Fetal and neonatal exposure to nicotine disrupts postnatal lung development in rats: role of VEGF and its receptors

Many women are unable to quit smoking during pregnancy and therefore are prescribed drugs, including nicotine (nicotine replacement therapy [NRT]), to aid with smoking cessation. However, the consequences to the offspring of pregnant NRT users have not been well studied. The goals of this study were to determine the consequences of fetal and neonatal exposure to nicotine on lung development and function. Female rats were exposed to nicotine for 2 weeks prior to mating until weaning. Lungs were collected from saline and nicotine-treated rats from birth to adulthood to assess postnatal lung structure and function. Although nicotine exposure altered alveolarization at weaning, an effect that resolved by adulthood, it did not affect lung function at any of the ages investigated. However, nicotine exposure significantly decreased lung vascularization. The current study suggests that perinatal exposure to nicotine alters lung development, an effect which may be mediated via decreased vascular endothelial growth factor (VEGF) signaling.     

Risks and benefits of nicotine to aid smoking cessation in pregnancy.

Cigarette smoking during pregnancy is the single largest modifiable risk for pregnancy-related morbidity and mortality in the US. Addiction to nicotine prevents many pregnant women who wish to quit smoking from doing so. The safety and efficacy of nicotine replacement therapy (NRT) for smoking cessation during pregnancy have not been well studied. Nicotine is classified by the US Food and Drug Administration as a Pregnancy Category D drug. Animal studies indicate that nicotine adversely affects the developing fetal CNS, and nicotine effects on the brain may be involved in the pathophysiology of sudden infant death syndrome (SIDS). It has been assumed that the cardiovascular effects of nicotine resulting in reduced blood flow to the placenta (uteroplacental insufficiency) is the predominant mechanism of the reproductive toxicity of cigarette smoking during pregnancy. Short term high doses of nicotine in pregnant animals do adversely affect the maternal and fetal cardiovascular systems. However, studies of the acute effects of NRT in pregnant humans indicate that nicotine alone has minimal effects upon the maternal and fetal cardiovascular systems. Cigarette smoking delivers thousands of chemicals, some of which are well documented reproductive toxins (e.g. carbon monoxide and lead). A myriad of cellular and molecular biological abnormalities have been documented in placentas, fetuses, and newborns of pregnant women who smoke. The cumulative abnormalities produced by the various toxins in cigarette smoke are probably responsible for the numerous adverse reproductive outcomes associated with smoking. It is doubtful that the reproductive toxicity of cigarette smoking is primarily related to nicotine. We recommend the following. Efficacy trials of NRT as adjunctive therapy for smoking cessation during pregnancy should be conducted. The initial dose of nicotine in NRT should be similar to the dose of nicotine that the pregnant woman received from smoking. Intermittent-use formulations of NRT (gum, spray, inhaler) are preferred because the total dose of nicotine delivered to the fetus will be less than with continuous-use formulations (transdermal patch). A national registry for NRT use during pregnancy should be created to prospectively collect obstetrical outcome data from NRT efficacy trials and from individual use. The goal of this registry would be to determine the safety of NRT use during pregnancy, especially with respect to uncommon outcomes such as placental abruption. Finally, our review of the data indicate that minimal amounts of nicotine are excreted into breast milk and that NRT can be safely used by breast-feeding mothers.     

Effects of Nicotine During Pregnancy: Human and Experimental Evidence

Prenatal exposure to tobacco smoke is a major risk factor for the newborn, increasing morbidity and even mortality in the neonatal period but also beyond. As nicotine addiction is the factor preventing many women from smoking cessation during pregnancy, nicotine replacement therapy (NRT) has been suggested as a better alternative for the fetus. However, the safety of NRT has not been well documented, and animal studies have in fact pointed to nicotine per se as being responsible for a multitude of these detrimental effects. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and exposure during development interferes with normal neurotransmitter function, thus evoking neurodevelopmental abnormalities by disrupting the timing of neurotrophic actions. As exposure to pure nicotine is quite uncommon in pregnant women, very little human data exist aside from the vast literature on prenatal exposure to tobacco smoke.     

