Changes in plasma brain-derived neurotrophic factor levels in smokers after smoking cessation

Several studies have reported that brain-derived neurotrophic factor (BDNF) might be associated with nicotine dependence. However, there are few studies on BDNF levels in humans with nicotine dependence. In the present study, we compared the differences in plasma BDNF levels in patients with nicotine dependence and in healthy nonsmokers, and we investigated serial changes in plasma BDNF levels in patients with nicotine dependence following smoking cessation. Forty-five voluntary smokers and 66 nonsmokers were recruited in this study. Of the 45 smokers, 12 were taking varenicline, 21 were using a nicotine patch, and 12 were unaided in their cessation effort by their own choice. Plasma BDNF levels were measured at baseline using an enzyme-linked immunosorbent assay (both smokers and nonsmokers) and at weeks 4 and 12 after smoking cessation (abstinent smokers only). A total of 19 smokers were able to remain abstinent during the entire study period. Baseline plasma BDNF levels were significantly lower in smokers compared to nonsmokers (F = 4.410, p = 0.002). The plasma BDNF levels in the abstinent smokers significantly increased from baseline after 4 weeks of smoking cessation (z = −2.86, p = 0.004) but had a tendency of decrease in the period between weeks 4 and 12. We could not find differences in the plasma BDNF levels among the three smoker subgroups at week 12 following cessation. Changes in plasma BDNF levels might be related to the process of abstinence and the pathophysiology of nicotine dependence.     

Effects of transdermal nicotine on prose memory and attention in smokers and nonsmokers

Previous research investigating cognitive effects of nicotine has produced mixed findings partly due to the use of abstaining smokers and cigarettes as a delivery system. The present study examined effects of nicotine delivered via a transdermal patch on prose memory and sustained attention in male smokers (n=25) and nonsmokers (n=22), who were randomly assigned to either a placebo or a nicotine condition. All groups were matched on their verbal ability and gross personality characteristics (state/trait anxiety levels, extroversion-introversion, and impulsivity level). In the nicotine condition, smokers were treated with a 21-mg transdermal patch, while nonsmokers received a 7-mg nicotine patch. Six hours following patch application, their performance was assessed on a computerized prose memory task and the Rapid Visual Information Processing task (RVIP) in a counterbalanced order and double-blind fashion. The results demonstrated that smokers in the placebo group recalled a significantly greater number of propositions than their counterparts in the nicotine group. Nonsmokers in the nicotine condition also remembered significantly more of the prose material than smokers in the same condition and showed a trend towards better recall of propositions of medium importance in the nicotine condition in comparison to the nonsmokers in the placebo group. No between-group differences were found on the RVIP task. A significant effect of time was found for systolic blood pressure and heart rate. The results cannot be interpreted using the arousal theory of nicotine effects on attention and are explained on the basis of a dose-dependent nicotinic action possibly recruiting cholinergic cortical projections.     

Individual variability in responses to nicotine

Individual variability in acute responses to nicotine, which may be defined as variable magnitude of effects following controlled dosing, is generally attributed to stable characteristics of tobacco users such as genetic/constitutional factors or to chronic behaviroral factors (e.g., long-term use of other drugs). Often overlooked, however, is that such variability may also be due to the transient influence of the situational factors in which people consume nicotine, such as acute stress or physical activity. Results of selected studies from the author's laboratory provide examples of each of these sources of variability in nicotine responding on subjective, behavioral, and physiological measures. All studies used a nasal spray method of nicotine dosing or controlled smoking (paced puffing) to control acute nicotine exposure, an essential methodological feature of any research on individual differences in acute responses to nicotine. As an example of genetic/constitutional factors, gender differences in nicotine responding have begun to receive some attention, with few differences emerging. However, females may be more responsive than males to nonnicotine stimuli associated with smoking (e.g., sight and taste of smoke). In terms of chronic behavioral factors, long-term use of nicotine produces attenuation of most subjective and some behavioral effects of nicotine, reflecting chronic tolerance, and the possibility that chronic use of other drugs may alter responses to nicotine (i.e., cross-tolerance or cross-sensitization) deserves greater study. Of particular emphasis in this review is the modulating influence of acute situational factors on nicotine responding. Human studies have shown that magnitude of nicotine's subjective effects may depend on the predrug subjective state, level of physical activity vs. rest, and concurrent acute intake of other drugs, among other situational factors. Proper consideration of these situational factors may reveal the greatest source of individual variability in responding to nicotine and clarify the impact of more stable genetic/constitutional or chronic environmental factors.     

