An animal model of adolescent nicotine exposure: effects on gene expression and macromolecular constituents in rat brain regions

Nearly all smokers begin tobacco use in adolescence, and approximately 25% of US teenagers are daily smokers. Prenatal nicotine exposure is known to p roduce brain damage, to alter synaptic function and to cause behavioral ano malies, but little or no work has been done to determine if the adolescent brain is also vulnerable. We examined the effect of adolescent nicotine exp osure on indices of cell damage in male and female rats with an infusion pa radigm designed to match the plasma levels found in human smokers or in use rs of the transdermal nicotine patch. Measurements were made of DNA and pro tein as well as expression of mRNAs encoding genes involved in differentiat ion and apoptosis (p53, c-Sos) in cerebral cortex, midbrain and hippocampus . Following nicotine treatment from postnatal days 30-47.5, changes in macr omolecular constituents indicative of cell loss (reduced DNA) and altered c ell size (protein/DNA ratio) were seen across all three brain regions. In a ddition, expression of p53 showed region- and gender-selective alterations consistent with cell damage; c-Sos, which is constitutively overexpressed a fter gestational nicotine exposure, was unaffected with the adolescent trea tment paradigm. Although these measures indicate that the fetal brain is mo re vulnerable to nicotine than is the adolescent brain, the critical period for nicotine-induced developmental neurotoxicity clearly extends into adol escence. Effects on gene expression and cell number, along with resultant o r direct effects on synaptic function, may contribute to increased addictiv e properties and long-term behavioral deficits. (C) 2000 Elsevier Science B .V. All rights reserved.