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Drug and alcohol dependence  2013;133(1):283-286.
Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse.
Smokers (N=24) with high quit interest were recruited for a within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO<10 ppm) on the first day of each quit attempt, while on bupropion and on placebo.
Compared to placebo, bupropion after abstinence improved correct response times for working memory (p=.01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p<.05).
Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation.
PMCID: PMC3786016  PMID: 23726977
cognition; working memory; attention; tobacco dependence; smoking cessation; bupropion
Drug and alcohol dependence  2013;133(1):167-171.
Nicotine’s acute effects on enhancing reinforcement from sensory rewards, shown in animal models, appear to occur with smoking in humans. These effects may vary due to reinforcer magnitude and amount of acute smoke intake (dose).
In a fully within-subjects design, dependent smokers (n=23) participated in 3 sessions. Each session followed overnight abstinence and involved 4 trials to assess responding via progressive ratio (PR50%) for sensory reinforcement from high, moderate, or low preference music, or no reward (counter-balanced, 30-sec/reinforcer). Sessions differed in smoking prior to each trial: 8 puffs on arrival and 2 puffs/trial (“8+2”), 2 puffs/trial only (“0+2”), or no smoking. Puffs were consumed via CReSS (Clinical Research Support System) to control topography, and smoking involved own brand to ensure palatability and increase generalizability of results.
Reinforced responding was influenced by main effects of smoking condition (p<.05) and music reward type (p<.001). Compared to no smoking, responding for music was increased after smoking 8+2/trial puffs (p<.005), but not after 0+2/trial puffs. Smoking condition significantly increased reinforced responding only for the high preference music (p=.01), and not for moderate or low preference music, or for no reward. Withdrawal did not differ between the two smoking sessions, ruling out withdrawal relief as an explanation for differential reinforcement enhancement.
Our findings confirm that just one cigarette after abstinence is sufficient for reinforcement enhancing effects and suggest that such enhancement is greater as magnitude of a reward’s reinforcing efficacy increases.
PMCID: PMC3786025  PMID: 23768842
nicotine; reinforcement enhancement; smoking; reinforcing efficacy; music; CReSS
Addiction (Abingdon, England)  2013;108(11):1962-1968.
Background and aim
It is important to find economical methods in early Phase 2 studies to screen drugs potentially useful to aid smoking cessation. A method has been developed that detects efficacy of varenicline and nicotine patch. This study aimed to evaluate whether the method would detect efficacy of bupropion and correctly identify lack of efficacy of modafinil.
Using a within-subject double crossover design, smokers attempted to quit during each treatment, with bupropion (150 mg b.i.d.), modafinil (100 mg b.i.d.), or placebo (double-blind, counter-balanced order). In each of three medication periods, all smoked with no drug on week 1 (baseline or washout), began dose run-up on week 2, and tried to quit every day during week 3.
A university research center in the United States.
Forty-five adult smokers high in quit interest.
Abstinence was verified daily each quit week by self-report of no smoking over the prior 24 hr and CO<5 ppm.
Compared with placebo, bupropion did (F(1,44)=6.98, p=.01), but modafinil did not (F(1,44)=.29, p=.60), increase the number of abstinent days. Also, bupropion (versus placebo) significantly increased the number of those able to maintain continuous abstinence on all 5 days throughout the quit week (11 vs 4), Z= 2.11, p <.05, while modafinil did not (6).
Assessing days abstinent during 1 week of use of medication versus placebo in a cross-over design could be a useful early Phase 2 study design for discriminating between medications useful vs not useful in aiding smoking cessation.
PMCID: PMC3797155  PMID: 23773319
Self-reported cigarettes per day (CPD) is a very common screening, as well as dependent or independent, measure in clinical and non-clinical research on smoking, but consistency of CPD across days in dependent smokers is uncertain. Adult dependent smokers (N=357; 170 men, 187 women) retrospectively reported “usual” CPD at screening and then prospectively self-monitored CPD on 3 consecutive days of one week during an ad libitum baseline period. Participants were those recruited for later tests of brief medication effects in those with high (n=170) versus low (n=187) interest in quitting smoking soon (within 3 months). Consistency was determined by intraclass correlation (ICC). Prospective daily CPD was generally consistent (ICC = 0.78, 95% CI of 0.74–0.81), but CPD changed (increase or decrease) by 5 cigarettes/day or more in 40% of participants and by at least 10/day in 10%. Consistency in CPD was greater in higher dependent smokers and in women with low (vs. high) quit interest, but consistency tended to be greater in men with high (vs. low) quit interest. Although retrospectively reported CPD at screening was consistent with the overall mean for prospectively monitored daily CPD, 15% of participants differed by at least 5/day between methods, and digit bias was twice as likely with retrospective versus prospective CPD, which was at chance levels. Understanding variability in CPD may improve knowledge of dependence and factors that foster or discourage daily smoking amount, but precise assessment of daily CPD likely requires prospective monitoring.
