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.     

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.     

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.     

A psychometric evaluation of cigarette stimuli used in a cue reactivity study.

Laboratory studies have demonstrated that cigarette smokers react with significant subjective and autonomic responses (e.g., increased craving and increased heart rate) in the presence of stimuli associated with smoking. Although cue reactivity effects are typically robust, a number of methodological considerations make interpretation and design of cue reactivity studies problematic. Previous research has paid scant attention to the psychometric properties of the cigarette cues presented, and standard cues would enhance comparison and synthesis of studies. In the present study, we evaluated 12 cigarette photos (compared with positive, negative, and neutral photos), used in a separate study, for their ability to evoke self-report of craving in both nicotine-deprived and nondeprived smokers. These photos performed as expected, with cigarette pictures evoking significantly higher craving than neutral pictures and deprived smokers showing a trend toward higher craving than nondeprived smokers. The cigarette picture set was evaluated for internal consistency (Cronbach's alpha = .97) as a 12-item scale and further reduced to multiple 2-item scales with reliability estimates ranging from .70 to .93. A cluster analysis of all pictures showed that, when rated for craving, cigarette pictures clustered together, indicating they had distinct properties compared with positive, negative, and neutral pictures. Effect sizes were calculated for each cigarette picture in both deprived and nondeprived smokers. The craving effect sizes ranged from .57 to .98 for nondeprived smokers, and from .61 to .99 for deprived smokers. The analyses suggest these cigarette pictures have excellent psychometric properties for use in future cue reactivity studies.     

Dopamine receptor (DRD2) genotype-dependent effects of nicotine on attention and distraction during rapid visual information processing.

The effects of nicotine, distractor type, and dopamine type-2 receptor (DRD2) genotype on rapid visual information processing (RVIP) task performance were assessed in habitual smokers. Four RVIP tasks differed in terms of distractor location (central vs. peripheral) and distractor type (numeric vs. emotional). Each participant performed each of the tasks on two different days, once while wearing an active nicotine patch and once while wearing a placebo patch. Overall, the nicotine patch produced more accurate detection of and faster reaction times to target sequences; however, these effects varied with distractor type and genotype. Nicotine speeded reaction time more with left-visual-field (LVF) than right-visual-field (RVF) emotional distractors but speeded reaction time more with RVF than LVF numeric distractors, especially when the distractor digit matched the target sequence in terms of numeric oddness or evenness. Nicotine tended to facilitate performance more in individuals with at least one A1 allele than in homozygous A2A2 individuals, especially with numeric distractors presented to the left hemisphere. Nicotine tended to reduce distraction by negative stimuli more than other types of stimuli. Few gender differences were observed. The overall pattern of results was consistent with the view that nicotine modulates selective attention or subsequent information processing in a manner that depends partly on the emotional versus numeric nature of task distractors, DRD2 genotype, and the brain hemisphere that initially processes the distractors (visual field of distractor).     

Extinguishing the rewarding value of smoke cues: pharmacological and behavioral treatments.

The present study examined several pharmacological and behavioral treatments designed to promote extinction of the responses to rewarding cigarette smoke cues. Pharmacological treatments comprised nicotine skin patches (21 mg/24 hr) and the nicotinic acetylcholine receptor antagonist mecamylamine (10 mg/day), administered separately or in combination. Behavioral manipulations included switching to denicotinized cigarettes, to cigarettes having different menthol flavor, or to ventilated-filter (low tar and nicotine) cigarettes. Smokers were assigned to the various treatments for 2 weeks before they quit smoking. During weekly test sessions, subjects rated the rewarding effects of their usual brands of cigarettes or cigarettes with different menthol content (mentholated vs. nonmentholated). Over the 2-week treatment period, all pharmacological treatments reduced ratings of reward for the usual-brand test cigarettes. Switching to smoking denicotinized cigarettes for 2 weeks similarly decreased rewarding effects of the usual-brand test cigarettes. Subjects also strongly preferred cigarettes with the same menthol content to which they were accustomed. However, manipulating the menthol content of the cigarettes smoked during the 2 weeks of treatment had different effects, depending on whether smokers habitually smoked mentholated or nonmentholated cigarettes. For menthol smokers, removal of the menthol cue hampered extinction of reward ratings for the usual-brand (mentholated) test cigarette. For nonmenthol smokers, addition of the menthol cue did not affect the progress of extinction of nonmenthol smoke cues. These findings demonstrate the importance of sensory cues in determining subjective reward and show that the reward value of these cues can be altered by removal of nicotine from tobacco or by pharmacological manipulations that interfere with the reinforcing effects of nicotine.     

