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.     

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.     

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.     

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.     

Effects of pregnancy on nicotine self-administration and nicotine pharmacokinetics in rats

Rationale Because of the adverse effects of smoking during pregnancy, understanding the factors that influence maternal smoking may help in developing better treatments to help women quit smoking during pregnancy. Animal models could be useful for this purpose. Objective The purpose of the present study was to begin the development of an animal model of smoking during pregnancy by initially characterizing nicotine self-administration (NSA) in pregnant rats. Another purpose was to begin to explore the effects of pregnancy on nicotine pharmacokinetics in rats. Materials and methods In experiment 1, female rats self-administering nicotine during 23-h sessions were examined throughout gestation and lactation. In experiment 2, locomotor activity was measured during pregnancy to assess further potential motor effects of pregnancy. Experiments 3 and 4 compared the single-dose pharmacokinetics of nicotine in male, nonpregnant female, and pregnant females in the first and third trimester of pregnancy and the first week of lactation. Results NSA decreased over the course of pregnancy with NSA significantly lower in the third trimester compared to nonpregnant controls. NSA remained suppressed for up to 10 days into lactation. Locomotor behavior was also significantly suppressed during the second and third trimesters and throughout lactation. Nicotine elimination was slower in pregnant females compared to nonpregnant females only in the third trimester. Conclusions NSA, locomotor behavior, and nicotine elimination in rats are decreased during late pregnancy. The present study is the first to characterize NSA during pregnancy in animals, providing a potential model of maternal smoking in humans.     

Effects of prenatal cigarette and marijuana exposure on drug use among offspring

The present study investigated whether maternal cigarette smoking and marijuana use during pregnancy were associated with an increased risk of initiation and daily/regular use of such substances among one hundred fifty-two 16- to 21-year-old adolescent offspring. The participants were from a low risk, predominately middle-class sample participating in an ongoing, longitudinal study. Findings indicated that offspring whose mothers reported smoking cigarettes during their pregnancy were more than twice as likely to have initiated cigarette smoking during adolescence than offspring of mothers who reported no smoking while pregnant. Offspring of mothers who reported using marijuana during pregnancy were at increased risk for both subsequent initiation of cigarette smoking (OR=2.58) and marijuana use (OR=2.76), as well as daily cigarette smoking (OR=2.36), as compared to offspring of whose mothers did not report using marijuana while pregnant. There was also evidence indicating that dose-response relationships existed between prenatal exposure to marijuana and offspring's use of cigarettes and marijuana. These associations were found to be more pronounced for males than females, and remained after consideration of potential confounds. Such results suggest that maternal cigarette smoking and marijuana use during pregnancy are risk factors for later smoking and marijuana use among adolescent offspring, and add to the weight of evidence that can be used in support of programs aimed at drug use prevention and cessation among women during pregnancy.     

Combined exposure to nicotine and ethanol throughout full gestation results in enhanced acquisition of nicotine self-administration in young adult rat offspring

Rationale Epidemiological evidence shows positive correlation between either maternal cigarette smoking or alcohol consumption on subsequent drug-taking behavior in offspring. However, the consequences of full gestational exposure to both drugs have not been studied experimentally despite concurrent use frequently reported among women of childbearing age. Such comorbid gestational drug exposure may increase susceptibility to acquiring cigarette smoking (i.e., nicotine self-administration), a major gateway drug. Objectives We developed a noninvasive rat model for exposure to both nicotine (2–6 mg kg⁻¹ day⁻¹) and EtOH (4 g/kg gavage) that continued throughout pregnancy and postnatal (P) days 2–12, the rodent equivalent of the human third trimester, a critical brain developmental period. Offspring with this full gestational exposure to both drugs (Nic+EtOH) were compared to controls: nicotine alone, EtOH alone, pair-fed (comparable nutrition and handling), and ad libitum chow-fed. At P60–90, offspring had unlimited chronic access to acquire i.v. nicotine self-administration. Results There were no differences in gender ratio, stillbirths, birth weights, righting reflex, eye opening age, or weight gain. However, Nic+EtOH offspring of both genders acquired nicotine self-administration (15 or 30 μg kg⁻¹ injection⁻¹) more rapidly, at a higher percentage, and at a higher level than offspring in the other cohorts. Conclusion Full gestational Nic+EtOH exposure produced no overt alterations in standard postnatal measures but resulted in an enhanced acquisition of nicotine self-administration in young adult offspring.     

Does early exposure to maternal smoking affect future fertility in adult males?

Animal data suggest that prenatal exposure to certain tobacco smoke components such as nicotine may affect the development of the male gonadal axis, which may in turn affect future adult fertility. There are no previous epidemiologic studies on the potential effects of early (prenatal and childhood) exposure to maternal smoking on the reproductive system in adult male offspring. To investigate this question, we used data from a follow-up study of reproductive function and fertility among young adult sons of mothers who had participated in a randomized clinical trial of diethylstilbestrol use during pregnancy. We observed no significant effects of early exposure to maternal smoking on conventional semen characteristics, hormone levels (follicle stimulating hormone [FSH], luteinizing hormone [LH] and testosterone), urogenital abnormalities and diseases, or perceived infertility problems. Current active smoking by the men was, however, associated with a significant decrease in the percentage of sperm with normal morphology.     

