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.     

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.     

A unique role for striatal serotonergic systems in the withdrawal from adolescent nicotine administration

Adolescent smokers experience more severe withdrawal symptoms upon smoking cessation than do adults, even when daily smoking has occurred for only a short period or with low levels of consumption. Animal models of nicotine withdrawal indicate involvement of striatal serotonin (5-HT) systems in nicotine reward, withdrawal and craving. We evaluated indices of striatal 5-HT and dopamine (DA) synaptic activity, neurotransmitter levels and turnover (metabolite/transmitter ratio), after continuous nicotine infusions to adolescent rats from postnatal days 30 to 47, using a dose rate (6 mg/kg/day) that produces plasma levels typical of smokers. Withdrawal was accompanied by a significant and persistent loss of striatal 5-HT synaptic activity, evidenced by an initial decline in turnover followed by a reduction in 5-HT content without a compensatory increase in turnover. Similar effects were seen for striatal DA activity. These effects were superimposed on a loss of stimulatory 5-HT cellular responses and promotion of inhibitory responses as identified in an earlier work with this model. None of these alterations was seen during withdrawal in adult rats given the same regimen. The unique adolescent withdrawal effects were not seen when the adolescent nicotine treatment period was shortened to early adolescence (days 30-37), even if the administration paradigm was changed to twice-daily injections to maximize withdrawal stress. Our results are consistent with unique effects of adolescent nicotine withdrawal on striatal 5-HT and DA systems, and point to a potential for serotonin-specific reuptake inhibitors as alternatives to nicotine replacement therapy for smoking cessation in adolescents.     

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.     

The role of physical activity in nicotine's effects on body weight

The present study examined the effects of chronic nicotine administration and cessation of nicotine administration on body weight and 24-hour physical activity of rats. There was a significant, inverse, dose-effect relationship between nicotine administration and body weight. Cessation of nicotine was accompanied by increased rates of body weight gain compared to controls. The changes in body weight during nicotine administration could not be explained by changes in physical activity. However, decreases in physical activity after cessation of nicotine appeared to contribute to post-drug body weight increases. These findings have implications for weight control after cessation of cigarette smoking.     

Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats

Vulnerability to nicotine addiction is significantly increased in individuals who begin smoking during adolescence; however, the underlying mechanisms of this phenomenon remain unclear. This study examined the motivational effects of nicotine withdrawal in adolescent (PND 27-42) and adult (PND 60-75) rats using the conditioned place aversion paradigm. Male Wistar rats were tested for their initial preference for either of two distinct compartments of our conditioning apparatus. Rats were then implanted with subcutaneous (sc) pumps that produce equivalent blood plasma levels of nicotine for 14 days. Conditioning was conducted over the last 8 days of nicotine exposure. Rats received the nicotinic antagonist mecamylamine (1.5 or 3.0 mg/kg, sc) to precipitate withdrawal in their initially preferred compartment, and on alternate days they received saline in their non-preferred compartment. Following conditioning, rats were re-tested for their preference for each compartment. A subsequent study was conducted to examine potential developmental differences in learning place aversion produced by another aversive stimulus, lithium chloride (LiCl). Rats received LiCl (0, 10, 30, or 100 mg/kg, sc) in their initially preferred side using similar conditioning procedures. Adults displayed robust place aversion produced by nicotine withdrawal. This effect was lower in adolescent rats even in a group of young rats that received 7 additional days of nicotine exposure prior to conditioning. This developmental difference was specific to nicotine withdrawal since there were no differences between adolescents and adults in learning place aversion with LiCl. Our findings demonstrating reduced effects of nicotine withdrawal constitute a powerful basis for the increased vulnerability to nicotine dependence during adolescence.     

Use of phenylpropanolamine to reduce nicotine cessation induced weight gain in rats

The present study was conducted to determine if phenylpropanolamine (PPA) administered during the first week of nicotine termination could reduce or eliminate the body weight rebound which accompanies nicotine cessation. Sprague-Dawley rats were administered nicotine for 2 weeks after which they received either PPA or saline for 1 week. Control animals received saline during both drug periods. Body weight, food consumption, and water consumption were measured daily before drug, during nicotine and PPA administration, and for 14 days after PPA administration. In contrast to animals receiving saline upon termination of nicotine, animals receiving PPA did not gain weight at an accelerated rate. Termination of PPA did not result in a body weight rebound. To the extent that these results generalize to humans, they suggest that PPA could be used to reduce or eliminate postcessation weight gain in smokers who stop smoking.     

Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats

Rationale Adolescent onset of smoking is associated with a rapid progression to dependence. Although adolescents may exhibit a greater susceptibility to nicotine addiction, relatively little is known about the influence of the aversive effects of nicotine withdrawal in maintaining smoking behavior. Objectives The present study investigated age differences in the motivational effects of mecamylamine-precipitated and spontaneous nicotine withdrawal in adolescent and adult rats using the conditioned place aversion procedure (CPA). Materials and methods In experiment 1, adolescent (postnatal day (PD) 28) and adult (PD60) male Wistar rats chronically treated with nicotine (3 or 6 mg/kg/day, s.c.) received mecamylamine (1 mg/kg, s.c.), a nicotinic receptor antagonist, or vehicle prior to place conditioning; physical withdrawal signs were also measured. Experiment 2 was conducted to increase nicotine levels in which adolescents were treated with 4.5 or 9 mg/kg/day nicotine. In experiment 3, age differences in spontaneous nicotine withdrawal were evaluated. Results Nicotine-treated adults developed a CPA to the mecamylamine-associated compartment and expressed significant physical withdrawal signs, whereas similarly treated adolescents did not. Increasing nicotine exposure levels did not modify the adolescent response to mecamylamine-precipitated withdrawal. Spontaneous nicotine withdrawal produced similar physical withdrawal signs in adolescents and adults, but did not elicit CPA. Conclusions The current study indicates that adolescent rats are less responsive to the aversive effects of mecamylamine-precipitated, but not spontaneous, nicotine withdrawal compared to adult rats. These findings suggest that adolescents and adults may exhibit similar sensitivity to the affective and physical effects of withdrawal following smoking cessation.     

Chronic nicotine exposure in rat: A behavioural and biochemical study of tolerance

Rats received nicotine (50 mg nicotine base/1) in their drinking fluid for 28 days. The daily consumption of nicotine was about 4 mg/kg per day. Controls received plain water. Body weight, food consumption and fluid intake were registered during the whole treatment period and up to 31 days after withdrawal of nicotine. A significant lower body weight was noted in rats, treated with nicotine, in comparison with control rats during the whole treatment period. After withdrawal of nicotine the body weight returned to normal. Only slight effects were seen on the food intake (at the beginning of the nicotine treatment). The fluid intake, on the other hand, was significantly lower in the nicotine group during the whole period of treatment and a reduced intake persisted 28 days after withdrawal of nicotine.Tolerance to nicotine was measured in rats 24 hours after withdrawal of nicotine, using two behavioural tests. No tolerance to nicotine was found after 31 days of withdrawal of nicotine.The number of nicotine-like binding sites was found to be reduced in the midbrain 24 hours after withdrawal of nicotine, while no significant change was found in the cortex and hippocampus.     

Neurobehavioral and metabolic long-term consequences of neonatal maternal deprivation stress and adolescent olanzapine treatment in male and female rats

Early maternal deprivation (MD), 24h of dam-litter separation on postnatal day (PND) 9, has been proposed as a suitable animal model to investigate some neuropsychiatric disorders with a base in neurodevelopment that also compromises metabolic and endocrine homeostasis. Atypical antipsychotics are frequently prescribed to children and adolescents as first-line treatment for several mental disorders despite the adverse metabolic effects frequently reported. However, persistent long-term effects after adolescent drug therapy have been scarcely investigated. In the present study we aimed to investigate the long-lasting metabolic and behavioral effects of MD in combination with the administration of an atypical antipsychotic, i.e. olanzapine, during adolescence. For that purpose, male and female Wistar rats not exposed (control group, Co) and exposed to the MD protocol were administered with oral olanzapine (Olan, 7.5mg/kg/day) or vehicle (Vh, 1mM acetic acid) in drinking water from PND 28 to PND 49. Body weight gain, glycaemia and plasma triglyceride (TG) levels were evaluated as relevant metabolic parameters. MD significantly diminished body weight gain, while Olan administration only induced a subtle decrease in body weight gain among female animals in the long-term. Olan discontinuation decreased plasma TG levels in adult rats, an effect that was counteracted by neonatal exposure to the MD protocol. Both MD and Olan treatment impaired cognitive function in the novel object recognition test, although no interaction between treatments was observed. Neither MD nor Olan administration affected psychotic-related symptoms evaluated in the prepulse inhibition task, although animals treated with Olan showed an increased reactivity to the first acoustic stimulus. MD diminished the corticosterone stress-induced response among females, and reduced the expression of CB1 receptors in the hippocampus of both male and female rats. Notably, Olan administration tended to counterbalance these two MD-induced effects (i.e. corticosterone response and CB1 receptor expression). Present findings provide evidence for the long-lasting effects of neonatal MD and Olan administration during adolescence, and suggest some sex-dependent interactions between these two protocols. Further research on the interactions between early life stress and antipsychotic drugs is urgently needed, and sex differences should be consistently considered both in animal models and in translation to human studies.     