Carry-over effects of smoking cue exposure on working memory performance.

The present study investigated the effects of drug cue exposure on working memory performance in cigarette smokers. Adult smokers (N = 23) deprived for 12 hr performed a working memory task during which they were exposed to three types of task-irrelevant stimuli: Pictures containing smoking related-content, pictures devoid of smoking content, and a fixation cross. Consistent with prior research, we found that drug cue exposure affected the processing of subsequent items (i.e., carry-over effects). Specifically, we found that working memory performance was worse on trials containing neutral pictures preceded by trials containing smoking cues compared with performance on trials containing neutral pictures preceded by trials not containing smoking-related stimuli. Previously observed effects of smoking cue exposure on cognitive processing were replicated but only after removing trials subject to carry-over effects. These results replicate and extend previous research demonstrating similar effects and highlight the significant methodological and conceptual implications of carry-over effects.     

Instructed smoking expectancy modulates cue-elicited neural activity: a preliminary study.

In recent years, research applying functional neuroimaging to the study of cue-elicited drug craving has emerged. This research has begun to identify a distributed system of brain activity during drug craving. A review of this literature suggested that expectations regarding the opportunity to use a drug affected the pattern of neural responses elicited by drug cues. Using functional magnetic resonance imaging (fMRI), we examined the effects of smoking expectancy on the neural response to neutral (e.g., roll of tape) and smoking-related (a cigarette) stimuli in male cigarette smokers deprived of nicotine for 8 hr. As predicted, several brain regions (e.g., the anterior cingulate cortex) exhibited differential activation during cigarette versus neutral cue exposure. Moreover, we found that subregions of the prefrontal cortex (i.e., ventromedial, ventrolateral, and dorsolateral prefrontal cortices) showed cue-elicited activation that was modulated by smoking expectancy. These results highlight the importance of perceived drug use opportunity in the neurobiological response to drug cues.     

Subjective and physiological responses to smoking cues in smokers with schizophrenia.

The prevalence of smoking is high among people with schizophrenia. Although several research groups are developing smoking treatments for these smokers, abstinence rates to date have been modest. Methodological tools such as cue exposure are useful in clinical research with smokers in general, but the value of these paradigms with smokers with schizophrenia has yet to be established. The aim of the present study was to determine the subjective and physiological effects of exposure to in vivo smoking cues in smokers with schizophrenia. A total of 25 heavy smokers with schizophrenia or schizoaffective disorder were assessed while nonabstinent and after 2-hr smoking abstinence. Urge to smoke, mood, nicotine withdrawal symptoms, heart rate, and blood pressure were measured during a precue relaxation period, after exposure to neutral cues, and after exposure to smoking cues. Results indicate that both exposure to smoking cues and brief abstinence increased urge levels, nicotine withdrawal symptom levels, and negative affect. Abstinence did not amplify the effects of cues on urges or other cue reactivity measures. These results indicate that smoking cue reactivity laboratory models may be useful for investigating potential smoking treatments for, or neurobiological contributions to, smoking behavior in smokers with schizophrenia.     

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.     