Prenatal nicotine exposure alters the response to nicotine administration in adolescence: effects on cholinergic systems during exposure and withdrawal.

Maternal smoking during pregnancy increases the likelihood that the offspring will become smokers in adolescence. In the current study, we evaluated effects of prenatal and adolescent nicotine exposure in rats to assess whether there is a biological basis for this relationship. Pregnant rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5), using a regimen (6 mg/kg/day by subcutaneous infusion) that produces plasma nicotine levels similar to those in smokers. Evaluations were made in the cerebral cortex and midbrain during adolescent nicotine administration (PN45) and for up to 1 month after the end of treatment. We assessed the magnitude and persistence of nicotinic acetylcholine receptor (nAChR) upregulation; in addition, we evaluated cholinergic synaptic activity by comparing the effects on choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, with those on hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, which is regulated by nerve impulse activity. Prenatal nicotine exposure had only minor effects on nAChRs but produced persistent cholinergic hypoactivity (reduced HC-3 binding relative to ChAT) throughout adolescence and into adulthood (PN75). Adolescent nicotine exposure evoked robust nAChR upregulation and also suppressed cholinergic activity. Prenatal nicotine exposure reduced the upregulation of nAChRs evoked by adolescent nicotine but worsened the cholinergic hypoactivity during withdrawal. Our results indicate that prenatal nicotine exposure alters the subsequent response to nicotine in adolescence, effects that may contribute to the association between maternal smoking during pregnancy and subsequent adolescent smoking in the offspring.     

Recommendations for the use of pharmacological smoking cessation strategies in pregnant women

Maternal smoking during pregnancy causes significant fetal morbidity and is a public health problem, as 36% of women in the UK and 11% of those in the US smoke during pregnancy. Behavioural support for smoking cessation, provided outside of routine antenatal care, is effective for promoting smoking cessation by pregnant women, but relatively few pregnant women access such support. Effective pharmacological aids to smoking cessation, which have been trialled in nonpregnant populations, include nicotine replacement therapy (NRT), bupropion and varenicline; however, there is very little evidence to justify the use of these drugs in pregnancy. Also, for safety reasons, it is doubtful that definitive trials investigating the effectiveness of either bupropion or varenicline for smoking cessation will be conducted in pregnant women in the foreseeable future. In the short to medium term, research information relating to the use of these drugs in pregnancy is, therefore, likely to be derived from observational studies that are more difficult to interpret than clinical trials. This article assesses the evidence for the effectiveness and safety of using NRT, bupropion and varenicline for smoking cessation during pregnancy. The principle recommendations made are that NRT may be safer than smoking in pregnancy, and pregnant women who have unsuccessfully tried to stop smoking without pharmacotherapy may consider using NRT in subsequent quit attempts after informed discussion with their doctor. There is no evidence, however, that NRT is actually effective for smoking cessation in pregnancy. With currently available evidence, bupropion and varenicline cannot be recommended in pregnancy for smoking cessation.     

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.     

If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents?

Tobacco use in pregnancy is a leading cause of perinatal morbidity and contributes in major ways to attention deficit hyperactivity disorder, conduct disorders and learning disabilities that emerge in childhood and adolescence. Over the past two decades, animal models of prenatal nicotine exposure have demonstrated that nicotine is a neurobehavioral teratogen that disrupts brain development by preempting the natural, neurotrophic roles of acetylcholine. Through its actions on nicotinic cholinergic receptors, nicotine elicits abnormalities of neural cell proliferation and differentiation, promotes apoptosis and produces deficits in the number of neural cells and in synaptic function. The effects eventually compromise multiple neurotransmitter systems because of the widespread regulatory role of cholinergic neurotransmission. Importantly, the long-term alterations include effects on reward systems that reinforce the subsequent susceptibility to nicotine addiction in later life. These considerations strongly question the appropriateness of nicotine replacement therapy (NRT) for smoking cessation in pregnant women, especially as the pharmacokinetics of the transdermal patch may actually enhance fetal nicotine exposure. Further, because brain maturation continues into adolescence, the period when smoking typically commences, adolescence is also a vulnerable period in which nicotine can change the trajectory of neurodevelopment. There are also serious questions as to whether NRT is actually effective as an aid to smoking cessation in pregnant women and adolescents. This review considers the ramifications of the basic science findings of nicotine's effects on brain development for NRT in these populations.     

