Original Article

Neuropsychopharmacology (2005) 30, 129–144, advance online publication, 18 August 2004; doi:10.1038/sj.npp.1300544

Preclinical Research

Effects of Prenatal Nicotine Exposure on Primate Brain Development and Attempted Amelioration with Supplemental Choline or Vitamin C: Neurotransmitter Receptors, Cell Signaling and Cell Development Biomarkers in Fetal Brain Regions of Rhesus Monkeys

Theodore A Slotkin1, Frederic J Seidler1, Dan Qiao1, Justin E Aldridge1, Charlotte A Tate1, Mandy M Cousins1, Becky J Proskocil2, Harmanjatinder S Sekhon2, Jennifer A Clark2, Stacie L Lupo2 and Eliot R Spindel2

  1. 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
  2. 2Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA

Correspondence: Dr TA Slotkin, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA. Tel: +919 681 8015; Fax: +919 684 8197; E-mail: t.slotkin@duke.edu

Received 6 May 2004; Revised 1 July 2004; Accepted 19 July 2004; Published online 18 August 2004.

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Abstract

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.

Keywords:

adenylyl cyclase, beta-adrenoceptor, choline supplementation, fetal brain development, muscarinic cholinergic receptor, nicotine, nicotinic cholinergic receptor, vitamin C supplementation

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