Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task

Rationale

Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward.

Objectives

To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward.

Materials and methods

Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays.

Results

Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine.

Conclusions

The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.     

Amplified reacquisition of nicotine self-administration in rats by repeated stress during abstinence

Rationale

Quitting smoking is often very challenging, leading to frequent relapse. Exposure to acute and chronic stress during abstinence increases the likelihood of relapse to smoking. In rodents, stress acutely reinstates nicotine seeking after extinction of nicotine self-administration (SA). However, whether reacquisition of nicotine taking is amplified by chronic stress during abstinence from nicotine SA has not been determined in animals.

Objectives

We sought to determine effects of repeated restraint stress during abstinence on reacquisition of nicotine SA.

Methods

Rats acquired nicotine SA (23 h/day) under a fixed-ratio (FR) 5 schedule of reinforcement, which was followed by an abstinence phase. Restraint (0, 2, and 4 times) was administered during abstinence. Animals reacquired nicotine SA, first under a progressive ratio (PR) schedule, beginning immediately after the final stress, followed by an FR5 schedule. In another experiment, reacquisition (FR5) began 24 h after the final stress. No PR testing was conducted.

Results

Four restraint stress exposures during abstinence, but not only two, enhanced reacquisition of nicotine SA by increasing nicotine injections under a PR schedule beginning immediately after the final stress (p?<?0.05) followed by increasing nicotine intake under an FR5 schedule (p?<?0.05). This was observed even when the final stress and reacquisition trial were separated by 24 h. Moreover, repeated stress-induced nicotine taking during the behaviorally inactive phase (i.e., lights on) of the 24-h diurnal cycle.

Conclusions

Chronic (i.e., repeated) stress during abstinence promotes reacquisition of nicotine SA and affects diurnal pattern of nicotine intake.     

Divergent effects of D2/3 receptor activation in the nucleus accumbens core and shell on impulsivity and locomotor activity in high and low impulsive rats

Rationale

Previously we demonstrated reduced D_2/3 receptor availability in the ventral striatum of hyper-impulsive rats on the five-choice serial reaction time task (5-CSRTT). However, the anatomical locus of D_2/3 receptor dysfunction in high impulsive (HI) rats is unknown.

Objective

In the present study, we investigated whether D_2/3 receptor dysfunction in HI rats is localised to the core or shell sub-regions of the nucleus accumbens (NAcb).

Methods

Rats were selected for low (low impulsive, LI) and high impulsivity on the 5-CSRTT and implanted with guide cannulae targeting the NAcb core and shell. The D_2/3 receptor agonist quinpirole was locally injected in the NAcb (0.1, 0.3 and 1 μg per infusion) and its effects investigated on the performance of LI and HI rats on the 5-CSRTT as well as spontaneous locomotor activity in an open field.

Results

Intra-NAcb core quinpirole increased premature responding in HI rats but not in LI rats. In contrast, intra-NAcb shell quinpirole strongly increased locomotor activity in HI rats, unlike LI rats. This effect was blocked by intra-NAcb shell infusions of the D_2/3 receptor antagonist nafadotride (0.03 μg). However, nafadotride was ineffective in blocking the effects of intra-NAcb core quinpirole on premature responding in HI rats.

Conclusions

These findings indicate that impulsivity and hyperactivity are separately regulated by core and shell sub-regions of the NAcb and that HI rats show an enhanced response to D_2/3 receptor activation in these regions. These results suggest that the symptom clusters of hyperactivity and impulsivity in attention-deficit hyperactivity disorder may be neurally dissociable at the level of the NAcb.     

Reinforcement enhancing effects of nicotine via smoking

Rationale

In animals, nicotine enhances reinforcement from stimuli unrelated to nicotine intake. Human research is suggestive but has not clearly shown a similar influence of nicotine.

Objectives

We assessed acute effects of nicotine via smoking on enhancement of positive (money, music) or negative (termination of noise) reinforcers, or no “reward” (control). These different rewards determined the generalizability of nicotine effects.

Materials and methods

Dependent (n?=?25) and nondependent (n?=?27) smokers participated in three sessions, each after overnight abstinence. Using a within-subjects design, sessions involved no smoking or smoking denicotinized (0.05 mg) or nicotine (0.6 mg) Quest^R brand cigarettes. For comparison, a fourth session involved no abstinence prior to smoking one's own brand to gauge responses under typical nicotine satiation. Reinforcement was assessed by responses on a simple operant computer task for the rewards, each available singly on a progressive ratio schedule during separate trials.

