© 2002 American Thoracic Society
Nicotine, Serotonin, and Sudden Infant Death Syndrome
a Department of Physiology Dartmouth Medical School Lebanon, New Hampshire Maternal smoking during pregnancy is a major risk factor for sudden infant death syndrome (SIDS), with nicotine likely as the active agent (1). The cause of the majority of SIDS deaths is unknown. The strongest clues for the pathogenesis of SIDS arise from receptor binding studies performed on the brainstems of infants who have died of SIDS. Neurons in the ventral medulla of these infants show abnormalities for kainate, muscarinic, and serotonergic receptor binding (2). Current emphasis is being placed on abnormalities in the "medullary serotonergic system," which includes medullary regions involved in "protective" reflexes such as the ventilatory, cardiovascular, and arousal responses to hypoxia (2). Failure of "protective" reflexes would place the infant at risk for sudden death during normal life stresses that may occur in sleep such as hypoxia due to prone sleeping and rebreathing or to airway obstruction. How does nicotine fit into this scenario? Newborn rodents with prenatal nicotine exposure hypoventilate and have a decreased ventilatory response to moderate hypoxia (8% O2) (3), as well as a diminished capability to tolerate severe hypoxia (0 to 5% O2) (4). Infants of smoking mothers arouse less in mild hypoxia (13 to 17% O2) (5) and have more frequent and longer obstructive sleep apnea episodes (6) but do not have altered ventilatory responses to hypoxia (5). In this issue of AJRCCM (pp. 1544–1549), Hafström and coworkers (7) show in 5-day-old lambs that prenatal nicotine exposure at doses producing blood levels similar to those observed with smoking in humans (1) decreases the heart rate responses to hypoxia (10% O2) in wakefulness and sleep, (2) decreases the ventilatory response to hypoxia in sleep, and (3) delays the time to arousal from hypoxia. These findings add important evidence to the proposed physiologic mechanisms by which prenatal nicotine exposure may adversely affect young infants. All three main findings could be detrimental to the survival of an infant exposed to hypoxic stress. The delay in arousal, which is also seen in human infants of smoking mothers (5), would prolong the duration and perhaps the intensity of the hypoxic stress. An impaired ventilatory response in sleep would enhance the severity of hypoxia in arterial blood, and the lessened cardiovascular response would enhance tissue hypoxia. How does nicotine produce these detrimental effects on "protective responses" to hypoxia? The nicotine effects have been attributed to abnormalities at the carotid body, the peripheral oxygen sensor (5, 7). Could there be a central effect? A knockout mouse with a deficient nicotine receptor subunit has an exaggerated ventilatory response to hypoxia and a delayed arousal from sleep, suggesting a role for the nicotine receptor in these functions (8). Nicotine receptor binding, however, is not abnormal in the brainstem of infants who have died of SIDS (9). Could the nicotine effect involve the medullary serotonergic neurons found to be abnormal in SIDS infants? Fetal nicotine exposure in rodents results in decreased serotonin transporter density (10), decreased binding at the transporter in forebrain (11), and increased binding in midbrain and brainstem (11). In the human fetus, nicotinic receptor binding is present in regions involved in cardiorespiratory control and arousal, including regions rich in serotonergic neurons (12). We must learn specifically whether medullary serotonergic neurons modulate hypoxic "protective reflexes" in the newborn, and whether prenatal nicotine treatment affects serotonergic neurons and this modulation. This evidence alone would not demonstrate causation of SIDS, but it would be a strong step forward in understanding how the altered "protective reflexes" for hypoxia, which are attributable to prenatal nicotine exposure, could occur via a nicotine-induced process in medullary neurons known to be abnormal in infants who have died of SIDS. REFERENCES
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