Smoking, cortisol and nicotine.

Cigarette smoking is associated acutely with elevated cortisol levels. However, the results of comparisons of cortisol levels in smokers and non-smokers have been inconsistent, and the significance of cortisol responses in smoking cessation is unclear. Here we describe one study comparing the cortisol profiles of smokers and nonsmokers over the day, and a second investigation in which cortisol was monitored during smoking cessation. In the first study, we collected saliva samples from 196 middle-aged men and women on working and weekend days repeatedly through the day. On both working and weekend days, cortisol levels were significantly higher in smokers after adjustment for age, gender and grade of employment. Cortisol responses to waking (the increase between waking and 30 min) were also greater in smokers. The elevation in cortisol among smokers is generally attributed to nicotine exposure. Nicotine replacement therapy substantially improves abstinence rates, and has become a standard component of smoking cessation treatments, but the effects of nicotine replacement on cortisol are not known. In the second study, cortisol was monitored over 6 weeks of abstinence in 112 smokers treated with behavioural support and 15 mg nicotine patches. Smoking cessation was accompanied by an abrupt decrease in salivary cortisol, and this was sustained over the abstinence period. There was a marginal association between the decrease in cortisol and smoking relapse rates. These results suggest that the nicotine supplied through patches was not sufficient to block the cortisol reduction following smoking cessation. The contribution of these findings to understanding the role of neuroendocrine function in smoking is described.     

Effects of cigarette smoking on prepulse inhibition, its attentional modulation, and vigilance performance

Startle eyeblink modification was measured during a degraded stimulus continuous performance test following both smoking and overnight abstinence among student smokers to measure the effects of smoking on both early and late attentional processes. A group of nonsmokers was tested twice without nicotine manipulation. A startling noise was presented either 240 or 1200 ms following target and nontarget stimuli presented during the task. Startle inhibition at 240 ms was greater following targets than nontargets following smoking and during both nonsmoker tests, but this attentional modulation was absent following abstinence. At the 1200-ms probe position, target and nontarget stimuli produced nondifferential inhibition during both tests for both groups. Abstinence among smokers produced reliably lower vigilance performance compared to ad lib smoking. The results indicate that smoking abstinence affects the early stages of stimulus processing.     

Increased plasma brain-derived neurotrophic factor levels in chronic smokers following unaided smoking cessation

Recent animal studies have suggested an association between nicotine and alterations in brain-derived neurotrophic factor (BDNF) expression levels. However, the role of BDNF in humans with nicotine dependence has not yet been investigated. In this study, we explored the differences in the plasma BDNF levels of chronic smokers and healthy nonsmokers, and we investigated the changes in plasma BDNF levels in chronic smokers following unaided smoking cessation. Forty voluntary participants (20 smokers and 20 nonsmokers) were enrolled in this study. We measured the plasma BDNF levels at baseline (both groups) and at the end of the two-month study period (smoker group only) using an enzyme-linked immunosorbent assay. A total of 12 smokers (60.0%) completed the two-month study. ANCOVA with age and body mass index as covariates showed that the baseline plasma BDNF levels in smokers were significantly lower than those in nonsmokers (F = 4.626, p = 0.038). The plasma BDNF levels in the smokers significantly increased from baseline after the two-month smoking cessation period (Z = −3.059, p = 0.002). These findings suggest that BDNF may play a role in the pathophysiology of smoking behavior.     

