TY - JOUR
T1 - Effects of prenatal nicotine exposure on primate brain development and attempted amelioration with supplemental choline or Vitamin C
T2 - Neurotransmitter receptors, cell signaling and cell development biomarkers in fetal brain regions of Rhesus monkeys
AU - Slotkin, Theodore A.
AU - Seidler, Frederic J.
AU - Qiao, Dan
AU - Aldridge, Justin E.
AU - Tate, Charlotte A.
AU - Cousins, Mandy M.
AU - Proskocil, Becky J.
AU - Sekhon, Harmanjatinder S.
AU - Clark, Jennifer A.
AU - Lupo, Stacie L.
AU - Spindel, Eliot R.
N1 - Funding Information:
Supported by a grant from Philip Morris USA, and NIH RR00163, HD/HL37131, and ES07031. We thank Dr John Fanton, Darla Jacob and the staff of the ONPRC Division of Animal Resources for assistance with animal surgeries and timed pregnancies.
PY - 2005/1
Y1 - 2005/1
N2 - Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.
AB - Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.
KW - Adenylyl cyclase
KW - Choline supplementation
KW - Fetal brain development
KW - Muscarinic cholinergic receptor
KW - Nicotine
KW - Nicotinic cholinergic receptor
KW - Vitamin C supplementation
KW - β-adrenoceptor
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U2 - 10.1038/sj.npp.1300544
DO - 10.1038/sj.npp.1300544
M3 - Article
C2 - 15316571
AN - SCOPUS:19944379789
SN - 0893-133X
VL - 30
SP - 129
EP - 144
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 1
ER -