Permanent, Sex-Selective Effects of Prenatal or Adolescent Nicotine Exposure, Separately or Sequentially, in Rat Brain Regions: Indices of Cholinergic and Serotonergic Synaptic Function, Cell Signaling, and Neural Cell Number and Size at 6 Months of Age

Abstract

Nicotine is a neuroteratogen that disrupts neurodevelopment and synaptic function, with vulnerability extending into adolescence. We assessed the permanence of effects in rats on indices of neural cell number and size, and on acetylcholine and serotonin (5HT) systems, conducting assessments at 6 months of age, after prenatal nicotine exposure, adolescent exposure, or sequential exposure in both periods. For prenatal nicotine, indices of cell number and size showed few abnormalities by 6 months, but there were persistent deficits in cerebrocortical choline acetyltransferase activity and hemicholinium-3 binding to the presynaptic choline transporter, a pattern consistent with cholinergic hypoactivity; these effects were more prominent in males than females. The expression of 5HT receptors also showed permanent effects in males, with suppression of the 5HT 1A subtype and upregulation of 5HT 2 receptors. In addition, cell signaling through adenylyl cyclase showed heterologous uncoupling of neurotransmitter responses. Nicotine exposure in adolescence produced lasting effects that were similar to those of prenatal nicotine. However, when animals were exposed to prenatal nicotine and received nicotine subsequently in adolescence, the adverse effects then extended to females, whereas the net effect in males was similar to that of prenatal nicotine by itself. Our results indicate that prenatal or adolescent nicotine exposure evoke permanent changes in synaptic function that transcend the recovery of less-sensitive indices of structural damage; further, prenatal exposure sensitizes females to the subsequent adverse effects of adolescent nicotine, thus creating a population that may be especially vulnerable to the lasting behavioral consequences of nicotine intake in adolescence.

Gender-Specific Effects of Prenatal and Adolescent Exposure to Tobacco Smoke on Auditory and Visual Attention

“…Converging evidence from preclinical work has identified nicotine as the chief teratogenic component of tobacco smoke contributing to adverse neurodevelopmental sequelae associated with prenatal exposure to maternal smoking (Slotkin, 2004;Slotkin et al, 2007). Nicotine binds to nicotinic acetylcholine receptors (nAChRs) which, when stimulated by endogenous acetylcholine, play a key role in the regulation of brain development, promoting cell replication, differentiation, and synaptic development (Lauder and Schambra, 1999;Metherate and Hsieh, 2004;Slotkin, 2004).…”

“…Nicotine binds to nicotinic acetylcholine receptors (nAChRs) which, when stimulated by endogenous acetylcholine, play a key role in the regulation of brain development, promoting cell replication, differentiation, and synaptic development (Lauder and Schambra, 1999;Metherate and Hsieh, 2004;Slotkin, 2004). Stimulation of nAChRs by nicotine during prenatal development produces persistent cholinergic and serotonergic hypoactivity, and reductions in neural cell membrane complexity, alterations in neurotransmitter responses mediated through adenyl cyclase and alterations in serotonin receptor expression (Navarro et al, 1989;Slotkin, 2004;Slotkin et al, 2007). The vulnerability of the developing brain to nicotine extends into the early postnatal period in the rodent (corresponding to the third trimester in humans), where exposure disrupts auditory learning and nicotinic regulation of primary auditory cortex (Liang et al, 2006).…”

“…Work in rodents has provided evidence that nicotine is also disruptive to adolescent brain development, resulting in changes in cholinergic neurotransmission, cell membrane complexity, cell signaling, and serotonin receptor density that are similar to but smaller in magnitude than those observed following prenatal nicotine exposure (Abreu-Villaca et al, 2003a, b;Slotkin et al, 2007). Consistent with this evidence that vulnerability to the developmentally disruptive effects of nicotine extends into adolescence, adolescent tobacco smokers were found to have impaired working memory performance accuracy, while male smokers demonstrated impairments of auditory selective attention relative to female smokers and to male and female nonsmokers (Jacobsen et al, 2005).…”

“…Recent work with a rodent model developed to study the effects of combined nicotine exposure during these two key developmental epochs (gestation and adolescence) has provided evidence of sexspecific effects (Slotkin et al, 2007). Whereas effects of prenatal or adolescent nicotine exposure alone on cholinergic neurotransmission, neural cell membrane complexity, cell signaling, and serotonin receptor expression were more prominent in males than in females, when prenatal exposure was followed by adolescent exposure the net effect on indices of neurodevelopment in females was similar to that in males (Slotkin et al, 2007). In contrast, among males, the magnitude of effects of dual (prenatal + adolescent) nicotine exposure on neurodevelopment was similar to that observed with prenatal or adolescent exposure alone (Slotkin et al, 2007).…”

“…Although exposure to nicotine during brain development has been shown to reduce cortical cholinergic markers in the rodent model (Slotkin et al, 2007), few prior studies have examined the impact of prenatal and adolescent exposure to tobacco smoke on attention in humans. Accordingly, we examined auditory and visual attention in 181 adolescent smokers and nonsmokers with and without prenatal exposure to active maternal smoking.…”