Results

The reinforcing effect of music, but not other rewards, was greater due to the nicotine cigarette, compared to the denicotinized cigarette or no smoking. Reinforcement enhancing effects of nicotine did not differ between dependent and nondependent groups, indicating no influence of withdrawal relief. Responding due to acute nicotine after abstinence was very similar to responding to one's own brand after no abstinence.

Conclusions

Acute nicotine intake per se from smoking after abstinence enhances the reinforcing value of rewards unassociated with smoking, perhaps in a manner comparable to ad lib smoking after no abstinence. Nicotine's reinforcement enhancing effects may be specific to certain rewards, perhaps those sensory in nature.     

Comparison of nicotine oral soluble film and nicotine lozenge on efficacy in relief of smoking cue-provoked acute craving after a single dose of treatment in low dependence smokers

Rationale

Pilot study results suggested that a new form of nicotine oral soluble film relieved smoking cue-provoked acute craving faster than nicotine lozenge or gum. The new nicotine film may provide smokers another choice to relieve acute craving.

Objectives

This study compared the efficacy of the 2.5 mg nicotine oral soluble film to 2 mg nicotine lozenge for acute relief of smoking cue-provoked craving.

Methods

A randomized, open label, active comparator controlled, parallel group study was conducted with 322 smokers enrolled. After 4 h of abstinence from smoking, eligible subjects were exposed to smoking cues as provocation. Immediately after the post-provocation baseline craving assessment using a 0–100 mm visual analogue scale (VAS), subjects took a randomized single dose of either the 2.5 mg nicotine film or the 2 mg nicotine lozenge. Craving assessments were completed at 50 s, 3 min, 5 min, 7 min, 15 min, 20 min, 25 min and 30 min after drug administration.

Results

Both treatments reduced cue-induced craving and had similar maximum effects on craving relief. However, the 2.5 mg nicotine film relieved cue-induced craving to a greater degree than the 2 mg nicotine lozenge at 50 s (mean difference: ?4.9, p?=?0.014), 3 min (mean difference: ?6.7, p?=?0.011), and 5 min (mean difference: ?5.6, p?=?0.049) post-treatment.

Conclusions

The study confirmed the results from the pilot study. The 2.5 mg nicotine film relieved cue-provoked craving much quicker than the 2 mg nicotine lozenge while both having similar maximum effects. Nicotine film could be useful to provide quick craving relief for low dependence smokers.     

Comparatively preserved impulse control in late-onset opiate users

Rationale

A substantial literature indicates that in alcohol addiction aspects of impulsive decision-making are typical of individuals with an early onset of addictive behaviour problems. It is not known whether the same applies to opiate addiction, and this insight has important theoretical and clinical implications.

Objectives

This study aims to examine the relationship between age at onset of addictive behaviour problems and decision-making in opiate addiction.

Methods

Ninety-three opiate-dependent, treatment-seeking individuals were divided in three groups, early, late and intermediate onset of problems, and completed impulsivity questionnaires and delay discounting and gambling tasks.

Results

Individuals with a late onset of opiate problems (25 years or above) had lower delay discounting rates than individuals with early (18 years or less) or intermediate onset. There were no differences in performance on the gambling tasks. Late-onset individuals were older and had shorter drug histories, but there was no relationship between either age or length of exposure to opiates and delay discounting rates.

Conclusions

In keeping with previous studies in alcohol addiction, these findings support the notion of at least two distinct subgroups of opiate-dependent individuals, characterised by a different onset of problems, different propensity to impulsive behaviour and perhaps distinct mechanisms leading to addiction.     

Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats

Rationale

Exercise appears to be a promising non-pharmacological treatment for nicotine addiction that may be useful for the vulnerable adolescent population.

Objectives

The aim of this study is to determine if wheel-running, an animal model of aerobic exercise, during an abstinence period would decrease subsequent nicotine-seeking in rats that had extended access to nicotine self-administration during adolescence.

Methods

Male adolescent rats (n?=?55) were trained to self-administer saline or nicotine infusions (5 or 10 μg/kg) under a fixed ratio 1 schedule with a maximum of 20 infusions/day beginning on postnatal day 30. After 5 days, access was extended to 23 h/day with unlimited infusions for a total of 10 days. After the last self-administration session, rats were moved to polycarbonate cages for a 10-day abstinence period where they either had access to a locked or unlocked running wheel for 2 h/day. Nicotine-seeking was examined following the 10th day of abstinence under a within-session extinction/cue-induced reinstatement paradigm.