PMCID: PMC3822912  PMID: 23088404
smoking behavior; cigarettes per day; dependence; sex differences
Psychopharmacology  2013;228(3):479-486.
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.
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) QuestR 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.
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 one’s own brand after no abstinence.
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.
PMCID: PMC3707934  PMID: 23494236
nicotine; reinforcement enhancement; reward; smoking; dependence
6.  Possible Reinforcement Enhancing Effects of Bupropion During Initial Smoking Abstinence 
Nicotine & Tobacco Research  2012;15(6):1141-1145.
Due to a drop in nicotine, smoking cessation may attenuate reinforcement from sensory stimuli unrelated to nicotine intake. Recent rodent research suggests that bupropion may reverse this attenuation, perhaps helping explain its efficacy in aiding cessation.
In a within-subjects, crossover study, smokers responded on a simple computer task for brief music reward available on a progressive ratio 50% schedule. Testing was done on three separate occasions: after ad lib smoking during prequit baseline and on the first day of two brief quit attempts while taking bupropion or placebo, in counter-balanced order. Number of operant responses was the measure of reinforcement. To more clearly assess abstinence and medication effects, those meeting 24-hr abstinence criteria (CO < 5 ppm; n = 5) or clearly failing to abstain (CO > 10 ppm; n = 5) during both medication conditions were compared.
Among abstainers, repeated measures ANOVA showed that reinforced responding decreased by nearly 50% from baseline after quitting on placebo (p = .03), while responding after quitting on bupropion was similar to that during baseline (–17%; p = .20). In contrast, those unable to abstain showed virtually identical reinforced responding due to either medication or baseline.
These exploratory findings confirm that responding for a reward unrelated to smoking decreases after abstinence and are consistent with animal research showing bupropion effects on enhancing reinforced responding.
PMCID: PMC3646646  PMID: 23100457
7.  Optimal Carbon Monoxide Criteria to Confirm 24-hr Smoking Abstinence 
Nicotine & Tobacco Research  2012;15(5):978-982.
Smoking cessation is typically verified biochemically by expired-air carbon monoxide (CO) levels below 9 ppm (i.e., ≤8 ppm), but this CO criterion may lead many who have smoked within 24hr to be misclassified as abstinent.
Adult dependent smokers (N = 261; 124 men, 137 women) prospectively recorded each cigarette smoked and provided CO on five consecutive days during each of two short-term attempts to quit smoking. Participants were those recruited for crossover tests of the effects of placebo versus medication (nicotine patch or varenicline) on the ability to initiate 24-hr abstinence. All had either a high or low interest in permanently quitting smoking soon (within 3 months) and were randomized to the presence or absence of daily ($12) monetary reinforcement of abstinence.
Total accuracy of sensitivity to detect smoking (83%) plus specificity to verify abstinence (87%) was optimal at a CO criterion for abstinence below 5 ppm (≤4 ppm), compared with below 9 ppm (sensitivity of 60%, specificity of 97%). Overall CO detection of sensitivity and specificity was higher in those with high versus low quit interest, but reinforcement of abstinence made no difference.
Results indicate a CO criterion half that used in most clinical research may optimally validate 24-hr cessation and reduce misclassification of smokers as “abstinent.”
PMCID: PMC3733388  PMID: 22990219
Addictive behaviors  2012;38(2):1527-1531.
Negative mood situations increase craving to smoke, even in the absence of any tobacco deprivation (e.g. “stressors”). Individual differences in effects of negative mood situations on craving have received relatively little attention but may include variability between men and women. Across two separate within-subjects studies, we examined sex differences in craving (via the QSU-brief) as functions of brief smoking abstinence (versus satiation; Study 1) and acute induction of negative mood (versus neutral mood; Study 2). Subjective ratings of negative affect (via the Mood Form) were also assessed. In study 1, we compared the effects of overnight (>12 hr) abstinence versus non-abstinence on craving and affect in adult male (n=63) and female (n=42) smokers. In study 2, these responses to negative versus neutral mood induction (via pictorial slides and music) were examined in male (n=85) and female (n=78) satiated smokers. Results from each study were similar in showing that craving during the abstinence and negative mood induction conditions was greater in women than men, as hypothesized, although the sex difference in craving due to abstinence was only marginal after controlling for dependence. Craving was strongly associated with negative affect in both studies. These results suggest that very acute negative mood situations (e.g. just a few minutes in Study 2), and perhaps overnight abstinence, may increase craving to smoke to a greater extent in women relative to men.
