title: Perinatal exposure to nicotine causes deficits associated with a loss of nicotinic receptor function.
abstract: 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.
authors.affiliation: Karolinska Institute, Neonatal Unit, Astrid Lindgren Children's Hospital, S-171 76 Stockholm, Sweden.
authors.forename: Gary
authors.initials: G
authors.lastname: Cohen
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Roux
authors.forename: Régis
authors.initials: R
authors.lastname: Grailhe
authors.forename: Girvan
authors.initials: G
authors.lastname: Malcolm
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.forename: Hugo
authors.initials: H
authors.lastname: Lagercrantz
mesh_terms: 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
chemical_list: D002395:Catecholamines; D009538:Nicotine; D011978:Receptors, Nicotinic
references.citation: Brain Res Bull. 1995;38(1):69-75
references.pmid: 7552377
references.citation: J Neurobiol. 2002 Dec;53(4):524-34
references.pmid: 12436417
references.citation: Am J Psychiatry. 2003 Nov;160(11):1978-84
references.pmid: 14594744
references.citation: Physiol Rev. 1999 Apr;79(2):325-60
references.pmid: 10221983
references.citation: J Physiol. 1984 Feb;347:1-16
references.pmid: 6707950
references.citation: J Pharmacol Exp Ther. 2002 May;301(2):594-8
references.pmid: 11961061
references.citation: Eur J Neurosci. 2003 Jun;17(11):2313-22
references.pmid: 12814364
references.citation: J Neural Transm (Vienna). 2003 Jan;110(1):51-65
references.pmid: 12541012
references.citation: J Clin Endocrinol Metab. 2001 Nov;86(11):5420-6
references.pmid: 11701716
references.citation: Respir Physiol. 2000 Feb;119(2-3):123-32
references.pmid: 10722855
references.citation: Dev Biol. 2001 Dec 1;240(1):143-56
references.pmid: 11784052
references.citation: Pediatr Res. 1986 Oct;20(10):920-4
references.pmid: 3774404
references.citation: Front Biosci. 1999 Dec 01;4:D883-97
references.pmid: 10577393
references.citation: Med J Aust. 2001 Sep 17;175(6):320-3
references.pmid: 11665947
references.citation: Neuroreport. 2002 May 24;13(7):961-3
references.pmid: 12004199
references.citation: Respir Physiol. 2000 Mar;120(1):35-45
references.pmid: 10786643
references.citation: J Neurophysiol. 2002 Oct;88(4):1851-8
references.pmid: 12364511
references.citation: Neuron. 2002 Mar 14;33(6):905-19
references.pmid: 11906697
references.citation: Neuropsychopharmacology. 2004 Aug;29(8):1440-50
references.pmid: 15039772
references.citation: J Neurosci. 2004 Jan 7;24(1):63-7
references.pmid: 14715938
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13272-7
references.pmid: 12228730
references.citation: J Pharmacol Exp Ther. 1998 Jun;285(3):931-45
references.pmid: 9618392
references.citation: BMJ. 2004 Apr 24;328(7446):965-6
references.pmid: 15105300
references.citation: J Physiol. 1996 Jan 15;490 ( Pt 2):551-7
references.pmid: 8821151
references.citation: Psychopharmacology (Berl). 1999 Jan;141(2):145-53
references.pmid: 9952038
references.citation: Mol Pharmacol. 2004 Dec;66(6):1712-8
references.pmid: 15383622
references.citation: Neuron. 1998 Nov;21(5):959-80
references.pmid: 9856454
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2803-7
references.pmid: 11226321
references.citation: Am J Epidemiol. 1988 Feb;127(2):274-82
references.pmid: 3337083
references.citation: J Appl Physiol (1985). 2001 Apr;90(4):1593-9
references.pmid: 11247965
references.citation: Am J Respir Crit Care Med. 2001 Sep 15;164(6):989-94
references.pmid: 11587984
references.citation: Pharmacol Biochem Behav. 1994 Apr;47(4):889-900
references.pmid: 8029259
references.citation: J Neuropathol Exp Neurol. 2001 Mar;60(3):228-47
references.pmid: 11245208
references.citation: Respir Physiol. 2000 Sep;122(2-3):167-82
references.pmid: 10967342
references.citation: J Neurobiol. 2002 Dec;53(4):447-56
references.pmid: 12436412
references.citation: Acta Obstet Gynecol Scand. 2000 Jun;79(6):485-9
references.pmid: 10857873
references.citation: Proc Nutr Soc. 2002 Nov;61(4):537-42
references.pmid: 12691183
references.citation: Pediatr Res. 2004 Sep;56(3):391-5
references.pmid: 15240857
references.citation: Pediatr Res. 2003 Jan;53(1):119-24
references.pmid: 12508090
references.citation: Am J Obstet Gynecol. 2003 Oct;189(4):939-43
references.pmid: 14586330
references.citation: J Neuropathol Exp Neurol. 1998 Nov;57(11):1018-25
references.pmid: 9825938
references.citation: Am J Respir Crit Care Med. 2004 Mar 15;169(6):733-8
references.pmid: 14684558