Results

Intake was higher at the 10 μg/kg dose as compared to the 5 μg/kg dose; however, intake did not differ within doses prior to wheel assignment. Compared to saline controls, rats that self-administered nicotine at either dose showed a significant increase in drug-seeking during extinction, and consistent with our hypothesis, exercise during abstinence attenuated this effect. Nicotine led to modest but significant levels of cue-induced reinstatement; however, in this adolescent-onset model, levels were variable and not affected by exercise.

Conclusions

Exercise may effectively reduce relapse vulnerability for adolescent-onset nicotine addiction     

Varenicline versus transdermal nicotine patch: a 3-year follow-up in a smoking cessation clinic in Taiwan

Rationale

A network meta-analysis of randomized trials and real-world comparative studies strongly suggest that varenicline is more effective in aiding smoking cessation than single form nicotine replacement therapy (NRT). Modeling the health benefits attributable to this difference relies on extrapolation to lifetime cessation, but to date, follow-up has only extended to 12 months. Longer term follow-up data are helpful in checking these assumptions.

Objectives

This study aimed to compare the sustained abstinence rates of smokers using varenicline versus nicotine patch in their quit attempt up to 36 months.

Method

Five hundred eighty-seven smokers were recruited at Kaohsiung Veteran General Hospital between Feb 2006 and Aug 2009. Participants received counseling from a physician and received either varenicline (N?=?296) or the nicotine patch (N?=?291) for smoking cessation. Both varenicline and nicotine patch users could receive their medications for a maximum of 8 weeks. Participants were followed up by telephone at 3, 6, 12, and 36 months from the first visit. The primary outcome measure was self-reported sustained abstinence up to 36 months. Measures were also taken of smoking characteristics, cigarette dependence, and sociodemographic characteristics.

Results

Multiple logistic regression of 36-month sustained abstinence on to medication adjusting for other baseline variables showed a significant advantage for varenicline, OR?=?7.94 (95 % CI 1.87–33.74).

Conclusion

An 8-week course of varenicline appears to yield higher abstinence rate up to 3 years than a similar length course of nicotine transdermal patch in routine clinical practice where behavioral support is available.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists

Rationale

Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.

Objective

The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).

Methods

We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ??HI?? and low impulsive ??LI??, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.

Results

Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.

Conclusions

These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.     

The effect of previous exposure to nicotine on nicotine place preference

Rationale

Prior exposure to drugs of abuse may increase or decrease the reinforcing effects of the drug in later consumptions. Based on the initial locomotor activity (LA) response to an acute drug administration or to novelty in an open-field arena, animals can be classified as low or high LA responders (LR or HR). Few studies have used this classification with nicotine, and the results are controversial. Some authors suggested that nicotine can induce conditioned-place preference (CPP) following prior nicotine exposure, whereas others suggested that previous nicotine exposure extinguishes nicotine-CPP.

Objective

To explore if the administration of nicotine in a novel environment without explicit behavioral consequences to classify animals in low and high nicotine responders (LNR and HNR) could affect the establishment of nicotine CPP in male Sprague–Dawley rats.

Results

Prior exposure to a single dose of nicotine (0.4 mg/kg, subcutaneously) induced CPP in LNR rats after 14 days of conditioning (seven-trial) but not after two or eight conditioning days. In contrast, HNR rats did not show CPP under any condition. In addition, our results indicated that previous exposure to nicotine decreased its rewarding effects in eight conditioning days CPP (four-trial), which can be regularly established without prior exposure to nicotine.

Conclusion

The results suggested that response to a single exposure to nicotine predicts the acquisition of nicotine preference in a 14-day conditioning protocol only for LNR rats. Thus, our findings demonstrated the relevance of using LNR and HNR classification when the individual susceptibility to nicotine preference is studied.     

Mecamylamine elicits withdrawal-like signs in rats following a single dose of nicotine

Rationale

The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established.

Objective

The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure.

Methods and Results

Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect.

Conclusions

Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.     

Tobacco smoke exposure induces nicotine dependence in rats

Rationale

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

Objectives

The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

Methods

The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs).

Results

The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus.

Conclusion

Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.     

Attenuation by baclofen of nicotine rewarding properties and nicotine withdrawal manifestations

Rationale

Nicotine is a major active ingredient in tobacco and plays a major role in tobacco addiction. In rodents, repeated nicotine administration produces behavioral responses related to its addictive properties, such as reinforcing effects and physical dependence.

