Prenatal Nicotine Exposure Alters the Response to Nicotine Administration in Adolescence: Effects on Cholinergic Systems During Exposure and Withdrawal

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Active maternal smoking during pregnancy elevates the risk of cognitive deficits and tobacco smoking among offspring. Preclinical work has shown that combined prenatal and adolescent exposure to nicotine produces more pronounced hippocampal changes and greater deficits in cholinergic activity upon nicotine withdrawal than does prenatal or adolescent exposure to nicotine alone. Few prior studies have examined the potential modifying effects of gestational exposure to active maternal smoking on cognitive or brain functional response to tobacco smoking or nicotine withdrawal in adolescents. We examined visuospatial and verbal memory in 35 adolescent tobacco smokers with prenatal exposure to active maternal smoking and 26 adolescent tobacco smokers with no prenatal exposure to maternal smoking who were similar in age, educational attainment, general intelligence, and baseline plasma cotinine. Subjects were studied during ad libitum smoking and after 24 h of abstinence from smoking. A subset of subjects from each group also underwent functional magnetic resonance imaging while performing a visuospatial encoding and recognition task. Adolescent tobacco smokers with prenatal exposure experienced greater nicotine withdrawal-related deficits in immediate and delayed visuospatial memory relative to adolescent smokers with no prenatal exposure. Among adolescent smokers with prenatal exposure, nicotine withdrawal was associated with increased activation of left parahippocampal gyrus during early recognition testing of visuospatial stimuli and increased activation of bilateral hippocampus during delayed recognition testing of visuospatial stimuli. These findings extend prior preclinical work and suggest that, in human adolescent tobacco smokers, prenatal exposure to active maternal smoking is associated with alterations in medial temporal lobe function and concomitant deficits in visuospatial memory.

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Visuospatial Memory Deficits Emerging During Nicotine Withdrawal in Adolescents with Prenatal Exposure to Active Maternal Smoking

Jacobsen

Slotkin

Westerveld

et al. 2005

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“…In that way, neurotoxicant effects of nicotine may then explain, in part, the existence of a vulnerable subpopulation of adolescents who are especially predisposed to nicotine addiction (Cornelius et al, 2000;Kandel et al, 1994;Niaura et al, 2001). The fact that prenatal nicotine exposure by itself elicits widespread, lasting alterations almost certainly contributes to long-term changes involving multiple neurotransmitter systems and circuits throughout the brain (Abreu-Villaça et al, 2003a-c; Levin and Slotkin, 1998;Roy et al, , 2002Sabherwal, 1994, 1998;Slotkin, 1992Slotkin, , 1998Slotkin, , 1999Slotkin, , 2002Slotkin et al, 2002;Trauth et al, 2000aTrauth et al, -c, 2001Xu et al, 2001Xu et al, , 2002Xu et al, , 2003 and thus future studies need to address how these pathways are affected by sequential prenatal and adolescent nicotine exposure; a parallel study from our group has already found similar worsening of outcomes directed toward cholinergic systems (Abreu-Villaça et al, 2004) but, given the more generalized neurotoxicant effects, there is no reason to suspect that the synaptic effects will be limited to acetylcholine. Our findings in rats thus point to specific biological bases for the increased susceptibility of adolescent smokers to nicotine dependence, and particularly the subpopulation of adolescents whose mothers smoked during pregnancy; we suggest that this higher vulnerability comprises components of nicotine neurotoxicity as well as selective alterations in synaptic communication.…”

Section: Discussionmentioning

confidence: 72%

Does Prenatal Nicotine Exposure Sensitize the Brain to Nicotine-Induced Neurotoxicity in Adolescence?

Abreu‐Villaça

Seidler

Slotkin

2004

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Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and adolescent nicotine exposure in developing rats to evaluate whether these contribute to a biological basis for this relationship. Rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5); this regimen reproduces the plasma nicotine levels found in smokers. Indices of neural cell number (DNA concentration and content), cell size (protein/DNA ratio), and cell membrane surface area (membrane/total protein) were then evaluated in brain regions during adolescent nicotine administration (PN45) and up to 1 month post-treatment. By itself, prenatal nicotine administration produced cellular alterations that persisted into adolescence, characterized by net cell losses in the midbrain and to a lesser extent, in the cerebral cortex, with corresponding elevations in the membrane/total protein ratio. The hippocampus showed a unique response, with increased DNA content and regional enlargement. Adolescent nicotine treatment alone had similar, albeit smaller effects, but also showed sex-dependence, with effects on protein biomarkers preferential to females. When animals exposed to nicotine prenatally were then given nicotine in adolescence, the net outcome was worsened, largely representing summation of the two individual effects. Our results indicate that prenatal nicotine exposure alters parameters of cell development lasting into adolescence, where the effects add to those elicited directly by adolescent nicotine; neurotoxicant actions may thus contribute to the association between maternal smoking and subsequent smoking in the offspring.

“…More specifically, the maturation of central cholinergic systems involved in learning, memory, and psychostimulant responses is consolidated during the periadolescent period Nadler et al, 1974;Zahalka et al, 1993), and an important aspect of this period is that neuronal stimulation induces synaptic rearrangement (Scheetz and Constantine-Paton, 1994), which indicates that adolescent brain is vulnerable to central nervous system stimulants. As an acetylcholine analog, the nicotinic acetylcholine receptors are the primary cellular mediators of nicotine's effects (Abreu-Villaça et al, 2003, 2004b. As for ethanol, it directly influences the function of various ligandgated ion channels, including nicotinic receptors (for review : Grant, 1994).…”

Section: Neurobiology Of Nicotine Vs Ethanol Interactionsmentioning

confidence: 99%

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

Abreu‐Villaça

Nunes

Queiroz-Gomes

et al. 2007

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Smoking and consumption of alcoholic beverages are frequently associated during adolescence. This association could be explained by the cumulative behavioral effects of nicotine and ethanol, particularly those related to anxiety levels. However, despite epidemiological findings, there have been few animal studies of the basic neurobiology of the combined exposure in the adolescent brain. In the present work we assessed, through the use of the elevated plus maze, the short-and long-term anxiety effects of nicotine (NIC) and/or ethanol (ETOH) exposure during adolescence (from the 30th to the 45th postnatal day) in four groups of male and female C57BL/6 mice: (1) Concomitant NIC (nicotine free-base solution (50 mg/ml) in 2% saccharin to drink) and ETOH (ethanol solution (25%, 2 g/kg) i.p. injected every other day) exposure; (2) NIC exposure; (3) ETOH exposure; (4) Vehicle. C57BL/6 mice were selected, in spite of the fact that they present slower ethanol metabolism, because they readily consume nicotine in the concentration used in the present study. During exposure (45th postnatal day: PN45), our results indicated that ethanol was anxiolytic in adolescent mice and that nicotine reverted this effect. Short-term drug withdrawal (PN50) elicited sex-dependent effects: exposure to nicotine and/or ethanol was anxiogenic only for females. Although neither nicotine nor ethanol effects persisted up to 1 month postexposure (PN75), the coadministration elicited an anxiogenic response. In spite of the fact that generalizations based on the results from a single strain of mice are prone to shortcomings, our results suggest that the deficient response to the anxiolytic effects of ethanol in adolescents co-exposed to nicotine may drive higher ethanol consumption. Additionally, increased anxiety during long-term smoking and drinking withdrawal may facilitate relapse to drug use.