Maternal smoking during late pregnancy and offspring smoking behaviour

We explored the influence of maternal smoking during late pregnancy on the likelihood of smoking among offspring in adolescence and adulthood, using birth cohort data collected in the United Kingdom as part of the 1958 National Child Development Study. Longitudinal analysis indicated that maternal smoking during late pregnancy was associated with an increased likelihood of being a non-smoker at 16-year, 23-year and 33-year follow-up. This association differed between male and female offspring, with women showing no significant association and men showing an increased likelihood of being a non-smoker. There did not appear to be any association between maternal smoking during late pregnancy and cigarette consumption among offspring who reported smoking for either sex. These results are inconsistent with some previous reports that maternal smoking during pregnancy increases the likelihood of smoking among female offspring, although the observation of a moderating effect of sex on smoking behaviour is consistent with several previous reports. We discuss possible mechanisms for this association, and suggest factors that may account for the observed sex differences in this association, and the discrepancy between our results and some previous reports.     

Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence.

Initiation of smoking behavior typically occurs during adolescence and rarely occurs during adulthood. Despite this epidemiological evidence, relatively little is known about possible neurobiological differences in the response to nicotine in adolescents that might make them more vulnerable to nicotine addiction. In the current study, we assessed nicotine self-administration under fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in adolescent (postnatal day (P) 33-35) and adult (P91-94) rats. We then assessed extinction and reinstatement of nicotine seeking in adulthood in rats that initiated nicotine self-administration during either adolescence or adulthood. Nicotine self-administration (0.03 mg/kg/infusion, i.v.) was higher in adult rats than in adolescent rats under FR5 and PR reinforcement schedules; no age differences in nicotine self-administration were observed under FR1 or FR2 reinforcement schedules. In contrast, saccharin self-administration under FR5 and PR reinforcement schedules was similar in both age groups, potentially ruling out age differences in general performance. Rats that initiated nicotine self-administration as adults demonstrated a greater resistance to extinction of nicotine taking behavior when saline was substituted for nicotine than rats that initiated self-administration as adolescents. Reinstatement of nicotine seeking following nicotine priming injections (0.075, 0.15, 0.3 mg/kg, s.c.) was independent of the age of onset of nicotine self-administration. The present data from established rat models of drug self-administration and drug relapse suggest that nicotine is less reinforcing in adolescent compared with adult rats and that processes other than the reinforcing effects of nicotine may be involved in the greater susceptibility to smoking during the adolescent developmental stage.     

Adolescent-onset nicotine self-administration modeled in female rats

Rationale Although the great majority of tobacco addiction begins during adolescence, little is known about differential nicotine effects in adolescents versus adults. Objectives A rat model was used to determine the impact of the age of onset on nicotine self-administration. Methods In expt 1, nicotine self-administration of female Sprague-Dawley rats over a range of acute doses (0.01–0.08 mg/kg per infusion) was determined in adolescent (beginning at 54–62 days) versus adult (beginning at 84–90 days). In expt 2, chronic nicotine self-administration over 4 weeks from adolescence into adulthood was compared with the chronic self-administration beginning in adulthood. In expt 3, adolescent-adult differences in nicotine effects on body temperature and locomotor responses were determined. Results Adolescent-onset rats showed a significant main effect of increased nicotine intake compared with adult-onset rats in an eight-fold range of acute unit doses/infusion. Significant age differences were also seen in the chronic level of nicotine self-administration. Over 4 weeks, the adolescent-onset group had nearly double the rate of nicotine self-administration of the benchmark nicotine dose (0.03 mg/kg per infusion) compared to the adult-onset group. This increased nicotine intake persisted into adulthood. Adolescent rats had significantly greater response than adults to the hypothermic effects of nicotine, but had significantly less response than adults to the reduction in locomotor activity seen after nicotine. Conclusions Adolescent-onset nicotine self-administration in female rats was associated with significantly higher levels of nicotine self-administration versus rats, which began nicotine self-administration in adulthood. This greater self-administration persists into adulthood and may underlie greater propensity of adolescents to nicotine addiction.     

Inhalational model of cocaine exposure in mice: neuroteratological effects

We developed a novel inhalation-based mouse model of prenatal cocaine exposure. This model approximates cocaine abuse via smoking, the preferred route of cocaine administration by heavy drug users. The model is also characterized by (i) absence of procedural stress from drug administration, (ii) long-term drug exposure starting weeks before pregnancy and continuing throughout the entire gestation, and (iii) self-administration of cocaine in multi-hour daily sessions reminiscent of drug binges, which allows animals to set up the levels of their own drug consumption. The offspring of female mice inhaling cocaine in our model displayed no gross alterations in their cortical cytoarchitecture. These offspring, however, showed significant impairments in sustained attention and spatial working memory. We hope that the introduction of the present model will lead to a significant increase in our understanding of outcomes of prenatal cocaine exposure.     