Objectives

The aim of the present study was to evaluate the possible role of GABA_B receptor in responses induced by repeated nicotine administration in Swiss Webster mice.

Results

Nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.) administration induced rewarding properties in the conditioning place preference test. The GABA_B receptor agonist, baclofen (3 mg/kg, i.p.) abolished the rewarding properties induced by nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.). In addition, naloxone-precipitated nicotine withdrawal induced somatic manifestations, anxiety-like effects in the elevated plus maze test and dysphoric manifestations in the conditioned place aversion paradigm. Baclofen (2 and 3 mg/kg, i.p.) prevented the somatic manifestations and the anxiety-like effects associated with naloxone-precipitated nicotine withdrawal but not the dysphoric manifestations.

Conclusions

These results showed that nicotine rewarding properties and negative aspects of nicotine withdrawal, such as anxiety-like effects and somatic manifestations, can be modulated by the GABA_B receptor activity. This study now reveals a novel possible application of baclofen to develop new therapeutic strategies to achieve smoking cessation.     

Varenicline blocks nicotine intake in rats with extended access to nicotine self-administration

Rationale

Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. Varenicline, a partial ??4??2 nicotinic acetylcholine receptor (nAChR) agonist, is effective in reducing nicotine craving and relapse in smokers, suggesting that ??4??2 nAChRs may play a key role in nicotine dependence. In rats, the effect of varenicline on nicotine intake has only been studied with limited access to the drug, a model of the positive reinforcing effect of nicotine. Varenicline has not been tested on the increase in motivation to take nicotine in nicotine-dependent rats.

Objectives

The present study evaluated the effects of varenicline on nicotine intake in rats with extended access to nicotine self-administration (23?h/day), a condition leading to the development of nicotine dependence. We hypothesized that varenicline??s effects on nicotine self-administration would be greater in rats with extended than limited access to the drug and after forced abstinence rather than during baseline self-administration.

Results

Varenicline dose-dependently decreased nicotine self-administration in rats with limited (1?h/day) and extended (23?h/day) access. Despite an increased sensitivity to the motivational effects of abstinence on nicotine intake compared with limited-access rats, varenicline was equally effective in decreasing nicotine intake in dependent rats with extended access to nicotine.

Conclusion

These results suggest that ??4??2 nAChRs are critical in mediating the positive reinforcing effects of nicotine but may not be a key element underlying the negative reinforcement process responsible for the increased nicotine intake after abstinence in dependent subjects.     

The interactive effects of ketamine and nicotine on human cerebral blood flow

Aim

The purpose of this study was to determine if acute nicotine attenuated ketamine-induced regional cerebral blood flow (rCBF).

Method

Following 2–4 h of nicotine abstinence, healthy chronic smokers participated in four sets of rCBF studies, H ₂ ¹⁵ O positron emission tomography, during a simple sensory motor control task. The four drug conditions studied were placebo, ketamine alone, nicotine alone, and ketamine?+?nicotine.

Results

Intravenous ketamine increased rCBF in frontal, orbital–frontal, and anterior cingulate areas. Nicotine alone induced marked rCBF elevations in the lateral occipital cortex and rCBF suppressions in the basal ganglia and anterior cingulate cortex. Nicotine added to ketamine attenuated the ketamine-induced elevated rCBF in the anterior cingulate cortex but caused a marked rCBF increase in the orbital frontal region.

Conclusion

This study illustrates the interactive effects of ketamine, an NMDA receptor antagonist, and nicotine in multiple brain regions. Nicotine substantially ameliorated the effects of ketamine on anterior cingulate rCBF and, when given alone, markedly suppressed anterior cingulate rCBF. The enhanced, synergistic orbitofrontal effects observed with ketamine and nicotine together suggest a marked increase in excitatory neurotransmission in a brain region often linked to psychosis, reward, and addictive behaviors.     

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

Rationale

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

Methods

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

Results

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

Conclusions

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

Isolating behavioural economic indices of demand in relation to nicotine dependence

Rationale

Characterisation of drug dependence using principles from behavioural economics has provided a more detailed understanding of the disorder. Although questionnaires assessing economic demand for cigarettes have extended these principles to nicotine addiction, aspects of the reliability and selectivity of these questionnaires remain uncertain.

Objective

Across two experiments, we attempted to reproduce significant associations of the cigarette purchase task with nicotine dependence in a young adult population of smokers and contrasted this measure with a novel chocolate purchase task. We also examined the association between these measures and performance on a preference task, measuring preference for cigarettes and chocolate.