Effects of cigarette smoking or ingestion of nicotine on platelet 5-hydroxytryptamine (5-HT) levels in smokers and non-smokers

Summary Platelets of healthy smokers and nonsmokers were prepared and their content of 5-hydroxytryptamine was determined by HPLC with electrochemical detection. Platelet 5-HT levels in smokers (728 ± 156 pmol per 108 platelets, mean ±SEM, n=9) were significantly higher than those in non-smokers (353 ± 156 pmol per 10⁸ platelets, n = 11). Smoking of a single cigarette caused a transient increase in platelet 5-HT levels by about 350% in non-smokers, but had no additional effect in smokers. Similarly, chewing of nicotine gum (48 mg nicotine) resulted in a transient increase in platelet 5-HT by about 100% in non-smokers, but not in smokers. In conclusion, smoking of cigarettes can cause an increase in platelet 5-HT, most likely via an enhanced supply of 5-HT from entero-chromaffm cells which can be stimulated via nicotine receptors.Abbreviations 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid     

Pituitary and adrenal hormone responses to pharmacological,physical, and psychological stimulation in habitual smokers and nonsmokers

Hormone responses to injection of corticotropin-releasing hormone following bicycle ergometry and psychological stress were studied in ten habitual smokers and ten nonsmokers. Compared to injection of saline, significant increases were found in adrenocorticotropin, prolactin, growth hormone, total serum cortisol, and salivary cortisol under all three stimulations except for salivary cortisol under ergometry. Furthermore, the smokers showed significant elevations of all five hormones investigated following the smoking of two cigarettes of the subject's preferred brand. Comparisons of hormone responses between smokers and nonsmokers revealed a general trend towards stronger responses in nonsmokers. However, due to the small number of subjects investigated and considerable variation in the individual hormone responses these differences reached statistical significance only for growth hormone responses following ergometry and salivary cortisol responses after psychological stress. In addition, the circadian rhythm of salivary cortisol was measured on two occasions between 9 a.m. and 9 p.m. in the subject's natural environment. The typical circadian pattern of decreasing cortisol levels was observed, with no significant differences between smokers and nonsmokers. We conclude that chronic nicotine consumption may lead to lower responses of multiple hormones not only to nicotine but to a variety of stimuli, and that these alterations do not necessarily affect unstimulated circadian profiles of free cortisol. Correspondence to: C. Kirschbaum     

EEG Changes During Tobacco Withdrawal

Tobacco smoking decreases theta and alpha power and increases the dominant alpha frequency in smokers deprived of cigarettes for 10-17 hrs. The slow alpha frequency in deprived smokers has been attributed to either (1) characterological differences between smokers and nonsmokers, or (2) nicotine withdrawal. Studies finding slower alpha in deprived smokers were not able to replicate previous findings of decreased alpha abundance after smoking, nor did they consider the importance of increased theta as a withdrawal sign. We studied 11 smokers for one day and 7 smokers for two days while they smoked a series of placebo and nicotine cigarettes. Theta and alpha power increased with tobacco deprivation but were decreased for 30-90 min by nicotine cigarettes. The dominant alpha frequency in deprived smokers was slower than after smoking a nicotine cigarette, but the decreases in frequency were not always statistically significant.     

Changes in brain activation associated with reward processing in smokers and nonsmokers

Tobacco smoking is the most frequent form of substance abuse. Several studies have shown that the addictive action of nicotine is mediated by the mesolimbic dopamine system. This system is implicated in reward processing. In order to better understand the relationship between nicotine addiction and reward in humans, we investigated differences between smokers and nonsmokers in the activation of brain regions involved in processing reward information. Using [H₂ ¹⁵O] positron emission tomography (PET), we measured regional cerebral blood flow (rCBF) in healthy smokers and nonsmokers while they performed a prelearned, pattern-recognition task. We compared two conditions involving nonmonetary reinforcement or monetary reward with a baseline condition in which nonsense feedback was presented. With monetary reward, we found activation in the frontal and orbitofrontal cortex, occipital cortex, cingulate gyrus, cerebellum, and midbrain in both groups. Additionally, monetary reward activated typical dopaminergic regions such as the striatum in nonsmokers but not in smokers. We found a similar pattern of activation associated with nonmonetary reinforcement in nonsmokers, whereas activation was found in smokers only in the cerebellum. The different patterns of activation suggest that the brains of smokers react in a different way to reward than those of nonsmokers. This difference involves in particular the regions of the dopaminergic system including the striatum. In principle these observations could be interpreted either as a consequence of tobacco use or as a primitive condition of the brain that led people to smoke. Supported by related nonimaging studies, we interpret these differences as a consequence of tobacco smoking, even if a short-term effect of smoking prior to the experiment cannot be excluded. Electronic Publication     