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.     

Increased expression of glial fibrillary acidic protein in cerebellum and hippocampus: differential effects on neonatal brain regional acetylcholinesterase following maternal exposure to combined chlorpyrifos and nicotine

Cigarette smoking and environmental exposure to chlorpyrifos during pregnancy could lead to developmental toxicity in the offspring. In the present study, pregnant female Sprague-Dawley rats (300-350 g) were treated daily with nicotine (1 mg/kg, sc) or chlorpyrifos (0.1 mg/kg, dermal) or a combination of nicotine and chlorpyrifos from gestational days (GD) 4-20. Control animals were treated with saline and ethanol. Male offspring from the mothers treated with nicotine alone gained significantly less weight on postnatal day (PND) 30 as compared to control. On PND 7, there was a significant increase in brain acetylcholinesterase (AChE) activity in pups from nicotine- and chlorpyrifos-treated dams, whereas plasma butyrylcholinesterase (BChE) activity was significantly elevated in pups of mothers treated with either chlorpyrifos alone or pesticide combined with nicotine. On PND 30 there was a significant increase in AChE activity in brainstem and cerebellum in all treated male pups. In female pups on PND 30 there was a significant rise in AChE activity in brainstem of chlorpyrifos alone and in cerebellum of the combination nicotine and chlorpyrifos group. Histopathological evaluation demonstrated an increased neuronal cell death in the cerebellum granular cell layer of female offspring from nicotine or combined nicotine with chlorpyrifos group. A rise in glial fibrillary acidic protein (GFAP) immunostaining was observed in the CA1 subfield of hippocampus and cerebellum on PND 30 in female and male offspring of mothers treated with either nicotine or nicotine in combination with chlorpyrifos, but to a lesser extent in males. Data suggest that maternal exposure to nicotine and chlorpyrifos, alone or in combination, produces differential alterations in brain regional AChE activity and expression of GFAP in cerebellum and hippocampus in offspring on PND 30.     

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.     

Prenatal cigarette smoking: Long-term effects on young adult behavior problems and smoking behavior

We examined the long-term effects of prenatal cigarette smoke exposure (PCSE) on the behavior problems and smoking behavior of 22-year-old offspring. The mothers of these offspring were interviewed about their tobacco and other drug use during pregnancy at the fourth and seventh gestational months, and at delivery. Data on the offspring are from interviews at age 22 (n = 608). Behavior problems were measured by the Adult Self-Report (ASR) with the following outcome scales: total behavior problems, externalizing, internalizing, attention, anxiety/depression, withdrawn, thought, intrusive, aggression, somatic and rule breaking behavioral problems. Young adult smoking behavior was measured using self-reported average daily cigarettes, and was validated with urine cotinine. Nicotine dependence was measured with the Fagerström Tobacco and Nicotine Dependence (FTND) scale. Regression analyses tested the relations between trimester-specific PCSE and young adult's behavioral problems and smoking behavior, adjusting for demographic and maternal psychological characteristics, and other prenatal substance exposures. Exposed young adults had significantly higher scores on the externalizing, internalizing, aggression, and somatic scales of the ASR. These young adults were also more likely to have a history of arrests. Young adults with PCSE also had a higher rate of smoking and nicotine dependence. Our previous findings of the relations between PCSE and aggressive behavior in early childhood and PCSE and smoking behavior in early adolescence extend into young adulthood.     

Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats

Rationale

Sazetidine-A is a selective ??4??2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined.

Objectives

This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4?weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats.

Methods

Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6?mg/kg/day for 4?weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2?weeks of infusion followed by 1?week of forced abstinence from nicotine and 1?week of resumed nicotine access.

Results

The 6?mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p?p?p?p?Conclusions The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.     

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.     

Maternal nicotine exposure and fetal programming of vascular oxidative stress in adult offspring

Despite the well-known harmful effects, many women continue to smoke throughout pregnancy. Consequently, nicotine replacement therapy (NRT) - which has been developed as a pharmacotherapy for smoking cessation - has been used as an alternative to smoking during pregnancy. However, like cigarette smoking, NRT results in biologically significant levels of nicotine crossing the placenta, leading to both fetal and neonatal exposure to nicotine, and yet, NRT safety during pregnancy has not been extensively evaluated. There is now evidence from studies in rats that maternal nicotine exposure throughout gestation results in fetal programming of vascular oxidative stress in the offspring during adulthood. This phenomenon involves vascular dysfunction mediated by reactive oxygen species in association with decreased superoxide dismutase activity and increased Nox2-NADPH oxidase expression in the vascular wall. If this phenomenon also occurs in humans, either smoking or NRT use during pregnancy may represent a novel risk factor for the unborn that results in accelerated cardiovascular disease in their adulthood.