Nicotine dose-concentration relationship and pregnancy outcomes in rat: biologic plausibility and implications for future research

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.     

吸烟的危害与尼古丁替代疗法

吸烟是引起死亡的主要原因之一,全球每年有500余万人死于吸烟。它已成为严重的公共卫生问题。研究显示,烟雾中含有4000余种化合物,其中至少有43种为致癌物。长期吸烟可致多种疾病如癌症、肺气肿、心脏病及脏器损害,并可引起依赖性（成瘾）。依赖性主要由烟草含有的尼古丁所致。经常吸烟者大多对尼古丁成瘾。因此,经常吸烟者停止吸烟可出现尼古丁戒断症状,表现为烦躁、焦虑、头晕、头昏、头痛、失眠及注意力不集中。大多数吸烟者戒烟失败主要与尼古丁成瘾有关。鉴此,推出了尼古丁替代疗法（nicotine replacement therapy,NRT）。NRT是一种不经吸烟而使尼古丁缓慢进入体内的方法。该法不仅能消除或减轻尼古丁戒断症状,并且能避免吸烟的危害。研究结果表明,NRT能明显提高戒烟的成功率,而且其成瘾风险低。NRT常用制剂有咀嚼胶、贴剂、吸入剂、鼻喷剂等。这些制剂均能引起一些不良反应,反应的程度均较轻,但反应类型各制剂有所不同。NRT制剂可安全地用于心血管病患者。NRT不宜用于孕妇、乳母及未成年人。总之,NRT对吸烟者而言是一种安全有效的戒烟方法,NRT制剂在很多国家已作为OTC使用多年,值得推荐。     

Which is the best primary medication for long-term smoking cessation--nicotine replacement therapy, bupropion or varenicline?

Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by approximately 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic alpha4beta2 receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion.     

Late emerging effects of prenatal and early postnatal nicotine exposure on the cholinergic system and anxiety-like behavior

Animal models of prenatal nicotine exposure clearly indicate that nicotine is a neuroteratogen. Some of the persisting effects of prenatal nicotine exposure include low birth weight, behavioral changes and deficits in cognitive function, although few studies have looked for neurobehavioral and neurochemical effects that might persist throughout the lifespan. Pregnant rats were given continuous infusions of nicotine (0.96 mg/kg/day or 2.0 mg/kg/day, freebase) continuing through the third trimester equivalent, a period of rapid brain development. Because the third trimester equivalent occurs postnatally in the rat (roughly the first week of life) nicotine administration to neonate pups continued via maternal milk until postnatal day (P) 10. Exposure to nicotine during pre- and early postnatal development had an anxiogenic effect on adult rats (P75) in the elevated plus maze (EPM), and blocked extinction learning in a fear conditioning paradigm, suggesting that pre- and postnatal nicotine exposure affect anxiety-like behavior and cognitive function well into adulthood. In contrast, nicotine exposure had no effect on anxiety-like behaviors in the EPM in adolescent animals (P30). Analysis of mRNA for the α4, α7, and β2 subunits of nicotinic acetylcholine receptors revealed lower expression of these subunits in the adult hippocampus and medial prefrontal cortex following pre- and postnatal nicotine exposure, suggesting that nicotine altered the developmental trajectory of the brain. These long-term behavioral and neurochemical changes strengthen the case for discouraging cigarette smoking during pregnancy and clearly indicate that the use of the patch as a smoking cessation aid during pregnancy is not a safe alternative.     