Arousing and De-Arousing Effects of Cigarette Smoking Under Conditions of Stress and Mild Sensory Isolation

The arousing and de-arousing effects of smoking a 1.3 mg nicotine delivery cigarette, measured by changes in electrodermal, heart rate and EEG alpha responding, were examined under conditions of stress, induced by aversive white noise, and mild sensory isolation. Compared with sham smokers and a situation control group, smokers showed significant arousal elevations in all response systems under sensory isolation conditions, but mixed stimulant (heart rate response) and depressant (EEG, skin conductance response) effects under stress conditions. Possible reasons for these differential effects are suggested.     

The moderating influence of nicotine and smoking on resting-state mood and EEG changes in remitted depressed patients during tryptophan depletion

Comorbidity between depression and tobacco use may reflect self-medication of serotonergically mediated mood dysregulation, which has been associated with aberrant cortical activation and hemispheric asymmetry in patients with major depressive disorders (MDD). This randomized, double-blind study in 28 remitted MDD patients examined the moderating effects of acute nicotine and smoker vs. nonsmoker status on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). In smokers, who exhibited greater posterior high alpha power and increased left frontal low alpha power (signs of deactivation) compared to nonsmokers, ATD increased self-ratings of depressed mood and elevated left frontal and right parietal high alpha power (i.e. further cortical deactivation). Smokers were not affected by nicotine administration. In nonsmokers, ATD did not influence depression ratings, but it reduced vigor ratings and increased frontal and posterior theta power; both of which were blocked by acute nicotine. These findings indicate a role for nicotinic receptors in disordered mood.     

Effects of Smoking/Nicotine on Anxiety, Heart Rate, and Lateralization of EEG During a Stressful Movie

The effects of smoking cigarettes with differing FTC nicotine deliveries on anxiety and EEG activity were evaluated in 40 smokers who were compared with 40 non-smokers, matched for age and gender. Following smoking (sham-smoking in the case of the non-smokers), the participants viewed a stress-inducing movie. Smoking higher-nicotine delivery cigarettes during the movie, as compared to smoking low-nicotine control cigarettes, was associated with reductions in anxiety and right hemisphere activation, increased heart rate, and enhancement of the ratio of left-hemisphere parietal EEG activation to right-hemisphere activation. These results are interpreted as indicating that the anxiolytic effects of nicotine may be mediated by the right hemisphere. The EEG activity and emotional responses of non-smokers were more like those of smokers who smoked the lower-nicotine cigarettes than those of smokers of the higher-nicotine cigarettes.     

Abstinence from smoking decreases habituation to food cues.

Smokers typically gain weight after cessation due, in part, to increased caloric intake. This increase may be due to enhanced responding to sensory characteristics of foods resulting from a failure to habituate to food cues. To test this possibility, salivation to eight presentations of strawberry yogurt was assessed in male smokers and nonsmokers in two sessions. To test stimulus specificity, on the ninth trial, subjects were presented either more strawberry yogurt or lemon yogurt. Smokers were studied under nonabstinent or abstinent conditions. Salivation for nonabstinent smokers and nonsmokers decreased over presentations, while abstinent smokers showed little change. Nonabstinent smokers and nonsmokers recovered salivation when the new flavor yogurt was presented, and showed greater consumption on the final trial for the different versus same flavor yogurt. Nonabstinent smokers participated in additional within-session smoking sessions to control for withdrawal. Nonabstinent subjects were not different across smoking or not smoking sessions, suggesting the effects are not due to the acute effects of withdrawal.     

