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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1530-1531, (2002)
© 2002 American Thoracic Society

Editorial

Nicotine, Serotonin, and Sudden Infant Death Syndrome

Eugene Nattie, M.D.a and Hannah Kinney, M.D.b

a Department of Physiology Dartmouth Medical School Lebanon, New Hampshire
b Department of Neuroscience Harvard Medical School Boston, Massachusetts

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

  1. Mitchell EA, Ford RP, Stewart AW, Taylor BJ, Becroft DM, Thompson JM, Scragg R, Hassall IB, Barry DM, Allen EM. Smoking and the sudden infant death syndrome. Pediatrics 1993;91:893–896.[Abstract/Free Full Text]
  2. Kinney HC, Filiano JJ, White WF. Medullary serotonergic network deficiency in the sudden infant death syndrome: review of a 15-year study of a single dataset. J Neuropathol Exp Neurol 2001;60:228–247.[Medline]
  3. St. John WM, Leiter JC. Maternal nicotine depresses eupneic ventilation of neonatal rats. Neurosci Lett 1999;267:206–208.[CrossRef][Medline]
  4. Fewell JE, Smith FG, Ng VKY. Prenatal exposure to nicotine impairs protective responses of rat pups to hypoxia in an age-dependent manner. Respir Physiol 2000;127:61–73.
  5. Lewis KW, Bosque EM. Deficient hypoxic awakening response in infants of smoking mothers: possible relationship to sudden infant death syndrome. J Pediatr 1995;127:691–699.[CrossRef][Medline]
  6. Kahn A, Groswasser J, Scottiaux M, Kelmanson I, Rebuffat E, Franco P, Dramaix M, Wayenberg JL. Prenatal exposure to cigarettes in infants with obstructive sleep apneas. Pediatrics 1994;93:778–783.[Abstract/Free Full Text]
  7. Hafström O, Milerad J, Sundell HW. Prenatal nicotine exposure blunts the cardiorespiratory response to hypoxia in lambs. Am J Respir Crit Care Med 2002;166:1544–1549.[Abstract/Free Full Text]
  8. Cohen G, Han Z, Grailhe R, Gallego J, Gaultier C, Changeux J, Lagercrantz H. ß2 nicotinic acetylcholine receptor subunit modulates protective responses to stress: a receptor basis for sleep-disordered breathing after nicotine exposure. Proc Natl Acad Sci USA 2002;99:13273–13277.
  9. Nachmanoff DB, Panigrahy A, Filiano JJ, Mandell F, Sleeper LA, Valdes-Dapena M, Krous HF, White WF, Kinney HC. Brainstem 3H-nicotine receptor binding in the sudden infant death syndrome. J Neuropathol Exp Neurol 1998;57:1018–1025.[Medline]
  10. Muneoka K, Ogawa T, Kamei K, Mimura Y, Kato H, Takigawa M. Nicotine exposure during pregnancy is a factor which influences serotonin transporter density in the rat brain. Eur J Pharmacol 2001;411:279–282.[CrossRef][Medline]
  11. Xu Z, Seidler FJ, Ali SF, Slikker W Jr, Slotkin TA. Fetal and adolescent nicotine administration: effects on CNS serotonergic systems. Brain Res 2001;914:166–178.[CrossRef][Medline]
  12. Kinney HC, O'Donnell TJ, Kriger P, White WF. Early developmental changes in 3H-nicotine binding in the human brainstem. Neuroscience 1993;55:1127–1138.[CrossRef][Medline]



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