Short-term adolescent nicotine exposure has immediate and persistent effects on cholinergic systems: critical periods, patterns of exposure, dose thresholds.

In adolescents, the symptoms of nicotine dependence can appear well before the onset of habitual smoking. We investigated short-term nicotine exposure in adolescent rats for corresponding cholinergic alterations. Beginning on postnatal day 30, rats were given a 1-week regimen of nicotine infusions or twice-daily injections, at doses (0.6, 2, and 6 mg/kg/day) set to achieve plasma levels found in occasional to regular smokers. In the cerebral cortex, midbrain, and hippocampus, we assessed nicotinic cholinergic receptor (nAChR) binding, choline acetyltransferase (ChAT) activity, a constitutive marker for cholinergic nerve terminals, and [(3)H]hemicholinium-3 (HC-3) binding to the high-affinity choline transporter, which responds to cholinergic synaptic stimulation. nAChR upregulation was observed with either administration route, even at the lowest dose; in the hippocampus, increases could be detected with as little as 2 days' treatment at 0.6 mg/kg/day. In the midbrain, upregulation was still significant even 1 month post-treatment. Adolescent nicotine treatment also produced lasting decrements in HC-3 binding that were separable from effects on ChAT, suggesting cholinergic synaptic impairment. Again, these effects were obtained at the lowest dose and remained significant 1 month post-treatment. Our results indicate that in adolescence, even a brief period of continuous or intermittent nicotine exposure, elicits lasting alterations in cholinergic systems in brain regions associated with nicotine dependence. As the effects are detected at exposures that produce plasma concentrations as little as one-tenth of those in regular smokers, the exquisite sensitivity of the adolescent brain to nicotine may contribute to the onset of nicotine dependence even in occasional smokers.     

Does prenatal nicotine exposure sensitize the brain to nicotine-induced neurotoxicity in adolescence?

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.     

Visuospatial memory deficits emerging during nicotine withdrawal in adolescents with prenatal exposure to active maternal smoking.

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.     

Prenatal nicotine exposure alters the responses to subsequent nicotine administration and withdrawal in adolescence: Serotonin receptors and cell signaling.

Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence, effects that are associated with a high rate of depression and increased sensitivity to withdrawal symptoms. To evaluate the biological basis for this relationship, we assessed effects on serotonin (5-hydroxytryptamine, 5HT) receptors and 5HT-mediated cellular responses in rats exposed to nicotine throughout prenatal development and then given nicotine in adolescence (postnatal days PN30-47.5), using regimens that reproduce plasma nicotine levels found in smokers. Evaluations were then made during the period of adolescent nicotine treatment and for up to one month after the end of treatment. Prenatal nicotine exposure, which elicits damage to 5HT projections in the cerebral cortex and striatum, produced sex-selective changes in the expression of 5HT(1A) and 5HT2 receptors, along with induction of adenylyl cyclase (AC), leading to sensitization of heterologous inputs operating through this signaling pathway. Superimposed on these effects, the AC response to 5HT was shifted toward inhibition. By itself, adolescent nicotine administration, which damages the same pathways, produced similar effects on receptors and the 5HT-mediated response, but a smaller overall induction of AC. Animals exposed to prenatal nicotine showed a reduced response to nicotine administered in adolescence, results in keeping with earlier findings of persistent desensitization. Our results indicate that prenatal nicotine exposure alters parameters of 5HT synaptic communication lasting into adolescence and changes the response to nicotine administration and withdrawal in adolescence, actions which may contribute to a subpopulation especially vulnerable to nicotine dependence.     