Emotional reactivity to emotional and smoking cues during smoking abstinence: Potentiated startle and P300 suppression

Negative affect is thought to be an important factor in the maintenance of cigarette smoking, and thus it is important to further develop objective measures of smoking‐related emotional responses. Nonsmokers, nonabstinent smokers, and abstinent smokers participated in a cue reactivity task where eyeblink startle amplitude and startle probe P300 (P3) suppression were measured during the presentation of emotional pictures. During unpleasant pictures, the amplitude of both measures was smaller in nonabstinent smokers than in nonsmokers or abstinent smokers. P3 suppression, but not startle amplitude, was larger in abstinent smokers than in nonsmokers. Abstinence‐induced increases in cigarette craving were associated with P3 suppression during tobacco‐related pictures. Results suggest that tobacco abstinence increases emotional reactivity to unpleasant stimuli, which is consistent with negative reinforcement models of tobacco addiction.     

Women addicted to nicotine

Summary Nicotine dependence is epidemic and the numbers of smoking women have increased significantly during the past few years. Given concerns about the effects of nicotine-dependence on women, a literature review was carried out to examine gender differences in nicotine effects and cessation programs. Women show an increased risk for tobacco-associated diseases, such as cardiovascular disorders, cancer, decreased fertility, premature menopause and they endanger themselves and their unborn child during pregnancy. As conventional smoking cessation programs are less effective in women, participation in women-only smoking cessation groups should be encouraged. Health professionals should also focus on smoking during pregnancy, since smoking cessation during early pregnancy can alter pregnancy outcomes. Clinical research on a variety of pharmacological and behavioural treatments may help to combat tobacco addiction. Recent work has looked at new therapeutic options for people who have problems attaining abstinence. Findings from these studies suggest that psychopharmacological treatment with antidepressants may be effective, although to date, gender differences in responsiveness to these treatments have not been reported. The heightened vulnerability of women to tobacco-related diseases and the harmful effects of smoking during pregnancy reinforce the need to develop specific treatment strategies that address both the psychological and physiological needs of women smokers.     

Nicotine regulation among heavy and light smokers in a non-stressful environment

The purpose of this study was to assess nicotine regulation among "heavy" and "light" smokers. Previous studies supporting the nicotine regulation model of smoking behavior have suggested that smokers compensate for a reduction in the amount of nicotine available in their cigarette by altering smoking frequency, puff volume, or other aspects of smoking topography. However, little is known about a smoker's decision to smoke a specific cigarette, and the concurrent changes in their blood nicotine. Manipulation of nicotine levels in the blood could play a critical role in smoking maintenance, by regulating the extent and quality of the CNS effects of smoking. In this study, 24 heavy and light smokers (cotinine above or below 260 ng/ml) smoked high- (1.0 mg) or low- (0.5 mg) dose nicotine cigarettes while watching non-stressful movies. Blood nicotine was assessed before and after smoking a preload and free operant cigarette. The results showed that blood nicotine levels after smoking the free operant cigarette were significantly more consistent (lower standard error) for the heavy smokers, following a low dose, as opposed to a high-dose preload. Light smokers showed a non-significant trend towards being more consistent when the high-dose nicotine preload was used. This suggests that heavy smokers may have maximized their dose of nicotine whenever available nicotine was in relatively short supply (low dose condition). However, light smokers may have minimized their exposure when available nicotine was relatively more plentiful (high dose condition).     

