore examined the effects of prenatal nicotine exposure on the development of breathing pattern and the ventilatory response to hypoxia (7.4% O2) in vivo using whole-body plethysmography at postnatal days 0, P3, P9, P19 and adult. To determine whether differences observed in vivo were due to altered activity of medullary respiratory networks, motoneurons (MNs) controlling the airway, or MN responsive-ness to nicotinic modulation, we recorded in vitro hypoglossal (XII) nerve and MN activity in rhythmic medullary slice preparations from control and nicotine-exposed P3 mice. Foetal mice were exposed to nicotine using osmotic micropumps implanted in the dam at gestational day 10.
Developmental changes in respiratory behaviour in vivo were delayed in the youngest nicotine-exposed animals. The high level of apnoea present during normoxia in P0 control animals (frequency of apnoea, fA, 6.7 ± 0.7 min-1, percent of time apnoeic, TA, 29 ± 6%) and nicotine-exposed groups (fA 8.1 ± 1.7 min-1,TA 25 ± 5%) persisted until P3 in the nicotine group but fell significantly in control animals (fA-2.2 ± 0.7 min-1, TA 5 ± 2%). At the onset of hypoxia, fA and TA fell rapidly and remained low throughout hypoxia except in P0 nicotine-exposed animals where they declined initially (fA 1.8 ± 0.5, TA 4 ± 2%) but then rose progressively during the 12 min hypoxic period to final values of 7.1 ± 2.9 min-1and 17 ± 6% respectively. During recovery, apnoea increased in both groups at P0 (fA 10.8 ± 0.8 and 11.3 ± 1.3 min -1; TA 50 ± 6 and 49 ± 5%). By P3, the absolute magnitude of this posthypoxic increase was reduced in control (fA 5.3 ± 0.1 min-1 ; TA 30 ± 7%) but not nicotine-exposed animals (fA 8.5 ± 1.0 min-1 ; T 44 ± 8%).
The frequency and variability of the inspiratory-related output in medullary slice preparations from control and nicotine-exposed animals were indistinguishable. The pattern of the inspiratory-related XII nerve burst and inspiratory synaptic currents recorded from XII MNs were also similar.
Local application of nicotine (10–100 μM) over the XII nucleus produced a small, TTX-resistant inward current in MNs that reversed near 0 mV, and potentiated XII nerve inspiratory burst amplitude (25 ± 5%). Both actions were hexamethonium-sensitive, suggesting nicotinic receptor involvement in upper airway control. This potentiation was significantly lower in nicotine-exposed animals (14 ± 3%).
Results indicate that prenatal nicotine exposure in mice delays development of breathing pattern, increasing incidence of apnoea in P0–P3 animals before, during and after hypoxia. This increased apnoea does not reflect alterations in the baseline behaviour of rhythm generating or pattern forming circuits, but may result from reduced nicotinic modulation of XII MN activity.
Approved by the University of Auckland Animal Ethics Committee. Supported by the Auckland Medical Research Foundation, New Zealand Cot Death Association, Health Research Council, New Zealand Neurological Foundation, Lotteries Health and the Wallath Trust.
- Slotkin TA: Fetal nicotine or cocaine exposure: which is worse. J Pharm Exp Therap. 1998, 285: 931-945.Google Scholar
- Fewell JE, Smith FG: Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia. J Appl Physiol. 1998, 85: 2066-2074.PubMedGoogle Scholar
- St John WM, Leiter JC: Maternal nicotine depresses eupneic ventilation of neonatal rats. Neurosci Lett. 1999, 267: 206-208. 10.1016/S0304-3940(99)00364-X.PubMedView ArticleGoogle Scholar