Increased nicotine self-administration following prenatal exposure in female rats

There is a significant association between maternal cigarette smoking during pregnancy and greater subsequent risk of smoking in female offspring. In animal models, prenatal nicotine exposure causes persistent alterations in cholinergic and monoaminergic systems, both of which are important for nicotine actions underlying tobacco addiction. Accordingly, the current study was conducted to determine if there is a cause-and-effect relationship between prenatal nicotine exposure and nicotine self-administration starting in adolescence. Pregnant rats were administered nicotine (6 mg/kg/day) by osmotic minipump infusion throughout gestation and then, beginning in adolescence and continuing into adulthood, female offspring were given access to nicotine via a standard operant IV self-administration procedure (0.03 mg/kg/infusion). Gestational nicotine exposure did not alter the initial rate of nicotine self-administration. However, when animals underwent one week of forced abstinence and then had a second opportunity to self-administer nicotine, the prenatally-exposed animals showed a significantly greater rate of self-administration than did the controls. Prenatal nicotine exposure causes increased nicotine self-administration, which is revealed only when the animals are allowed to experience a period of nicotine abstinence. This supports a cause-and-effect relationship between the higher rates of smoking in the daughters of women who smoke cigarettes during pregnancy and implicates a role for nicotine in this effect. Our results further characterize the long-term liabilities of maternal smoking but also point to the potential liabilities of nicotine-based treatments for smoking cessation during pregnancy.     

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.

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.

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.     

Enhanced nicotine reward in adulthood after exposure to nicotine during early adolescence in mice

Approximately one million adolescents begin smoking cigarettes every year. Studies show that adolescents may be particularly vulnerable to various aspects of nicotine dependence. Work on rodents demonstrates parallel findings showing that adolescence is a time of changed sensitivity to both rewarding and aversive effects of nicotine. However, it is unclear if these effects are long-lasting and whether they contribute to a lifetime of nicotine addiction. In this study we have characterized the effects of adolescent nicotine exposure on the rewarding properties of nicotine in adulthood using the CPP model. Specifically, we have addressed whether the phase of adolescence (early, middle, or late adolescence) plays a role in the susceptibility to the enhanced rewarding effects of nicotine. Furthermore, we have investigated the long-term effects of adolescent nicotine exposure on nicotine reward in adulthood and have correlated these behavioral adaptations with possible molecular mechanisms. We observed that early adolescence in the mouse is a unique phase for elevated sensitivity to nicotine reward using a CPP model. In addition, exposure to nicotine during this phase, but not during late adolescence or adulthood, resulted in a lasting enhancement of reward in adulthood. Finally, we have shown that early adolescent nicotine exposure significantly elevates nAChR function in adulthood. Overall, we demonstrate that early adolescence represents a period of development, distinct from middle and late adolescence, during which nicotine exposure can cause persistent changes in behavior and molecular adaptations.     

Gestational ethanol and nicotine exposure: effects on maternal behavior, oxytocin, and offspring ethanol intake in the rat

Alcohol consumption and smoking during pregnancy is common, despite the known adverse effects of these drugs on fetal development. Though studies on the effects of each drug separately are published, little is known about the effect of concurrent use of alcohol and nicotine in humans or in preclinical models. In this report, we examined the impact of continuous gestational exposure to both ethanol via liquid diet and nicotine via an osmotic minipump on maternal behavior, offspring ethanol intake, and oxytocin levels in a rat model. Dams were tested for the onset of maternal behavior with litters of unexposed surrogate pups and then killed to examine oxytocin levels within specific brain regions. Drug-exposed offspring reared by surrogate dams were tested for ethanol intake at either adolescence or adulthood, and oxytocin levels were measured in relevant brain regions after behavioral tests. Dams exhibited minor deficits in maternal care, which were associated with lower oxytocin levels in both the ventral tegmental and medial preoptic areas compared to control dams. Prenatal exposure altered sex-specific ethanol intake, with differential effects at adolescence and adulthood. Oxytocin system changes were also apparent in the ventral tegmental and medial preoptic regions of drug-exposed adolescent and adult offspring. These results suggest that dam treatment with ethanol and nicotine can somewhat negatively affect the early rearing environment, and that prenatal exposure to both of these drugs results in drinking behavior differing from what would be expected from either drug alone. Oxytocin's possible involvement in the mediation of these effects is highlighted.     

