Does Maternal Smoking Impair Neonatal Control of Breathing?

Institution:	University of California, Los Angeles
Investigator(s):	Xuesi Shao, M.D.
Award Cycle:	2009 (Cycle 18)	Grant #: 18XT-0183	Award: $250,000
Subject Area:	Pulmonary Disease
Award Type:	Exploratory/Developmental Award

Abstracts

Initial Award Abstract

Sudden infant death syndrome (SIDS) is a leading cause of infant death between one month and one year of age. Maternal smoking is strongly correlated with the incidence of SIDS. The underlying biological mechanisms are unknown. Breathing is generated and controlled by the central nervous systems. Impairment in central control of breathing in infants can be fatal in some stress conditions such as being placed for sleep in the prone position. Whether prenatal exposure to nicotine, a major component of tobacco, per se, causes impairment in neonatal central control of respiration is poorly understood. Nicotine replacement therapy (NRT) is often recommended in smoking cessation programs for pregnant women. If nicotine is the teratogen that causes SIDS and other developmental brain disorders in babies, the safety of NRT for pregnant women would be a serious concern. The long-term goal of our project is to understand the cellular mechanisms by which nicotine/cigarette smoke exposure contributes to the pathogenesis of SIDS. We have demonstrated, with the supports of previous TRDRP grants, that nicotine at concentrations as low as the arterial blood nicotine concentrations after smoking a cigarette alters respiratory rhythm and pattern in vitro. We have determined that the nicotinic acetylcholine receptors (nAChRs) mediating the nicotinic effects on central respiratory control in the preBötzinger Complex (preBötC, the primary brain site for respiratory rhythm generation) is α4* nAChRs. However, the link between maternal exposure to nicotine and impairment in neonatal respiratory control is still lacking.

The objective of this application is to test the hypothesis that exposure to maternal smoking-relevant doses of nicotine in pregnant animals induces long-term changes in neuronal excitability or neurotransmission in the preBötC that can lead to instability of central control of breathing in neonates. We will pursue two specific aims:

Specific aim 1: Determine whether exposure to maternal smoking-relevant doses of nicotine in early or late pregnancy in rats results in changes in respiratory pattern or changes in response to hypoxia in their pups in vivo.

Specific aim 2: Determine whether exposure to maternal smoking-relevant doses of nicotine in early or late pregnancy results in long-lasting changes/impairments in neuronal excitability and glutamate transmission in neonatal preBötC neurons, a subset of which underlie respiratory rhythm generation.

We will administer a dose of nicotine in pregnant rats that produces arterial blood nicotine concentrations equivalent to those observed after smoking a cigarette in humans in a single dose or in multiple doses episodically. We will measure the respiratory pattern or changes in response to hypoxia in their pups in vivo. We will examine the excitability and excitatory synaptic strength of preBötC inspiratory neurons using a unique experimental preparation, a medullary slice from neonatal rat that contains the preBötC and generates respiratory rhythm in vitro. This is a model especially powerful for studying the effects of prenatal exposure to toxicants on neonatal respiratory control.

Successful completion of this project will establish links between maternal smoking and impairments of central control of breathing in neonates in system levels in vivo and in cellular levels in preBötC neurons. The proposed study will advance our understanding on the cellular mechanisms by which nicotine from maternal smoking impairs the central control of breathing in neonates and contributes to the pathogenesis of SIDS. The proposed in vivo and in vitro animal studies will provide pharmacological targets for therapeutic intervention for SIDS, as well as critical information for strategies for cessation of maternal smoking and prevention of SIDS. Positive results will provide evidence against NRT for smoking cessation in pregnant women.

Publications

Central cholinergic regulation of respiration: nicotinic receptors
Periodical: Acta Pharmacol Sin			Index Medicus:
Authors: Shao XM, Feldman JL				ART
Yr: 2009	Vol:	Nbr: 30	Abs:	Pg: 761-770

Central cholinergic regulation of respiration: nicotinic receptors
Periodical: Acta Pharmacol Sin			Index Medicus:
Authors: Shao XM, Feldman JL				ART
Yr: 2009	Vol:	Nbr: 30	Abs:	Pg: 761-770