Negative emotional state shortens the duration of the chewing sequence

Although the effect of the quality of dental state on the quality of chewing has been studied extensively, almost nothing is known about the repercussions of emotional states on masticatory muscles activity observed during chewing. The objective of this study was to evaluate the effects of positive and negative emotional states on the electromyographic (EMG) activity during food ingestion. With this aim in view, we employed an association of pictures and sounds taken from the international affective picture system (IAPS) and the international affective digitized sound (IADS) system was used. These effects which varied in valence neutral to pleasant or unpleasant were used to investigate masticator muscle activity in 26 young adults exposed to these stimuli during the mastication of cheese. The emotional state was evaluated by recording variations in cardiac rhythm. There were fewer chewing bursts and less muscle activity during unpleasant stimuli compared to pleasant and neutral stimuli, resulting in a shortened chewing sequence.     

Nicotine, cotinine, withdrawal, and craving patterns during smoking and nicotine nasal spray use: results from a pilot study with African American men.

Nicotine intake via smoking is highly variable. Individualized dosing of nicotine replacement therapy (NRT) may improve product efficacy, but a better understanding of the within-day and within-subject relationships between smoking, NRT use, nicotine and cotinine concentrations in blood, and cravings and withdrawal symptoms is needed to inform dosing algorithms. A pilot study was undertaken to collect data on these relationships and to assess the feasibility of the methods needed for this type of research, including a sophisticated statistical modeling technique (a two-part mixed-effects model with correlated random effects that accounts for clumping at zero). Because nicotine metabolism varies by gender and race, the sample was homogeneous with respect to these characteristics. In a within-subjects study, 27 African American adult male smokers carried a computerized cigarette dispenser for 1 week, capturing the time each cigarette was smoked. Subjects then entered an inpatient setting for 1 day of scheduled smoking (matched to data from the cigarette dispenser to create an ecologically valid schedule) and 4 days of ad libitum nicotine nasal spray use, while tobacco abstinent. Eight times per day, at 2-hour intervals, blood was drawn and ratings of cigarette cravings and withdrawal symptoms were obtained. On average, subjects used less than half of the manufacturer's recommended minimum daily dose of nicotine nasal spray. Large differences in nicotine and cotinine levels were observed between individuals. When predicting nicotine, cotinine, withdrawal, and cravings, we observed significant interactions between route of nicotine intake and a variety of independent variables.     

Walking reduces cue-elicited cigarette cravings and withdrawal symptoms, and delays ad libitum smoking.

Stress and exposure to smoking cues influence smoking cravings and behavior. Exercise appears to reduce cigarette cravings and withdrawal symptoms, but no study has investigated the effects of exercise on cue-elicited cravings and withdrawal symptoms, or ad libitum smoking behavior. In this study, 60 regular smokers, invited by public advertisements, were assessed at baseline following 2 hr of abstinence, and randomized to a 15-min brisk walk or passive condition. Both groups then completed three tasks (Stroop color-word interference task, speech task, and handling a lit cigarette). Cravings were assessed with two single items, and withdrawal symptoms were assessed using the seven-item Mood and Physical Symptoms Scale. After the laboratory session, ad libitum smoking was determined from the subject's cell phone text message. Exercise (mean heart rate reserve = 24%) attenuated increases in strength of desire to smoke, tension, poor concentration, and stress, in response to a lit cigarette, but had minimal effects on increases in cravings and withdrawal symptoms in response to the stressors. Absolute levels of cravings and withdrawal symptoms were reduced during and following exercise. Exercisers engaged in ad libitum smoking a net 57 min (CI = 31-83) later than those in the passive condition. A 15-min brisk walk not only reduced cigarette cravings and withdrawal symptoms but also could attenuate increases in cue-elicited cravings and withdrawal symptoms, and increase the time between cigarettes smoked.     

The role of impulsivity on smoking maintenance.

