Brain indices of nicotine's effects on attentional bias to smoking and emotional pictures and to task-relevant targets.

Aversive and smoking-related stimuli are related to smoking urges and relapse and can be potent distractors of selective attention. It has been suggested that the beneficial effect of nicotine replacement therapy may be mediated partly by the ability of nicotine to reduce distraction by such stimuli and thereby to facilitate attention to task-relevant stimuli. The present study tested the hypothesis that nicotine reduces distraction by aversive and smoking-related stimuli as indexed by the parietal P3b brain response to a task-relevant target digit. We assessed the effect of nicotine on distraction by emotionally negative, positive, neutral, and smoking-related pictures immediately preceding target digits during a rapid visual information processing task in 16 smokers in a double-blind, counterbalanced, within-subjects design. The study included two experimental sessions. After overnight smoking deprivation (12+ hr), active nicotine patches were applied to participants during one of the sessions and placebo patches were applied during the other session. Nicotine enhanced P3b responses associated with target digits immediately subsequent to negative emotional pictures bilaterally and subsequent to smoking-related pictures only in the right hemisphere. No effects of nicotine were observed for P3bs subsequent to positive and neutral distractor pictures. Another measure of attention, contingent negative variation amplitude in anticipation of the target digits also was increased by nicotine, especially in the left hemisphere and at posterior sites. Together, these findings suggest that nicotine reduces the distraction by emotionally negative and smoking-related stimuli and promotes attention to task-related stimuli by modulating somewhat lateralized and task-specific neural networks.     

The reinforcing effects of nicotine and stimulant medication in the everyday lives of adult smokers with ADHD: A preliminary examination.

Whereas the smoking prevalence rates in the general population are declining, rates among people diagnosed with attention-deficit/hyperactivity disorder (ADHD) continue to be elevated. Previous research has shown that nicotine may improve attention and mood, suggesting that nicotine may help ameliorate the attentional and emotional problems associated with ADHD. The present study examined the effects of nicotine with and without stimulant medication on ADHD symptoms, moods, and arousal in the everyday lives of smokers with ADHD. A total of 10 smokers with ADHD who were being treated with stimulant medication were asked to abstain from smoking while participating in the study. Participants underwent four conditions in randomized order: (a) Nicotine patch+stimulant medication, (b) nicotine patch only, (c) placebo patch+stimulant medication, and (d) placebo patch only. Each condition continued for 2 days, during which self-reports of ADHD symptoms and moods were obtained using electronic diaries. Lightweight ambulatory monitors recorded cardiovascular activity at each diary entry. Smoking abstinence was verified by expired carbon monoxide and salivary cotinine analysis. Results showed that nicotine patches and stimulant medication alone and in combination reduced difficulty concentrating and core ADHD symptoms compared with placebo patch only. Borderline improvement in impatience and self-control was seen with nicotine patch administration primarily on day 1. Nicotine patches also tended to elevate systolic and diastolic blood pressure compared with placebo patch during day 2. The findings suggest that smokers with ADHD experience nicotine-related reductions in ADHD symptoms during their everyday lives.     

Effects of nicotine on affect are moderated by stressor proximity and frequency, positive alternatives, and smoker status

The Situation x Trait Adaptive Response (STAR) model hypothesizes that nicotine reduces negative and enhances positive affect to a greater degree in situations involving internally driven attention, as when stressor stimuli are distal (past or future), thereby allowing nicotine-primed biasing of attentional processing away from negative and toward positive stimuli. To test this hypothesis, the effects of nicotine were assessed in 64 smokers and 64 never-smokers, half of whom viewed emotionally negative pictures in a no-choice picture attention task that required them to focus on the picture stressors. The other half viewed the same stimuli in a two-choice picture attention task that presented stressor pictures in one visual field and simultaneously presented positive or neutral pictures in the other visual field. Participants received a nicotine patch during one session and a placebo patch during the other session. Nicotine modulated affect only in smokers. In smokers, compared with placebo, nicotine patch reduced negative affect more during the distal periods (between stressors) than during actual stressor exposure and in women reduced negative affect more when the proportion of negative stimuli was low. Nicotine also enhanced positive affect more during distal than proximal stressors. Nicotine tended to reduce eye-gaze at negative pictures, especially when the alternative picture was positive. The overall findings are consistent with the view that nicotine biases attention away from negative stimuli when equally salient positive or benign stimuli are present.     

