Prenatal Nicotine Exposure Alters the Responses to Subsequent Nicotine Administration and Withdrawal in Adolescence: Serotonin Receptors and Cell Signaling

Prenatal nicotine exposure (PNE) has been associated with increased prevalence of attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD) and substance abuse in exposed children and adolescents. Whether these syndromes are caused by nicotine exposure, or genetic and psychosocial adversities associated with maternal smoking is not completely clear. Animal models suggest a direct impact of PNE. However, the fact that nicotine is forcefully administrated in these paradigms raises some questions about the specificity of these findings. Pregnant C57BI/6J mice were allowed to choose drinking saccharin/nicotine solutions or pure water. Controls could choose saccharin solutions or pure water. Offspring were tested in spontaneous locomotion, fear-associated learning (trace conditioning), addictive (conditioned place preference), and depression-like (learned helplessness) behaviors. There was no significant difference in weight or pup number between the prenatal treatment groups. A significant effect of PNE was observed on spontaneous locomotion, preference for a cocaine-associated place, and latency to escape in the learned helplessness paradigm. Surprisingly, PNE mice exhibited an increased learning of trace-conditioned fear-associated cues. The hyperlocomotive behavior reported in animal models of PNE is not likely an artifact of forceful nicotine administration. The increased prevalence of ADHD, MDD and substance abuse observed in PNE children and adolescents is probably caused by direct behavioral teratogenic effects of PNE. The role of PNE as a risk factor of syndromes associated to increased learning of fear-associated cues such as post-traumatic stress disorder (PTSD) warrants further evaluation.

Section: Discussionsupporting

confidence: 61%

Behavioral Teratogenicity Induced by Nonforced Maternal Nicotine Consumption

Paz

Barsness

Martenson

et al. 2006

“…Earlier work has demonstrated alterations in serotonin receptor 1A (5HT 1A ) and 2 (5HT 2 ) binding in patients with depression (Arango et al, 2001;Parsey et al, 2006;Yatham et al, 2000). In the rodent model, both prenatal and adolescent exposure to nicotine were found to increase cerebrocortical 5HT 1A and 5HT 2 receptor binding, while shifting 5HT signaling patterns toward inhibition (Slotkin et al, 2006(Slotkin et al, , 2007Xu et al, 2002), suggesting that tobacco exposure-associated increases in depressed mood observed in the present sample may stem from nicotine-induced alterations in 5HT receptor function. Although effects of prenatal and adolescent nicotine exposure on 5HT 1A and 5HT 2 receptor binding were greater in males in the rodent model (Slotkin et al, 2007), gender differences in the impact of prenatal or adolescent exposure to tobacco smoke on depressed mood in human adolescents did not achieve statistical significance in the present study.…”

Section: Discussionmentioning

confidence: 57%

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

Jacobsen

Slotkin

Mencl

et al. 2007

Self Cite

136

143

Prenatal exposure to active maternal tobacco smoking elevates risk of cognitive and auditory processing deficits, and of smoking in offspring. Recent preclinical work has demonstrated a sex-specific pattern of reduction in cortical cholinergic markers following prenatal, adolescent, or combined prenatal and adolescent exposure to nicotine, the primary psychoactive component of tobacco smoke. Given the importance of cortical cholinergic neurotransmission to attentional function, we examined auditory and visual selective and divided attention in 181 male and female adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. Groups did not differ in age, educational attainment, symptoms of inattention, or years of parent education. A subset of 63 subjects also underwent functional magnetic resonance imaging while performing an auditory and visual selective and divided attention task. Among females, exposure to tobacco smoke during prenatal or adolescent development was associated with reductions in auditory and visual attention performance accuracy that were greatest in female smokers with prenatal exposure (combined exposure). Among males, combined exposure was associated with marked deficits in auditory attention, suggesting greater vulnerability of neurocircuitry supporting auditory attention to insult stemming from developmental exposure to tobacco smoke in males. Activation of brain regions that support auditory attention was greater in adolescents with prenatal or adolescent exposure to tobacco smoke relative to adolescents with neither prenatal nor adolescent exposure to tobacco smoke. These findings extend earlier preclinical work and suggest that, in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention, with concomitant alterations in the efficiency of neurocircuitry supporting auditory attention.

“…In addition, the adolescent brain is much more responsive to nicotine than is the adult, enhancing the synaptic and behavioral responses that contribute to dependence and addiction (Abreu-Villaça et al, 2003a-c;Collins et al, 2004;Elliott et al, 2005;Faraday et al, 2001;Slotkin, 2002), echoing observations made in adolescent smokers (DiFranza et al, 2000(DiFranza et al, , 2002a. Furthermore, the synaptic alterations evoked by fetal nicotine exposure affect the response to nicotine in adolescence (Abreu-Villaça et al, 2004a, b;Jacobsen et al, 2006;Slotkin et al, 2006), likely contributing to the subpopulation in the offspring of smokers that are especially vulnerable to nicotine dependence (Jacobsen et al, 2006;Kandel et al, 1994;Niaura et al, 2001;Porath and Fried, 2005;Roberts et al, 2005).…”

Section: Introductionmentioning

confidence: 63%

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

Slotkin

MacKillop

Rudder

et al. 2006

Self Cite

146

116

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.