In order to better understand why those higher in impulsivity experience more difficulties during smoking abstinence, the current study examined the possible mechanisms contributing to cigarette smoking relapse. Fifty dependent cigarette smokers completed measures designed to assess craving, tobacco withdrawal severity, and negative affect during 48 hours of nicotine abstinence. Using a series of multilevel models (SAS Proc Mixed Procedure), significant impulsivity x time analyses revealed differences in craving, F(2, 96) = 3.74, p<.05, and anxiety, F(2, 96) = 3.23, p<.05. Simple slopes analyses indicated that heightened trait-impulsivity predicted greater increases in craving and anxiety during a 48-hour abstinence period. These findings suggest that smokers with higher levels of impulsivity may lack the ability to find an accessible and comparable substitute for cigarette smoking during a cessation attempt. This study also highlights the importance of considering individual differences when treating those who wish to quit smoking.     

Randomised trial investigating effect of a novel nicotine delivery device (Eclipse) and a nicotine oral inhaler on smoking behaviour, nicotine and carbon monoxide exposure, and motivation to quit

OBJECTIVE: To monitor the effect of a novel nicotine delivery device that may produce fewer carcinogens (Eclipse) on cigarette smoking, carbon monoxide and nicotine concentrations, and motivation to give up smoking. The smoker's own brand of cigarette and a nicotine replacement product (Nicotrol inhaler) were used as comparisons. DESIGN: After baseline data were recorded, smokers were randomised to either Eclipse or inhaler for two weeks and then switched to the other product for another two weeks. Thereafter a second baseline was obtained. SETTING AND PARTICIPANTS: Fifty smokers were included and data are reported for the 40 with complete data sets. The smokers were not trying to quit but were interested in trying a new product to reduce their risk. They visited a smoking clinic 10 times during the six week period of the trial. INTERVENTION: No counselling to aid reduction by Eclipse or inhaler was given. MAIN OUTCOME MEASURES: At each visit smoking status and carbon monoxide concentrations were recorded. In half of the visits withdrawal symptoms, attitudes towards smoking, heart rate, and blood nicotine concentrations were also recorded. RESULTS: Eclipse use decreased the number of cigarettes smoked per day (cpd) from 19.1 cpd at baseline to 2.1 cpd (p < 0.001), but increased carbon monoxide concentrations in parts per million (ppm) from 21.0 ppm to 33.0 ppm (p < 0.001). A similar decrease in cigarettes smoked per day was seen with the Nicotrol inhaler, from 19.1 cpd to 4.8 cpd (p < 0.001), but carbon monoxide decreased from 21.0 ppm to 12.7 ppm (p < 0.001). The blood nicotine concentration remained fairly stable with Eclipse, increasing slightly from 16.8 ng/ml to 18.0 ng/ml, while for the inhaler a significant drop was noted, from 16.8 ng/ml to 12. 2 ng/ml (p < 0.002). Craving and withdrawal did not increase with Eclipse. Few significant adverse events occurred with Eclipse. CONCLUSIONS: Eclipse can dramatically decrease cigarette consumption without causing withdrawal symptoms or decreases in nicotine concentrations or motivation to quit altogether. Unlike the inhaler, Eclipse produces an increase in carbon monoxide concentration. Thus Eclipse may not be a safer cigarette.     

Reactivity to in vivo smoking cues in older adolescent cigarette smokers.

Most smokers initiate smoking in adolescence, and craving for cigarettes may play an important role in maintenance of smoking behavior and relapse to smoking during a quit attempt. Although a significant body of literature explores cue-reactivity in adult smokers, little has been published on cue-reactivity among adolescent smokers. In a previously published work, we found that videotaped smoking cues may not be robust in eliciting craving among adolescent smokers. Hence, in this preliminary study, we examined reactivity to in vivo smoking cues among adolescent smokers (N = 11, average age = 18.1 years, range = 15-19 years, predominantly female). Participants were presented with in vivo smoking and neutral cues (counterbalanced). We recorded subjective craving and real-time heart rate in response to each type of cue. Adolescent smokers had a significantly greater "desire" to smoke (p < .05) in response to smoking cues vs. both baseline and neutral cues. Participants had faster heart rates after the smoking cues during the epochs of 21-30 s and 31-40 s (p values<.05) as compared with baseline, and mean heart rate was higher during the smoking cues relative to neutral cues among participants who received the smoking cues first (p < .05). Results of this preliminary study further demonstrate the feasibility of conducting cue-reactivity studies with adolescent cigarette smokers. Findings from this study suggest that adolescent smokers may show patterns of responding to smoking cues similar to those of adult smokers. Implications for future laboratory studies with adolescent smokers are discussed.     