DRD2/ANKK1 TaqI polymorphism and smoking behavior of Egyptian male cigarette smokers.

Little is known about the genetic contribution to cigarette smoking and nicotine addiction in Egypt. The dopamine D2 receptor gene contains a TaqI repeat fragment length polymorphism creating two alleles with functional significance, DRD2*A1 and DRD2*A2. We investigated the relationship between these alleles and tobacco use in a study of 389 Egyptian male current smokers (mean age = 40 years; SD = 12). Participants were interviewed in 2004 on their smoking behaviors and quit attempts, and were given the Fagerstr?m Test for Nicotine Dependence (FTND). Blood samples were obtained and genotyped for DRD2 A1and A2 alleles. The frequencies of A1/A2, A1/A2, and A2/A2 genotypes were 6%, 29%, and 65%, respectively. We found no statistically significant association between genotype and age at onset of smoking, years of smoking, FTND score, or average number of cigarettes smoked per day. DRD2 genotype was associated with the number of cigarettes smoked in the past 48 hr (42.2 in A1 carriers vs. 37.6 in A2, p = .03), the previous quit duration (28% in A1 vs. 40% in A2 quit for more than 1 month, p = .05), and the depth of inhalation (82% in A1 vs. 72% in A2 inhaled the smoke deeply, p = .03). Logistic regression analysis including DRD2 genotype, FTND score, age at smoking initiation, marital status, and education as predictors showed that maximum duration of quit time was associated with FTND score (p = .003), DRD2 genotype (p = .01), marital status (p = .03), and age at smoking initiation (p = .04). These findings suggest a modest association between DRD2 genotype and quitting behavior in male cigarette smokers in Egypt.     

Effects of nicotine on brain responses to emotional pictures.

Given that nicotine reduces negative affect, one would expect nicotine to have different effects on brain responses to emotionally negative stimuli than it does on responses to emotionally neutral or positive stimuli. However, no studies have assessed this possibility. The present study assessed the effects of nicotine patch versus placebo patch on brain event-related potential (ERP) responses to emotion-inducing negative, positive, and neutral color pictures in 16 smokers in a double-blind, counterbalanced, within-subjects design. The study included four experimental sessions. After overnight smoking deprivation (12 hr or more), active nicotine patches were applied to participants during one of the first two sessions and during one of the last two sessions. Placebo patches were applied during the other two sessions. Nicotine reduced frontal ERP processing voltage negativity (from 144-488 ms poststimulus onset) evoked by viewing emotionally negative pictures to a greater extent than it did when emotionally neutral pictures were viewed, whereas it had no effect on processing negativity evoked by positive pictures. Nicotine also enhanced P390 amplitudes evoked by emotionally negative pictures more than it did when emotionally neutral and positive pictures were viewed. Across picture types, nicotine (relative to placebo) reduced N300 amplitude (more at anterior and dorsal sites) and increased P390 amplitude. Overall, nicotine influenced ERPs to emotionally neutral and positive pictures less than it did to negative pictures.     

Rate of nicotine onset from nicotine replacement therapy and acute responses in smokers.

The subjective and reinforcing effects of drugs of abuse may depend partly on their rate of onset, with faster acting formulations typically producing stronger effects than slower ones. In this within-subjects study, we examined the acute effects of nicotine replacement therapy via nicotine nasal spray (fast delivery) vs. transdermal nicotine patch (slow delivery) on craving, withdrawal, cardiovascular responses, subjective ratings, and reinforcing effects of smoking. Smokers (N=30) not seeking treatment participated in three sessions, each after overnight smoking abstinence, involving 14-mg nicotine (Nicoderm) or placebo patch, followed 4 hr later by intermittent administration of nicotine (Nicotrol) or placebo nasal spray. Specifically, the three group comparisons were nicotine patch condition (with placebo spray), nicotine spray condition (with placebo patch), and placebo condition (placebo spray and patch). Nicotine patch and nicotine spray were never administered in the same session. Blood nicotine levels were similar between nicotine patch and nicotine spray conditions, by design. Heart rate and systolic blood pressure were higher following nicotine spray vs. the other conditions, as hypothesized. However, other than reductions in craving related to nicotine spray and patch at some points, no differences between conditions were observed in withdrawal, subjective effects of sprays and smoking, or smoking reinforcement assessed by a computer task. Thus, under these acute conditions, the speed of nicotine delivery from nasal spray vs. patch differentially affected cardiovascular responses and perhaps craving but did not influence withdrawal, subjective ratings, and smoking reinforcement.     