Effects of high dose transdermal nicotine replacement in cigarette smokers

RATIONALE: Nicotine replacement therapies (NRT) have been evaluated to facilitate cigarette smoking reduction in smokers unwilling or unable to quit. In most of these studies, only conventional doses of NRT have been tested and higher doses may be required to result in significant reductions in smoking and in biomarkers of exposure. OBJECTIVE: To determine if higher NRT doses in conjunction with smoking are safe and may promote significant reductions in cigarette smoking and biomarkers of exposure. METHODS: A dose-ranging, within-subject design was implemented to evaluate the effects of 15, 30 and 45 mg nicotine-patch treatment on measures of safety and the extent of smoking reduction and biomarker exposure per cigarette in smokers (N=20 completers) not immediately interested in quitting. RESULTS: Concurrent smoking and NRT were generally tolerated and resulted in no changes in blood pressure or heart rate. Slightly less than 10% of the study sample was not given the highest dose of NRT due to side effects. Self-reported cigarette smoking decreased with increasing doses of nicotine replacement and significant reductions were observed for total NNAL (a carcinogen biomarker) and carbon monoxide. However, even at the 45 mg dose, increased carbon monoxide and total NNAL per cigarette occurred, even though cotinine levels increased on average, 69.3% from baseline. CONCLUSIONS: The present results suggest that the use of high dose NRT is safe, leads to significant reductions in smoking (-49%), significant but less reductions in total NNAL (-24%) and carbon monoxide (-37%) due to compensatory smoking.     

Evidence for carbon monoxide as the major factor contributing to lower fetal weights in rats exposed to cigarette smoke.

One of the major effects of cigarette smoking during pregnancy is bearing a child with lower birth weight. It has previously been demonstrated under experimental conditions in rats that exposure to reference cigarette smoke results in reduced birth weight (E. L. Carmines et al., 2003, Toxicol. Sci. 75, 134-147; C. L. Gaworski et al., 2004, Toxicol. Sci. 79, 157-169). The role of various smoke constituents on lower birth weight was evaluated by exposing time-pregnant Sprague-Dawley rats at the concentrations found in cigarette smoke. The rats were exposed for 2 h/day 7 days/week by nose-only inhalation. The target concentrations were designed to produce the same plasma levels of biomarkers as exposure to 2R4F reference cigarette smoke at a concentration of 600 mg/m(3) total particulate matter. The smoke constituents evaluated included carbon monoxide (CO), nicotine, and a mixture of aldehydes (acrolein, acetaldehyde, and formaldehyde). The smoke constituents were tested individually as well as in mixtures to evaluate potential interactions. Exposure to cigarette smoke during gestation produced a reduction in both maternal body weight gain and fetal weights. Exposure to nicotine reduced maternal body weight gain but had no effect on fetal weight. Exposure to CO had no effect on maternal body weight gain but reduced fetal weight to a degree comparable to cigarette smoke. Exposure to a mixture of aldehydes (acrolein, acetaldehyde, and formaldehyde) had no effect on either maternal body weight gain or fetal weight. Exposure to mixtures of nicotine and CO or nicotine, CO, and aldehydes did not demonstrate any interactions. The results of this study suggest that the observed reduction in fetal weight after exposure to cigarette smoke in rats is due to CO toxicity and not nicotine toxicity.     

Nicotine-replacement therapy in pregnancy-the end of the road?

ABSTRACT:: Smoking in pregnancy is associated with serious perinatal risks, leading to attempts to prevent smoking with the use of nicotine-replacement therapy (NRT). After more than a decade of studies failing to show the effectiveness of NRT for smoking cessation in pregnancy, a recent large, randomized trial has clearly shown that the failure may be caused by >90% dropout rate. Several secondary analyses of randomized trials have shown that NRT is efficacious in decreasing smoking in pregnancy and in optimizing fetal growth among women who take the product. But to be effective in smoking cessation, any drug has to be taken by the patients. Can we overcome the dismal rates of pregnant women's adherence to NRT, so we can save unborn babies from the serious risks associated with their mothers' smoking?     