Adult vs. adolescent rats differ in biobehavioral responses to chronic nicotine administration

More than 90% of smokers begin smoking during adolescence, suggesting that nicotine's actions may differ in adults vs. adolescents in ways that render adolescents vulnerable to smoking initiation. This experiment tested the hypothesis that nicotine's biobehavioral actions differ in adult and adolescent rats. Forty-two male (21 adolescents, 21 adults) and 41 female (21 adolescents, 20 adults) Sprague–Dawley rats were administered saline or 12 mg/kg/day nicotine via osmotic minipump for 21 days. Body weight, feeding, and locomotion (horizontal activity, vertical activity, center time) were measured before, during, and after saline or nicotine administration. Nicotine's effects depended on age and sex. Nicotine reduced body weight and feeding of adult males and females, and of adolescent males, but not of adolescent females. In addition, adolescent males were more sensitive than adults or adolescent females to nicotine's activity-enhancing effects. In cessation, nicotine-exposed adolescent males continued to exhibit greater activity than saline-exposed animals. Results indicate that nicotine's biobehavioral actions differ depending on age and sex.     

Cotinine: effects with and without nicotine

 The purpose of this study was to examine the effects of the metabolite of nicotine, cotinine, in comparison to the effects of the nicotine patch, and a combination thereof during cigarette abstinence. More specifically, this study examined the effects of cotinine on physiological measures, subjective measures assessing craving, withdrawal symptoms and mood, and performance measures. A between-subject, 2 × 2 factorial design was used, with the daily administration of a 15-mg nicotine patch (Nicotrol) versus placebo patch as one factor and 80 mg of oral cotinine fumarate versus placebo drug as the other factor. Baseline measures were obtained while the subjects smoked cigarettes on an ad lib basis for 1 week. Subjects (n = 106) were then randomly assigned to one of four treatment conditions and for the next 14 days were required to be abstinent from cigarettes and take the study drugs. Cotinine administration, with or without nicotine patch, produced serum cotinine concentrations 3–4 times higher than during ad lib smoking. Results showed a reduction of self-reported tobacco withdrawal symptoms using the nicotine patch alone. Cotinine alone had no effect on withdrawal symptoms. However, when nicotine patch was combined with cotinine, the beneficial effect of the nicotine patch on withdrawal symptoms was absent. Therefore, cotinine appears to antagonize the effects of nicotine in the alleviation of withdrawal symptoms at concentrations higher than that attained from normal smoking. This effect does not appear to be mediated by changes in nicotine disposition. Received: 27 March 1997/Final version: 14 July 1997     

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.     

Blockade of the expression of mecamylamine-precipitated nicotine withdrawal by calcium channel antagonists.

The present study focused on the evaluation of nicotine abstinence syndrome in mice and on the influence of calcium channel blockers on the expression of the somatic signs of nicotine withdrawal. Our experimental protocol consisted of intermittent administration of nicotine, 2.5 mgkg(-1), subcutaneously (s.c.), four times daily for 7 days. In attempt to precipitate nicotine abstinence, mice were given one injection of mecamylamine (3 mgkg(-1), intraperitoneally (i.p.)), 1h after the last nicotine injection, on the test day (day 8) in the morning. Additionally, body weight changes, locomotor activity and anxiogenic responses in the elevated plus maze test were also evaluated in nicotine withdrawn mice. Our data shown that the L-type calcium channel antagonists, nimodipine, verapamil, flunarizine and diltiazem (5 and 10 mgkg(-1), i.p., each), injected before mecamylamine administration, dose-dependently attenuated the expression of nicotine withdrawal signs. Moreover, 24h after terminating nicotine treatment, we also observed additional nicotine abstinence measures, such as loss of body weight followed by a slight body weight gain, decrease of spontaneous locomotor activity and anxiogenic responses. These findings obtained using our valuable rodent model of nicotine dependence suggest the involvement of calcium-dependent mechanisms in the expression of mecamylamine-precipitated nicotine abstinence syndrome.     

Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats

Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21-35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.     

Effects of naltrexone on smoking cessation outcomes and weight gain in nicotine-dependent men and women

ABSTRACT: This study examined whether the opioid receptor antagonist naltrexone is efficacious in smoking cessation and whether sex moderates the response. We assessed smoking quit rates and weight gain in a double-blind randomized trial comparing oral naltrexone (n = 162) with placebo (n = 154) in nicotine-dependent participants who wanted to quit smoking. The medication was gradually titrated up to 50 mg during the week before the quit date and then maintained at this dose for 12 weeks. For the first 4 weeks after the quit date, all participants received a nicotine patch to mitigate tobacco withdrawal and attended weekly individual cognitive-behavioral smoking cessation counseling sessions. After this time, participants continued with naltrexone or placebo through 12 weeks. Follow-up assessments were conducted at 26 and 52 weeks. During treatment, naltrexone (vs placebo) increased quit rates, attenuated smoking urge, and reduced weight gain. At follow-up, after medication discontinuation, the effect of naltrexone on improving quit rates was no longer evident. Men and women experienced different benefits from naltrexone; men showed greater reductions in smoking, whereas women showed greater reductions in weight gain. In sum, naltrexone showed acute efficacy in treating nicotine dependence, but after the medication was discontinued, the effect on quit rate was not maintained. Further study of naltrexone in smoking cessation treatment and reduction of cessation-related weight gain, as well as preclinical investigation of mechanisms underlying sex differences, is warranted.     