Nicotine does not compromise resting myocardial blood flow autoregulation in smokers at high cardiovascular risk

Nicotine has been recognized for years as being pharmacologically responsible for the sympathoexcitatory effects of smoking. The effects of nicotine supplementation on myocardial blood flow as assessed by positron emission tomography are, however, unknown. We tested the hypothesis that nicotine substitution could interfere with myocardial blood flow autoregulation at rest in habitual smokers at risk of coronary artery disease. The short-term effect of a 4-mg nicotine tablet on myocardial blood flow was quantified with 13N ammonia positron emission tomography in 12 smokers with high cardiovascular risk (10 males and 2 females; mean age = 58+/-8 years; SCORE risk >5%). Nicotine increased systolic blood pressure from 129+/-7 to 134+/-7 mmHg (p = .03) and heart rate from 67+/-2 to 69+/-2 bpm (p = .04). As a result, nicotine raised the rate-pressure product from 8618+/-622 to 9285+/-627 bpm mmHg (p = .02). Nicotine tended to increase myocardial blood flow in the circumflex artery territory, but this effect failed to reach the level of statistical significance (from 0.56+/-0.06 to 0.63+/-0.03 ml/min/g; p>.15). This trend disappeared when myocardial blood flow was normalized for the rise in the rate-pressure product. Global myocardial perfusion, normalized for the changes in rate-pressure product, remained unchanged from 0.70+/-0.06 at baseline to 0.71+/-0.03 (ml/min/g)/(bpm mmHg) after nicotine. Nicotine supplementation in habitual smokers with high cardiovascular risk increased myocardial work without compromising resting myocardial blood flow autoregulation.     

Nicotine decreases attentional bias to negative-affect-related Stroop words among smokers

The present study examined the hypothesis that nicotine is associated with reduced attentional bias to affective and smoking-related stimuli in a modified Stroop task. A total of 56 habitual smokers were each tested on 4 days with 14 mg nicotine patches and placebo patches, counterbalanced, as a within-subjects factor in a double-blind design. A modified Stroop using negative-affect words, smoking words, color words, and neutral words was presented via computer in blocked format. As predicted, nicotine, relative to placebo, was associated with decreased attentional bias to negative words. Nicotine speeded performance during smoking-word and color-word blocks to the same degree as during neutral words and thus appeared to also have a nonspecific performance-enhancing effect. In an exploratory analysis, nicotine-attention effects occurred only in the initial presentation of pairs of blocked word pages. Nicotine also was associated with improved mood. The results are discussed in terms of affect-attention and smoking literatures.     

The effects of smoking deprivation and nicotine administration on emotional reactivity.

Although converging lines of evidence suggest that nicotine and mood are related at a fundamental biological level, this link has not been reliably demonstrated in laboratory studies. In this study, startle probe methodology was used to examine the effects of nicotine administration and deprivation on emotional processes associated with motivation. Smokers (N = 115) completed four laboratory sessions crossing deprivation (12-hr deprived vs. nondeprived) with nicotine spray (active vs. placebo). Participants viewed affective pictures (positive, negative, neutral) and pictures involving cigarette cues, while startle probes were administered. Deprivation decreased startle responding to cigarette cues, suggesting an activation of appetitive processes. Nicotine administration suppressed overall startle responding during deprivation. In addition, during deprivation, random exposure to negative stimuli over two blocks of trials resulted in decreased adaptation of the startle response, suggesting that some sensitization to negative emotional cues may take place during nicotine withdrawal. These effects are consistent with formulations of addiction, stressing that withdrawal may both increase the reinforcement salience of smoking stimuli and decrease habituation to negative emotional stimuli.     