Hair nicotine:cotinine metabolic ratio in pregnant women: a new method to study metabolism in late pregnancy

A large number of smoking women cannot quit their habit when they become pregnant. Preliminary evidence suggests an enhanced nicotine clearance rate in late pregnancy. To evaluate the change in nicotine metabolism in late pregnancy, we undertook a prospective cohort study of a large, diverse group of pregnant women recruited from four Montreal maternal hospitals. Smoking histories were obtained by structured questionnaires administered at 24 to 26 weeks of gestation and postpartum. Hair concentrations of nicotine and cotinine were measured by immunoassays for each trimester based on sectioning the hair and assuming average hair growth of 1 cm per month. A strong correlation was observed between average number of cigarettes smoked per day and hair nicotine and cotinine in all three trimesters. A significant decrease in hair nicotine was observed among steady smokers from the first to third trimester paralleled by a significant increase in hair cotinine. The ratio of hair nicotine:cotinine decreased significantly from the first to the third trimester. Increased nicotine metabolism in late pregnancy results in lower systemic exposure to nicotine. This phenomenon may explain why many pregnant women feel the urge to continue smoking and why standard-dose nicotine replacement therapy has not been effective in reducing smoking during pregnancy in several clinical trials.     

Which is the best primary medication for long-term smoking cessation – nicotine replacement therapy,bupropion or varenicline?

Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by ～ 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic α₄β₂ receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion.     

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.     

Adolescent nicotine exposure disrupts context conditioning in adulthood in rats

Despite the prevalence of smoking among adolescents, few studies have assessed the effects of adolescent nicotine exposure on learning in adulthood. In particular, it remains unclear whether adolescent nicotine exposure has effects on hippocampus-dependent learning that persist into adulthood. The present experiment examined whether there were effects of adolescent nicotine exposure on context conditioning, a form of learning dependent on the integrity of the hippocampus, when tested during adulthood. Rats were exposed to nicotine during adolescence (postnatal days [PD] 28-42) via osmotic minipump (0, 3.0 or 6.0 mg/kg/day). Context conditioning occurred in early adulthood (PD 65-70). Animals were exposed to an experimental context and were given 10 unsignaled footshocks or no shock. Additional groups were included to test the effects of adolescent nicotine on delay conditioning, a form of learning that is not dependent upon the hippocampus. Conditioning was assessed using a lick suppression paradigm. For animals in the context conditioning groups, adolescent nicotine resulted in significantly less suppression of drinking in the presence of context cues compared with vehicle-pretreated animals. For animals in the delay conditioning groups, there was a trend for adolescent nicotine (3.0 mg/kg/day) to suppress drinking compared to vehicle-pretreated animals. There were no differences in extinction of contextual fear or cued fear between rats previously exposed to vehicle or nicotine. The data indicate that adolescent nicotine administration impairs context conditioning when animals are trained and tested as adults. The present data suggest that adolescent nicotine exposure may disrupt hippocampus-dependent learning when animals are tested during adulthood.     

Nicotine and nonnicotine factors in cigarette addiction

Rationale A great deal of research supports the role of nicotine in cigarette addiction. However, the effectiveness of nicotine replacement therapy (NRT) as a smoking cessation treatment has fallen short of initial hopes. A key reason may be that NRT does not address nonnicotine components of smoking reinforcement. These include constituents that provide reinforcing sensory stimulation, components that minimize excessive irritation from inhaled nicotine and other pharmacologically active compounds in cigarette smoke. Objective Studies using various paradigms to dissociate nicotine from other components of smoking are summarized. Results Nonnicotine components provide many rewarding effects, often surpassing the direct effects of nicotine. Substitutes for the sensory effects of smoking may be effective in relieving craving for cigarettes and in facilitating smoking cessation. Moreover, techniques for devaluing smoking-related cues may decrease craving and enhance subsequent abstinence. Promising approaches for devaluing smoke cues include extinction-based treatments employing denicotinized cigarettes and the use of nicotinic agonist and/or antagonist treatment during the weeks leading up to a quit attempt. Recent studies suggest that incorporating these approaches into a treatment program may significantly increase smoking abstinence rates. Preliminary findings also suggest that replacement of the effects of monoamine oxidase inhibitors contained in cigarette smoke may enhance quit rates. Conclusions While current NRT methods have been the mainstay of smoking cessation treatment and will likely continue to serve a useful role, the next stage of progress will likely entail the development of tools designed with recognition of the importance of nonnicotine components of cigarette smoking.