Simultaneous prenatal ethanol and nicotine exposure affect ethanol consumption,ethanol preference and oxytocin receptor binding in adolescent and adult rats

Ethanol consumption and smoking during pregnancy are common, despite the known adverse effects on the fetus. The teratogenicity of each drug independently is well established; however, the effects of concurrent exposure to ethanol and nicotine in preclinical models remain unclear. This study examined the impact of simultaneous prenatal exposure to both ethanol and nicotine on offspring ethanol preference behaviors and oxytocin system dynamics. Rat dams were given liquid diet (17% ethanol derived calories (EDC)) on gestational day (GD) 5 and 35% EDC from GD 6–20 and concurrently an osmotic minipump delivered nicotine (3–6 mg/kg/day) from GD 4–postpartum day 10. Offspring were tested for ethanol preference during adolescence (postnatal day (PND) 30–43) and again at adulthood (PND 60–73), followed by assays for oxytocin mRNA expression and receptor binding in relevant brain regions. Prenatal exposure decreased ethanol preference in males during adolescence, and decreased consumption and preference in females during adulthood compared to controls. Oxytocin receptor binding in the nucleus accumbens and hippocampus was increased in adult prenatally exposed males only. Prenatal exposure to these drugs sex-specifically decreased ethanol preference behavior in offspring unlike reports for either drug separately. The possible role of oxytocin in reduction of ethanol consumption behavior is highlighted.     

Effects of prenatal nicotine exposure on primate brain development and attempted amelioration with supplemental choline or vitamin C: neurotransmitter receptors, cell signaling and cell development biomarkers in fetal brain regions of rhesus monkeys.

Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.     

Nicotinic acetylcholine receptors controlling attention: Behavior,circuits and sensitivity to disruption by nicotine

Attention is a central cognitive function that enables long-term engagement in a task and suppression of irrelevant information to obtain future goals. The prefrontal cortex (PFC) is the main link in integrating emotional and motivational state of an animal to regulate top-down attentional processes. Acetylcholine modulates PFC neuronal networks by activating nicotinic acetylcholine receptors (nAChRs) to support attention. However, how neuronal activity changes in the PFC during attention and which nAChR subtypes mediate this is only rudimentarily understood, but progress is being made. Recently, exciting new insights were obtained in the dynamics of cholinergic signaling in the PFC and modes of acetylcholine transmission via nAChRs in the cortex. In addition, mechanisms are uncovered on how the PFC circuitry is regulated by nAChRs. Novel studies show that endogenous activation of nAChRs in the PFC plays a central role in controlling attention. Here, we review current insights into how different subtypes of nAChRs expressed by distinct types of neurons in the PFC circuitry shape attention. In addition we discuss the impact of nicotine on the cholinergic system and prefrontal cortical circuits. Low concentrations of nicotine, as experienced by smokers, interfere with cholinergic signaling. In the long-term exposure to nicotine during adolescence leads to maladaptive adaptations of the PFC circuitry, which ultimately leads to a decrement in attention performance, again emphasizing the importance of nAChRs in attention.     

Fetal and offspring arrhythmia following exposure to nicotine during pregnancy

Although recent studies have demonstrated prenatal nicotine can increase cardiovascular risk in the offspring, it is unknown whether exposure to nicotine during pregnancy also may be a risk for development of arrhythmia in the offspring. In addition, in previous studies of fetal arrhythmia affected by smoking, only two patterns, bradycardia and tachycardia, were observed. The present study examined acute effects of maternal nicotine on the fetal arrhythmia in utero, and chronic influence on offspring arrhythmia at adult stage following prenatal exposure to nicotine. Nicotine was administered to pregnant ewes and rats. In the fetal sheep, intravenous nicotine not only induced changes of fetal heart rate, but also caused cardiac cycle irregularity, single and multiple dropped cardiac cycles. Although maternal nicotine had no influence on fetal blood pH, lactic acid, hemocrit, Na⁺, K⁺ levels and plasma osmolality, fetal blood PO₂ levels were significantly decreased following maternal nicotine in ewes. In offspring rats at 4–5 months after birth, prenatal exposure to nicotine significantly increased heart rate and premature ventricular contraction in restraint stress. In addition, arrhythmias induced by injection of nicotine were higher in the offspring prenatal exposure to nicotine in utero. The results provide new evidence that exposure to nicotine in pregnancy can cause fetal arrhythmia in various patterns besides tachycardia and bradycardia, the possible mechanisms for nicotine‐induced fetal arrhythmia included in utero hypoxia. Importantly, following exposure to nicotine significantly increased risk of arrhythmia in the adult offspring. The finding offers new insight for development of cardiac rhythm problems in fetal origins. Copyright © 2009 John Wiley & Sons, Ltd.     