Methods

Questionnaire measures were used within a university setting.

Results

In experiment 1, we observed associations between nicotine dependence and measures of behavioural economic demand for cigarettes, particularly O _max. In experiment 2, we replicated these findings again and extended them to show that similar correlations between nicotine dependence and demand for chocolate were not observed. Moreover, the indices of demand and choices on a concurrent choice cigarette task were moderately associated with each other and independently associated with nicotine dependence.

Conclusions

The two experiments clearly supported previous findings regarding the association between nicotine dependence and economic demand for cigarettes. We extend these observations by showing that the generalisation of economic demand across different commodities is relatively weak, but that generalisation across different procedures is strong. Our results therefore support behavioural economic models of nicotine addiction which emphasise a robust proximal role for the incentive value of cigarettes.     

A selective reversible monoamine oxidase B inhibitor in smoking cessation: effects on its own and in association with transdermal nicotine patch

Rationale

Monoamine oxidase B (MAO-B) activity is reduced in smokers. A MAO-B inhibitor alone or co-administered with nicotine may mimic the effects of smoking and be a candidate drug for smoking cessation.

Objective

This study aims to determine the efficacy and safety of EVT302, a selective reversible MAO-B inhibitor, alone and on top of nicotine patch (NP) in smoking cessation.

Methods

This was a randomised, double blind, placebo-controlled phase II, multicentre trial. Smokers (≥10 cigarettes/day) received either EVT302 (N?=?145) or placebo (N?=?145), or EVT302 (N?=?61) or placebo (N?=?61) on top of open label NP 21 mg/day for 8 weeks. The main comparison was between EVT302 and placebo without NP. The primary outcome measure was end-of-treatment 4-week continuous abstinence rate (CAR). Secondary outcome measures: point prevalence abstinence rate, saliva cotinine concentrations in the groups without NP, urge to smoke, nicotine withdrawal symptoms and assessment of subjective effects of cigarettes.

Results

The 4-week CAR was 15.2 % in the placebo, 17.2 % in the EVT302, 26.8 % in the NP?+?placebo and 32.8 % in the NP?+?EVT302 groups, respectively. There was no difference between EVT302 and placebo either alone (adjusted OR: 1.45, 95 % CI: 0.65–3.26) or when co-administered with NP. No statistically significant difference occurred for the secondary outcome measures.

Conclusions

The selective, reversible MAO-B inhibitor EVT302 was not superior to placebo in helping smokers quit, in line with data with selegiline and confirms that MAO-B inhibitors are not effective in smoking cessation. Co-administration of NP does not provide a supplementary benefit.     

Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus

Rationale

The effects of nicotine on cognitive processes may play an important role in nicotine addiction. Nicotine withdrawal impairs hippocampus-dependent learning and genetic factors influence this effect. However, the neural changes that contribute to these impairments are unknown. Chronic nicotine upregulates hippocampal nicotinic acetycholine receptors (nAChRs), which may contribute to cognitive deficits when nicotine administration ceases. If nAChR upregulation underlies withdrawal deficits in learning, then strains of mice exhibiting withdrawal deficits in hippocampus-dependent learning should also show upregulation of hippocampal nAChRs.

Objectives

Here, we examined the effects of nicotine withdrawal on fear conditioning and [³H]epibatidine binding in the dorsal and ventral hippocampus in two inbred mouse strains and their F1 hybrids.

Methods

Male C57BL/6NTac, 129S6/SvEvTac, and B6129SF1/Tac mice were administered chronic nicotine (18 mg/kg/day) for 12 days through osmotic pumps and then were trained and tested in fear conditioning 24 h after cessation of nicotine treatment.

Results

Nicotine withdrawal impaired hippocampus-dependent contextual conditioning in C57BL/6NTac mice but not 129S6/SvEvTac or B6129SF1/Tac mice; no changes were observed in hippocampus-independent cued fear conditioning. Upregulated [³H]epibatidine binding was found in the dorsal, but not ventral, hippocampus of C57BL/6NTac mice and in the ventral hippocampus of B6129SF1/Tac mice after chronic nicotine.

Conclusions

Upregulation of high-affinity binding sites in the dorsal hippocampus of C57BL/6NTac mice, the only strain that exhibited nAChR upregulation in this region and withdrawal deficits in contextual conditioning, suggests that upregulation of high-affinity binding sites in the dorsal hippocampus mediates, in part, nicotine withdrawal deficits in contextual conditioning and genetic background modulates these effects.