Effect of high-dose nicotine patch therapy on tobacco withdrawal symptoms among smokeless tobacco users.

No pharmacotherapies have been shown to increase long-term (> or = 6-month) abstinence rates among smokeless tobacco (ST) users. Available evidence suggests that underdosing may occur with standard-dose nicotine replacement therapy (NRT) in ST users. We investigated the effect of high-dose nicotine therapy on tobacco withdrawal symptoms among ST users in a randomized, controlled clinical pilot study. A total of 42 ST users using at least 3 cans or pouches per week were randomized to nicotine patch doses of 63, 42, or 21 mg/day or placebo for 8 weeks. Multiple daily assessments of tobacco withdrawal and nicotine toxicity were obtained with an electronic diary. During the first week of nicotine patch therapy, we observed a dose-response relationship such that higher nicotine patch doses were associated with less decreased arousal (chi2 = 6.87, p = .009), less negative affect (chi2 = 3.85, p = .05), and less restlessness (chi2 = 3.90, p = .048). During the second week, higher nicotine patch doses were associated with less decreased arousal (chi2 = 6.77, p = .009). Overall, the frequency of nicotine toxicity symptoms did not differ by dose group. Of specific symptoms, nausea was observed to be more frequent in the 63 mg/day dose group compared with placebo (p = .035). In conclusion, high-dose nicotine patch therapy resulted in a greater reduction of tobacco withdrawal symptoms among ST users using at least 3 cans per week. High-dose nicotine patch therapy is safe and well tolerated in this population of tobacco users.     

An association of CYP2A6 genotype and smoking topography.

Nicotine is metabolized into biologically inactive cotinine primarily by the cytochrome P450 enzyme CYP2A6. CYP2A6 genetic variations have been phenotypically grouped as slow, intermediate, and normal metabolizers. Slow metabolizers smoke fewer cigarettes daily and weekly, and have lower carbon monoxide (CO) and plasma nicotine levels, suggesting a reduced smoking rate compared with normal metabolizers. CYP2A6 also is involved in the metabolic activation of tobacco-specific procarcinogenic nitrosamines, such as 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). NNK is one of the most abundant and potent procarcinogens in cigarette smoke. The present study investigated the association of CYP2A6 genotype with smoking topography, a quantifiable measure of smoking behavior, in a sample of treatment-seeking smokers prior to treatment. Smoking topography measures indicative of quantity of smoke exposure--number of puffs, mean puff volume, and total puff volume--were the outcome variables. Covariates associated with smoking topography were included in the analyses. Results indicated that CYP2A6 genotype group had a significant effect on mean puff volume and total puff volume, but not number of puffs, such that slow metabolizers exhibited reduced puffing compared with others. Smokers having CYP2A6 variants resulting in low activity metabolize nicotine more slowly, and convert procarcinogen nitrosamines to carcinogens more slowly, than do normal metabolizers. The results from this study also suggest a behavioral mechanism that may account for reduced cancer risk in slow metabolizers.     

Instructions about nicotine dose influence acute responses to nasal spray.

Effects of substance use are typically assumed to be related to pharmacological actions. However, beliefs about the drug content of a substance may strongly influence subjective and reinforcing responses to that substance (i.e., "placebo" effects). We examined the subjective and reinforcing effects of a nasal spray containing no nicotine as a function of instructions about the nicotine content of the spray (Told Nicotine vs. Told No Nicotine). Smokers (n=49) not interested in quitting smoking abstained overnight prior to a single session in which they were randomly assigned to one of three groups, involving one of the two instructional sets or a group that got no spray. Following dose instructions, subjects in the two spray groups were administered one set of four sprays from the spray bottle and then rated them intermittently on items related to "reward" (e.g., "liking", amount they would pay for more) and other effects. At the same time points, they also rated mood, craving, and withdrawal, and had heart rate and blood pressure measured. Reinforcement was then determined by the number of ad libitum sprays they self-administered during a 20-min period. The no-spray group simply rested quietly during the session, while measures were assessed at the same time points as subjects in the other two groups. Those in the Told Nicotine group reported greater spray ratings of "how much nicotine," "liking," "satisfying," "buzz/head rush," and "similar to smoking" compared with the Told No Nicotine group. Craving decreased more for those Told Nicotine versus those Told No Nicotine, but also decreased more for those Told No Nicotine compared with the no spray group. There were no significant differences in amount they would pay for more sprays, withdrawal, mood, cardiovascular responses, or in spray self-administration. These results show that instructions about the nicotine content of a novel delivery device (nasal spray) can influence self-reported spray ratings and reduce craving but are limited with respect to effects on other measures of drug response.     