Prenatal nicotine exposure is associated with an increase in [125I]epibatidine binding in discrete cortical regions in rats

Previously, it was reported that hyperactive male offspring of dams exposed to nicotine (6 mg/kg/day) during gestation had an increase in cortical alpha4-beta2 nicotinic receptor subtype density as determined by [3H]cytisine binding in tissue homogenate [Tizabi Y, Popke EJ, Rahman MA, Nespor SM, Grunberg NE. Hyperactivity induced by prenatal nicotine exposure is associated with an increase in cortical nicotinic receptors. Pharmacol, Biochem Behav 1997;58:141-6]. [125I]Epibatidine labels alpha4beta2 nicotinic receptors with higher affinity than [3H]cytisine. In the present study, using quantitative autoradiography, we evaluated the effects of in-utero exposure to nicotine (9 mg/kg/day) on [125I]epibatidine binding in 46 discrete brain regions of 36-day-old male offspring of Sprague-Dawley rats. This dosage of nicotine administered during pregnancy to same rats was shown to result in increased vertical activity in the male offspring [Tizabi Y, Russell LT, Nespor SM, Perry DC, Grunberg NE. Prenatal nicotine exposure: effects on locomotor activity and central [125I]alpha-BT binding in rats. Pharmacol, Biochem Behav (in press).]. Prenatal nicotine exposure resulted in increases in receptor densities of the somatosensory cortex (90%) and the visual cortex (107%) only. Moreover, these increases were restricted to cortical layer 1. Collectively, these results indicate that prenatal nicotine exposure affects specific nicotinic receptors in selective cortical regions of male offspring. These neurochemical effects may be responsible for some of the behavioral abnormalities seen in such offspring.     

Combined exposure to nicotine and ethanol in adolescent mice differentially affects anxiety levels during exposure, short-term, and long-term withdrawal.

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 microg/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.     

Hyperactivity, increased nicotine consumption and impaired performance in the five-choice serial reaction time task in adolescent rats prenatally exposed to nicotine

Rationale

Prenatal exposure to nicotine has been linked to accelerated risk for different psychiatric disorders, including conduct disorder, attention deficit hyperactivity disorder (ADHD) and drug abuse. We examine a potential link between prenatal nicotine exposure, hyperactivity, anxiety, nicotine consumption, and cognitive performance in rats.

Methods

Adolescent offspring of females exposed during pregnancy to 0.06?mg/ml nicotine solution as the only source of water and of a group of pair-fed females, used as a control for anorexic effects of nicotine, were evaluated in a battery of tests, including locomotor activity, the elevated plus maze, two-bottle free-choice nicotine solution consumption, the five-choice serial reaction time test (5-CSRTT) and a delay-discounting test. All tests were conducted between postnatal day (PND) 25 and PND 50.

Results

Nicotine-exposed animals expressed hyperactivity, increased number of open arms entries in the elevated plus maze and increased numbers of anticipatory responses in the 5-CSRTT. Decreased aversion for nicotine solution in the free-choice test and decreased numbers of omission errors in the 5-CSRTT were observed both in nicotine-exposed and pair-fed offspring. Neither nicotine exposure nor pair-feeding had an effect on impulsive choice in a delay-discounting test.

Conclusions

Our study confirms deleterious effects of prenatal nicotine exposure on important aspects of behaviour and inhibitory control in adolescent rats and supports epidemiological findings that show increased levels of symptoms of ADHD and related disorders among those whose mothers smoked during their pregnancy. It also suggests a link between food restriction during pregnancy and addiction-related behaviours in offspring.     