Subjective and autonomic responses to smoking-related visual cues

Nicotine, like several other abused drugs, is known to act on the reward system in the brain. Smoking-associated cues produce smoking urges and cravings accompanied by autonomic dysfunction to these cues in smokers. The present study was aimed at investigating whether cues related to smoking elicit the autonomic response in smokers. The subjective and physiological reactivity of 7 smokers and 12 nonsmokers in a supine position to smoking-related visual cues was assessed under indirect dim light using a self-assessment manikin and a specially designed pupillometer. The experimental procedure consisted of the elicitation and measurement of pupil size (PS) while the subjects viewed a smoking image and images from three valence-defined categories (i.e., pleasant, unpleasant, and neutral), based on normative affective ratings selected from the International Affective Picture System. Both groups produced significantly larger PS increases in response to pleasant or unpleasant images compared to neutral images. Smokers, viewing smoking-related visual cues but no other affective images, produced significantly larger PS's compared to nonsmokers. Moreover, smokers rated the smoking image with more pleasure and arousal than nonsmokers. These findings suggest that cues related to smoking induce not only a subjective emotional alteration, but also sympathetic activation, measured by the time-series PS data in smokers.     

Effects of nicotine and caffeine, separately and in combination, on EEG topography, mood, heart rate, cortisol, and vigilance

Effects of nicotine and caffeine, separately and in combination, were assessed in 12 male habitual smokers in a repeated-measures design. Caffeine (0-mg vs. two 150-mg doses administered in a decaffeinated/sugar-free cola drink post-baseline and 90 min later) was crossed with nicotine (ad libitum own dosing vs. 1.0-mg machine-delivered dose vs. 0.05-mg machine-delivered dose). Participants smoked a total of five cigarettes at 30-min intervals over a 2-hr period. Caffeine and nicotine had large effect sizes on electroencephalogram (EEG) power; however, these effects were modulated by the eyes open versus closed condition, the other drug, and electrode site. EEG effects of open versus closed eyes tended to be of the same size and direction as those of nicotine and caffeine. However, whereas nicotine increased EEG power in some higher frequency bands in some conditions, caffeine decreased EEG power across almost all conditions. Serum cortisol concentration, vigor, and pleasantness were increased by nicotine, but not by caffeine. Level of depressive mood depended on an interaction of caffeine and nicotine. Vigilance performance was enhanced significantly by caffeine and was increased almost significantly by nicotine. The findings were interpreted in terms of common and differential mechanisms of the two drugs.     

Sex, ADHD symptoms, and smoking outcomes: an integrative model

Both females and individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) have been found to be at increased risk for a range of smoking outcomes, and recent empirical findings have suggested that women with ADHD may be particularly vulnerable to nicotine dependence. On a neurobiological level, the dopamine reward processing system may be implicated in the potentially unique interaction of nicotine with sex and with ADHD status. Specifically, nicotine appears to mitigate core ADHD symptoms through interaction with the dopamine reward processing system, and ovarian hormones have been found to interact with nicotine within the dopamine reward processing system to affect neurotransmitter release and functioning. This article synthesizes data from research examining smoking in women and in individuals with ADHD to build an integrative model through which unique risk for cigarette smoking in women with ADHD can be systematically explored. Based upon this model, the following hypotheses are proposed at the intersection of each of the three variables of sex, ADHD, and smoking: (1) individuals with ADHD have altered functioning of the dopamine reward system, which diminishes their ability to efficiently form conditioned associations based on environmental contingencies; these deficits are partially ameliorated by nicotine; (2) nicotine interacts with estrogen and the dopamine reward system to increase the positive and negative reinforcement value of smoking in female smokers; (3) in adult females with ADHD, ovarian hormones interact with the dopamine reward system to exacerbate ADHD-related deficits in the capacity to form conditioned associations; and (4) during different phases of the menstrual cycle, nicotine and ovarian hormones may interact differentially with the dopamine reward processing system to affect the type and value of reinforcement smoking provides for women with ADHD. Understanding the bio-behavioral mechanisms underlying cigarette addiction in specific populations will be critical to developing effectively tailored smoking prevention and cessation programs for these groups. Overall, the goal of this paper is to examine the interaction of sex, smoking, and ADHD status within the context of the dopamine reward processing system not only to elucidate potential mechanisms specific to female smokers with ADHD, but also to stimulate consideration of how the examination of such individual differences can inform our understanding of smoking more broadly.