Naltrexone,smoking behaviour and cigarette withdrawal

In order to examine the role of endogenous opioids in the reinforcing effects of nicotine, a double-blind, placebo-controlled, cross-over design was used to study the effects of the opiate antagonist, naltrexone, on smoking behaviour and cigarette withdrawal in 12 heavy smokers. Although naltrexone (50 mg) appeared to reduce the perceived difficulty of abstaining during 24-h cigarette withdrawal, other withdrawal symptoms were unaffected. Naltrexone also had no effect on a variety of biochemical and behavioural measures of nicotine intake or on subjective satisfaction and enjoyment from the first cigarette smoked after 24-h abstinence. Similarly naltrexone (100 mg) had no effect on smoking behaviour, nicotine intake or satisfaction from smoking during a 48-h period of ad libitum smoking. However, during the ad libitum smoking period naltrexone caused mood changes of the kind that occur during tobacco withdrawal. Since nicotine intake and smoking behaviour were unaffected, the mood changes are unlikely to have been mediated by blockade or any other form of opioid interaction with nicotinic mechanisms. These findings provide evidence against the notion that the endogenous opioids are involved in mediating the reinforcing properties of nicotine in smokers under normal conditions.     

Effect of quinpirole on striatal dopamine release and locomotor activity in nicotine-treated mice

The effect of chronic oral nicotine treatment which in its intermittent delivery resembles human smoking was studied on the sensitivity of dopamine autoreceptors in mice. On the 50th day of nicotine administration in the drinking water or after 23-25 h withdrawal quinpirole (D2/D3 agonist, 0.01-0.1 mg/kg s.c.) was given, and accumbal and dorsal striatal dopamine outflow, locomotor activity and body temperature were measured. Dorsal striatal extracellular dopamine concentration and locomotor activity were found to be elevated during nicotine administration. Chronic nicotine did not alter the effects of small, autoreceptor preferring doses of quinpirole on accumbal or dorsal striatal dopamine, locomotor activity or body temperature. However, quinpirole's locomotor activity reducing effect was slightly diminished in mice treated repeatedly with nicotine (0.4 mg/kg twice daily for 10 days s.c.). Thus, although repeated nicotine treatment for 5-14 days decreases dopamine autoreceptor sensitivity, after long-term oral nicotine treatment such a decrease is not seen. Thus, the changes occurring in the sensitivity of D2-like dopamine receptors probably play a minor role in regulating the dopaminergic transmission during long-term nicotine administration.     

Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction

Rationale Enhanced reinforcing effects of nicotine during adolescence appear to contribute to the rapid development of dependence in this age group. However, the contribution of nicotine withdrawal to dependence in adolescents is unclear.Objective We compared motivational and somatic signs of nicotine withdrawal in adolescent and adult rats.Materials and methods In experiment 1, motivational signs of nicotine withdrawal were compared using intracranial self-stimulation procedures after administration of mecamylamine (1.5 mg/kg, i.p.) in adolescent and adult rats made dependent on nicotine (9 mg/kg/day). Somatic signs of withdrawal were compared in two experiments using various doses of nicotine (adolescent doses: 0, 1.6, 3.2, 4.7 mg/kg/day; adult doses: 0, 1, 2.1, 3.2 mg/kg/day, expressed as nicotine base) to produce dependence and one dose of mecamylamine (1.5 mg/kg, i.p.) to precipitate withdrawal (experiment 2) and in a subsequent experiment, using various doses of mecamylamine (0, 0.75, 1.5, 3.0 mg/kg, i.p.) to precipitate withdrawal and a dose of nicotine (adolescent dose: 4.7 mg/kg/day; adult dose: 3.2 mg/kg/day) that produced equivalent nicotine blood levels in these age groups (experiment 3).Results Adolescents did not display the decreases in brain reward function observed in adults experiencing withdrawal, and displayed fewer somatic signs of nicotine withdrawal relative to adults regardless of the dosing procedure used.Conclusion The negative effects of nicotine withdrawal are lower during adolescence relative to later periods of development. Both the enhanced rewarding effects and the diminished nicotine withdrawal likely contribute to the rapid development of nicotine use during adolescence.