Acute effects of Advance: a potential reduced exposure product for smokers

OBJECTIVE: To examine the acute effects of Advance, a potential reduced exposure product (PREP) for smokers marketed as a means to reduce exposure to toxic gases and tobacco specific nitrosamines. Design, setting, participants: Latin square ordered, three condition, laboratory based, crossover design with 20 smokers of light or ultra-light cigarettes (15 or more cigarettes/day). In each 2.5 hour condition, participants completed an 8-puff smoking bout from their own brand, Advance, or an unlit cigarette (that is, sham smoking) every 30 minutes for a total of four bouts. MAIN OUTCOME MEASURES: Subject rated measures of tobacco/nicotine withdrawal; carbon monoxide (CO), and heart rate; plasma nicotine concentrations. RESULTS: Relative to own brand, Advance produced similar withdrawal suppression and heart rate increase, lower CO boost, and higher plasma nicotine concentrations. CONCLUSIONS: PREPs for smokers need to be evaluated using a comprehensive strategy that includes empirical examination of acute and long term effects. Adequate withdrawal suppression and potentially lower concentrations of CO associated with Advance use are positive factors, although higher nicotine concentrations do not constitute "reduced exposure". Overall, longer exposure periods are necessary to determine carcinogen delivery. PREP evaluation is complex and should be completed objectively.     

Effects of smoking abstinence, smoking cues and nicotine replacement in smokers with schizophrenia and controls.

The mechanisms underlying the low smoking cessation rates among smokers with schizophrenia (SS) are unknown. In this laboratory study, we compared the responses of 21 SS and 21 non-psychiatric controls (CS) to manipulations of 5-hour smoking abstinence, transdermal nicotine replacement (0 mg, 21 mg and 42 mg), and in vivo smoking cues. Results indicate that SS were more sensitive than CS to the effects of acute abstinence on carbon monoxide (CO) boost, but not more sensitive to the effects of abstinence on urge levels or withdrawal symptoms. SS and CS did not differ in urge response to in vivo smoking cues, but SS were less consistent in their reactions. These findings suggest that heightened sensitivity to the effects of abstinence on smoke intake may partially account for the low cessation rates experienced by SS, but other potential mechanisms should be explored using behavioral laboratory models.     

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.     

Tolerance does not develop to the decrease in nicotine self-administration produced by repeated bupropion administration.

The atypical antidepressant bupropion has been shown to be an efficacious smoking cessation agent; however, its therapeutic mechanism of action is unknown. To further understand the mechanism by which bupropion reduces smoking, the present study determined the effect of repeated bupropion pretreatment on nicotine self-administration or sucrose-maintained responding. Rats were trained to self-administer intravenous nicotine (0.02 mg/kg/infusion; Experiment 1) or to respond for sucrose pellets (45 mg each; Experiment 2) on a fixed-ratio 5 schedule. Once rats reached stable responding, bupropion (70 mg/kg, subcutaneously) or vehicle was injected 15 min before the session for 14 consecutive sessions. Bupropion acutely decreased both nicotine self-administration and sucrose-maintained responding by approximately 60%-70%. With repeated bupropion pretreatment, however, responding for nicotine decreased completely. In contrast, the bupropion-induced decrease in responding for sucrose following acute administration did not change significantly with repeated bupropion administration. These results suggest that bupropion acquired some specificity with repeated use, decreasing the intake of nicotine and producing an extinction-like pattern in nicotine self-administration. Thus the present results parallel human clinical studies with bupropion demonstrating its smoking cessation properties following repeated treatment. These results indicate that the rat nicotine self-administration paradigm is a useful animal model for assessing smoking cessation pharmacotherapies.