Transdermal nicotine use in postmenopausal women: does the treatment efficacy differ in women using and not using hormone replacement therapy?

This study of postmenopausal female smokers (N = 94) asked: During short-term smoking abstinence, do the beneficial effects of transdermal nicotine replacement therapy (NRT) on acute symptomatology (i.e., withdrawal, cigarette craving, smoking urges, mood, depressive symptoms, motor speed, and reaction time) differ in women who use and do not use hormone replacement therapy (HRT)? Participants were recruited according to HRT and non-HRT use (self-selecting), then randomized within strata to active nicotine or placebo nicotine patch. After 1 baseline week of smoking, participants quit smoking for 2 weeks. Women received cessation counseling and were monitored for abstinence. Dependent measures were collected during five clinic visits. Two-way analysis of covariance (ANCOVA) were run on change scores for dependent variables, with nicotine patch group (active/placebo) and HRT group (HRT/non-HRT) as independent variables and age as a covariate. No interactions were found between HRT and patch condition, but both showed specific effects. During the first abstinent week, women on active nicotine patch (compared with placebo) experienced less severe withdrawal, greater reductions in cigarette cravings, and lower (more favorable) Factor 1 scores on the Questionnaire of Smoking Urges. During the second abstinent week, women using HRT (compared with the non-HRT group) exhibited better mood (Profile of Mood States scores) and less depression (Beck Depression Inventory scores). These results suggest the following: First, the efficacy of transdermal nicotine replacement is not adversely modified by women's HRT use; second, ovarian hormones might influence women's responses to smoking cessation, and thus should be considered in developing effective strategies for women to quit smoking.     

烟碱抑制单胺氧化酶B活性及其对抗帕金森病作用研究

[背景和目的]流行病学调查结果表明,吸烟与帕金森发病率呈负相关,但吸烟对抗帕金森病的机制仍不清楚.本文拟探讨烟碱对单胺氧化酶B (MAO-B)的抑制作用,明确对抗帕金森病的机制.[方法]通过小分子与蛋白对接模型模拟技术,分析烟碱和MAO-B相互作用及蛋白活性抑制率;对细胞及果蝇的帕金森病模型给予烟碱药物干预,利用分子生...     

The effects of the DRD2 polymorphism on smoking cessation and negative affect: evidence for a pharmacogenetic effect on mood.

This study evaluated the relationship between smoking cessation treatment outcome and the DRD2 polymorphism. Participants were 134 smokers who took part in a larger clinical trial evaluating the effects of an antidepressant medication (venlafaxine or placebo) plus standard care (brief counseling and nicotine replacement therapy). Venlafaxine is an antidepressant that inhibits the reuptake of serotonin and norepinephrine. A1 smokers were expected to quit significantly less often on placebo, although the abstinence rates between A1s and A2s on active drug were not expected to differ (i.e., an interaction between genotype and drug was hypothesized). In addition, antidepressant therapy was expected to have a similar genotype x treatment interaction on negative affect reduction. The results showed that smokers carrying the DRD2 A1 allele (A1/A1/A2) quit significantly less often than the homozygous A2s (OR=1.54, 95% CI=1.01-2.36). No interaction with treatment was observed. A significant pharmacogenetic effect of the drug on negative mood while quitting also was noted. Smokers absent the A1 allele (A2/A2) responded to the drug with a substantial reduction in negative affect, whereas those with the A1 allele showed no significant reduction in negative mood, F(1, 130)=5.95, p=.01. These results are contrary to expectations and suggest that although A1s may have more difficulty quitting, adding venlafaxine does not improve abstinence or mood. However, the results for the A2s provide evidence for a genotype-specific response to a pharmacological intervention, which could have implications for the development of future treatments.     

