Chronic neonatal nicotine upregulates heteromeric nicotinic acetylcholine receptor binding without change in subunit mRNA expression

Brain Res. 2006 Oct 3;1113(1):94-109. doi: 10.1016/j.brainres.2006.06.084. Epub 2006 Aug 30.

Abstract

Smoking during pregnancy chronically exposes the fetus to nicotine resulting in long-term behavioral and cognitive deficits. Nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels widely expressed in the nervous system. Chronic nicotine upregulates high-affinity nAChRs in animals and smokers. Here we determined if chronic nicotine treatment during a developmental period corresponding to the human third trimester regulates nAChR expression. Rat pups were intubated orally three times per day with or without nicotine (6 mg/kg/day) from postnatal day 1 to 8. Subunit mRNA expression was assessed by in situ hybridization. Expression of heteromeric and homomeric nAChR receptor was evaluated by autoradiography using (125)I-epibatidine and (125)I-alphabungarotoxin, respectively. nAChR expression was analyzed in cortex, hippocampus, thalamus and medial habenula from autoradiograms using computer assisted image analysis. Nicotine induced significant upregulation of heteromeric but not homomeric nAChRs in hippocampus, cortex and thalamus without changes in subunit mRNA expression. No effect of chronic nicotine on receptor expression was detected in the medial habenula, suggesting that nicotine's effect was mainly on alpha4beta2-type heteromeric nAChRs. The nicotine-induced upregulation was reversed after nicotine withdrawal. Receptor blockade by DHbetaE, an antagonist for heteromeric alpha4/beta2 nAChRs, did not prevent upregulation but increased expression to a similar degree as nicotine. Combination of both drugs had a cumulative effect. Thus, although transient, intermittent nicotine exposure as seen in smoking mothers is sufficient to upregulate heteromeric nAChRs during a critical period of brain development and could contribute to the behavioral deficits found in children whose mother smoked.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Binding, Competitive / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bungarotoxins / pharmacokinetics
  • Female
  • Gene Expression Regulation, Developmental / drug effects*
  • In Situ Hybridization / methods
  • Iodine Isotopes / pharmacokinetics
  • Male
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Pregnancy
  • Protein Binding / drug effects
  • Protein Subunits / genetics*
  • Protein Subunits / metabolism
  • Pyridines / pharmacokinetics
  • RNA, Messenger / metabolism*
  • Radioligand Assay / methods
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Bungarotoxins
  • Iodine Isotopes
  • Nicotinic Agonists
  • Protein Subunits
  • Pyridines
  • RNA, Messenger
  • Receptors, Nicotinic
  • Nicotine
  • epibatidine