Perinatal exposure to nicotine causes deficits associated with a loss of nicotinic receptor function.
We investigated the role played by beta2-containing neuronal nicotinic receptors [nicotinic acetylcholine receptors (nAChRs)] in mediating nicotine's side effects in the fetus and newborn. Pregnant WT and mutant mice lacking the beta2 nAChR subunit were implanted with osmotic minipumps that delivered either water or a controlled dose of nicotine. Subsequently, we compared the development of the sympathoadrenal system and breathing and arousal reflexes of offspring shortly after birth, a period of increased vulnerability to nicotine exposure. Newborn WT pups exposed to nicotine exhibited all of the deficits associated with maternal tobacco and nicotine use, and linked to poor neonatal outcome: growth restriction, unstable breathing, and impaired arousal and catecholamine biosynthesis. Remarkably similar deficits were detected in pups lacking beta2-containing nAChRs. Loss-of-function of these nAChRs consequently reproduces with astonishing fidelity many of the abnormalities caused by perinatal nicotine exposure. We propose that the underlying mechanisms of nicotine's detrimental side effects on a range of crucial defensive reflexes involve loss of function of nAChR subtypes, possibly via activity-dependent desensitization.
Cohen
Gary
G
Karolinska Institute, Neonatal Unit, Astrid Lindgren Children's Hospital, S-171 76 Stockholm, Sweden.
Roux
Jean-Christophe
JC
Grailhe
Régis
R
Malcolm
Girvan
G
Changeux
Jean-Pierre
JP
Lagercrantz
Hugo
H
D000818:Animals; D001143:Arousal / Q000187:drug effects; D002395:Catecholamines / Q000096:biosynthesis; D005260:Female; D005333:Fetus / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000633:toxicity*; D011247:Pregnancy; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D012119:Respiration / Q000187:drug effects
D002395:Catecholamines; D009538:Nicotine; D011978:Receptors, Nicotinic
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