The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: follow-up of a randomized controlled trial.

In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotypextreatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care-based trial.     

Lack of effect of D2 dopamine receptor TaqI A polymorphism on smoking cessation.

One previous report (Cinciripini et al., [2004] Nicotine & Tobacco Research, 6, 229-239) found that the D2 dopamine receptor (DRD2) TaqI A polymorphism was associated with smoking cessation: Carriers of the A1 allele were less likely to quit than were those who were not carriers. If confirmed, this finding would allow one to use precessation genotyping to predict the likelihood of successful quitting. The present study reports on results of a similar smoking cessation study and uses the same methods and data analysis in a larger number of smokers. It fails to replicate the effect of DRD2 TaqI A polymorphism on smoking cessation.     

Comparison of the effects of a 24-hour nicotine patch and a 16-hour nicotine patch on smoking urges and sleep.

This randomized, open-label, crossover study was conducted to compare the effects of a 24-hr nicotine patch and a 16-hr nicotine patch on morning smoking urges and sleep quality of dependent smokers during a short period of cigarette abstinence. A total of 20 smokers (9 women and 11 men) smoking at least 20 cigarettes/day completed the two smoke-free study periods. For each period, cigarette abstinence started on the first evening and a nicotine patch was applied the next morning (for 16 or 24 hr), after baseline measures; a second patch was applied the next morning, 1 hr before the end of the experimental period. Smoking urges, mood and behavior self-reports, psychomotor performance, and polysomnographic recordings were compared between the two types of nicotine patch according to changes from baseline. Both patches decreased morning smoking urges, although results were significantly superior for the 24-hr patch. Furthermore, the 24-hr patch was more effective than the 16-hr patch in reducing the positive reinforcing dimension of smoking urges. Regarding polysomnographic recordings, the proportion of slow wave sleep was significantly increased from baseline with the 24-hr patch compared with the 16-hr patch. As for psychomotor performance measured through the critical flicker fusion test, significant improvement in morning alertness was observed in the 24-hr patch group. In conclusion, the 24-hr nicotine patch formulation is more effective than the 16-hr formulation in alleviating morning smoking urges and more specifically the positive reinforcing factor. The present findings do not support the idea that nicotine delivery during bedtime might disturb sleep, but rather it improves restorative sleep and postwaking arousal.     

Treating smokers before the quit date: can nicotine patches and denicotinized cigarettes reduce cravings?

The present study investigated whether treatment with the combination of denicotinized cigarettes and 21-mg nicotine patch for 2 weeks before a designated quit date could lessen cravings for smoking, thereby helping smokers abstain from smoking. The study was a randomized controlled clinical trial conducted at Roswell Park Cancer Institute, Buffalo, New York, in 2004 and 2005. Patients included 98 adult heavy smokers (using 20 or more cigarettes/day). Half of the subjects received 2 weeks of combination of denicotinized cigarettes (Quest 3) and 21-mg nicotine patch for 2 weeks before the quit date. The remaining smokers were switched to light cigarettes (Quest 1) during the 2 weeks before the quit date. After the quit date, all subjects received counseling for smoking cessation and were provided nicotine patches for up to 8 weeks after the quit date. Self-reported cravings for smoking, withdrawal symptoms, and smoking abstinence were measured at predetermined intervals using phone-based surveys and in clinical visits. The group that used denicotinized cigarettes and nicotine patch before quitting reported less frequent and less intense cravings for cigarettes in the 2 weeks before and after the designated quit date. Self-reported withdrawal symptoms and quit rates did not differ significantly between the groups. The use of a denicotinized cigarette combined with the nicotine patch appears to lessen cravings to smoke in the immediate postcessation period. A larger, better-powered study is needed to test if this treatment combination has merit for increasing quit rates.