Mouse tests link nicotine to crib death. (Smoking Gun?).

Nicotine may impair a molecule that's necessary for arousing people and other animals from sleep, a study of mice finds. The effect could account for the heightened risk of sudden infant death syndrome (SIDS) in babies born to women who smoked during pregnancy. This well-established link has never been fully explained.

SIDS, also called crib death or cot death, occurs when babies suffocate accidentally or stop breathing in an event called sleep apnea. Surprisingly, these babies don't struggle to breathe sufficiently when they're deprived of oxygen.

At the core of the normal alert system is acetylcholine, a chemical that among other duties transmits nerve signals. Low concentrations of oxygen in the blood appear to trigger the binding of acetylcholine to a specific receptor molecule on cell surfaces, which then initiates a series of signals that spur the respiratory system to crank up. "These are internal regulatory mechanisms for arousal," says Jean-Pierre Changeux, a molecular neurobiologist at the Pasteur Institute in Paris.

To investigate respiratory arousal during sleep, Changeux and his colleagues studied mice that lack a portion of the receptor molecule. When exposed to low-oxygen conditions, these mice step up their breathing more readily than normal mice do. This suggests that the missing portion of the receptor acts as a brake on the arousal response.

Earlier research had indicated that nicotine dampens the arousal reaction. The receptors that Changeux is studying are called nicotinic acetylcholine receptors because both nicotine and acetylcholine bind to them. He and his colleagues gave sleeping mice nicotine injections without waking them. The mice, in airtight boxes that measured their breathing responses, were again deprived of oxygen.

Nicotine significantly blunted the arousal reaction in the normal mice, the scientists report in an upcoming issue of the Proceedings of the National Academy of Sciences. In contrast, mice with an incomplete receptor showed the same reaction that they had exhibited without nicotine. This indicates that continual exposure to nicotine overactivates the brake portion of the receptor, damaging the arousal response, the authors say.

The work shows "a very specific mechanism that explains the relationship between smoking and SIDS," says Theodore A. Slotkin, a pharmacologist at Duke University Medical Center in Durham, N.C. Earlier, his laboratory had found that rats exposed in the womb to nicotine lose the capacity to withstand episodes of low oxygen as newborns, but the biological connection hadn't been established. The new study "really cements it," he says.

"This is extremely interesting and important work," agrees pediatrician Hakan W. Sundell of Vanderbilt University School of Medicine in Nashville. However, it's still unclear whether nicotine numbs arousal solely by slowing the acetylcholine reaction or in part by stimulating release of another neurotransmitter, dopamine, which can slow the respiratory response, he says.

"A significant proportion of the lay public and practicing physicians are under the impression that the damaging effects of tobacco are from low oxygen and ingredients other than nicotine," says Slotkin, but the current study "draws the noose tighter around nicotine." It thus raises the possibility of fetal harm from nicotine patches used during pregnancy.