Prenatal nicotine exposure: effects on locomotor activity and central [125I]alpha-BT binding in rats

Maternal smoking during pregnancy or in utero exposure of the fetus to nicotine may result in learning difficulties and hyperactivity in the child. To elucidate possible involvement of the alpha(7) nicotinic receptor subtype in these behavioral impairments, pregnant dams were treated with nicotine (9 mg/kg/day) via osmotic minipumps throughout gestation. Male offspring were weaned at postnatal day 18, and were tested for locomotor activity at postnatal days 20-24. Pups were sacrificed on postnatal day 36-38 and 18 discrete brain areas were analyzed for [125I]alpha-bungarotoxin (alpha-BT) binding by quantitative autoradiography. Prenatal nicotine caused an elevation in locomotor activity (vertical movements) in offspring. [125I]alpha-BT binding was significantly reduced in the hippocampal CA1 region (29%), dentate gyrus (22%), and medial geniculate nucleus (29%). These findings suggest that some of the behavioral abnormalities induced by prenatal nicotine exposure may be due to a reduction of alpha(7) nicotinic receptors in discrete brain regions.     

Increased anxiety-like behavior in adult rats exposed to nicotine as adolescents

OBJECTIVE: Twenty percent of adolescents between 12 and 18 years old are regular smokers. Recently developed animal models demonstrate that adolescent nicotine exposure produces behavioral and electrophysiological changes, which persist into adulthood. The purpose of this study was to further define the behavioral effects of nicotine exposure during adolescence. METHODS: Male 31-36-day-old adolescent rats were administered 5.0 mg/kg/day nicotine using transdermal Nicoderm CQ patches (SmithKline Beecham). During nicotine exposure, motor activity was assessed. Behavior in both standard open field and modified open field was examined 2-3 weeks after exposure ended. RESULTS: Nicotine exposure significantly enhanced motor activity in nicotine-exposed rats compared with controls, demonstrating the acute stimulatory effects of transdermal nicotine. Two to three weeks after nicotine exposure ended, significantly lower levels of exploratory activity were observed relative to controls in the standard open field. Rats exposed to nicotine during adolescence also retreated to the perimeter of the open field more quickly than control rats. In a modified open field, nicotine exposure reduced approaches to food, contact with food and food intake. CONCLUSIONS: Taken together, these data suggest that adolescent nicotine exposure may induce an anxiogenic profile, which persists beyond acute nicotine withdrawal. Given the hypothesized role of stress and anxiety in the maintenance of smoking, it could be speculated that anxiety associated with smoking abstinence may play an important role in continued adolescent tobacco use.     

Respiratory dysfunctions induced by prenatal nicotine exposure

• 1 Maternal tobacco smoking is the principal risk factor associated with sudden infant death syndrome (SIDS), a leading cause of death of infants under 1 year of age. Victims of SIDS show a higher incidence of respiratory control abnormalities, including central apnoeas, delayed arousal responses and diminished ventilatory chemoreflexes.
• 2 Nicotine is likely the link between maternal tobacco smoking and SIDS. Prenatal nicotine exposure can alter the breathing pattern and can reduce hypoxia‐ and hypercarbia‐induced ventilatory chemoreflexes. In vitro approaches have revealed that prenatal nicotine exposure impairs central chemosensitivity, switching the cholinergic contribution from a muscarinic to a nicotinic receptor‐based drive. In addition, serotonergic, noradrenergic, GABAergic, glycinergic and glutamatergic, among others, are affected by prenatal nicotine.
• 3 Here we propose that prenatal nicotine affects the respiratory network through two main processes: (i) reorganization of neurotransmitter systems; and (ii) remodelling of neural circuits. These changes make breathing more vulnerable to fail in early postnatal life, which could be related to the pathogenesis of SIDS.

     

Adolescent exposure to nicotine results in reinforcement enhancement but does not affect adult responding in rats

Background

Adolescence is a period of development associated with a peak in an organism's responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether (1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and (2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood.

Methods

Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (postnatal day 29–42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules.

Results

Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood.

Conclusions

Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.