PMCID: PMC3462895  PMID: 22726579
sex; abstinence; negative mood; craving; affect; smoking
9.  Smoking in Response to Negative Mood in Men Versus Women as a Function of Distress Tolerance 
Nicotine & Tobacco Research  2012;14(12):1418-1425.
Negative mood situations often increase smoking behavior and reward, effects that may be greater among women and smokers low in tolerance for distress.
Adult dependent smokers (N = 164; 86 men, 78 women) first completed measures of distress tolerance via self-report and by mirror-tracing and breath-holding tasks. They then participated in 2 virtually identical laboratory sessions, involving induction of negative versus neutral mood (control) via pictorial slides and music. They rated negative affect (NA) before and during mood induction and smoked their preferred brand ad libitum during the last 14 min of mood induction. Our aim was to examine mood effects on NA, smoking reward (“liking”), and smoking intake (puff volume and number) as a function of sex and distress tolerance.
Negative mood induction increased NA, as planned, and smoking reward and intake compared with neutral mood. Increases in NA and puff volume due to negative mood were greater in women compared with men, as hypothesized, but no main effects of the self-report or behavioral distress tolerance measures were seen in responses to mood induction. However, unexpectedly, lower self-reported distress tolerance was associated with greater smoking intake due to negative (but not neutral) mood in men and generally due to neutral (but not negative) mood in women.
Negative mood may increase smoking intake more in women compared with men. Yet, low distress tolerance may enhance smoking intake due to negative versus neutral mood differentially between women and men, suggesting that sex and distress tolerance may interact to influence smoking responses to negative mood.
PMCID: PMC3509012  PMID: 22416115
10.  The Reliability of Puff Topography and Subjective Responses During Ad lib Smoking of a Single Cigarette 
Nicotine & Tobacco Research  2011;14(4):490-494.
Acute smoking behavior (i.e., puff topography) and subjective responses during the ad lib smoking of a single cigarette in the laboratory may provide useful measures of smoking reinforcement and reward, respectively. However, the reliability of such measures is not clear, leaving uncertain the utility of a single assessment of smoking behavior as an individual difference measure.
Dependent smokers (N = 94) smoked normally prior to each of 4 laboratory sessions during which they were instructed to smoke 1 cigarette of their preferred brand in ad libitum and unblinded fashion and then rate it for subjective effects. Puff topography (puff number, total volume, and maximum volume) was assessed via portable Clinical Research Support System device. Subjective reward and perception were assessed by visual analog scales of “liking” and “how strong,” respectively. The reliability of puff topography and subjective measures was determined across days by intra-class correlations (ICCs). Differences due to sex and nicotine dependence (high and low Fagerström Test for Nicotine Dependence score) were also examined.
Reliability was highly significant for each measure. ICCs were .70 for total puff volume, .60 for maximum puff volume, .73 for puff number, .64 for liking, and .78 for how strong. Reliability generally did not differ by sex or dependence, but absolute values for total volume and maximum puff volume were greater in men and in high dependent smokers. Liking was also greater in high dependent smokers.
Puff topography and subjective measures during the ad lib smoking of a single cigarette are highly reliable. Smoking responses during a single ad lib smoking session may be useful in identifying stable individual differences in smoking reinforcement and reward.
PMCID: PMC3313780  PMID: 22039077
11.  Differences in negative mood-induced smoking reinforcement due to distress tolerance, anxiety sensitivity, and depression history 
Psychopharmacology  2010;210(1):25-34.
Negative mood increases smoking reinforcement and may do so to a greater degree in smokers vulnerable to negative mood dysregulation.
Adult smokers (N = 71) without current depression were randomly assigned to one of two smoking conditions (nicotine or denic cigarettes, presented blind) maintained across all sessions. Subjects completed one neutral mood session and four negative mood induction sessions. Negative mood inductions included one each of the following: 1) overnight smoking abstinence, 2) challenging computer task, 3) public speech preparation, 4) watching negative mood slides. In each session, subjects took 4 puffs on their assigned cigarette, rated it for “liking” (reward), and then smoked those cigarettes ad libitum (reinforcement) during continued mood induction. Affect was assessed intermittently before and after smoking. Differences in responses were examined as functions of self-reported history of major depression and levels of distress tolerance and anxiety sensitivity.
Smoking reinforcement, but not reward or negative affect relief, was greater in all sessions in those with a history of depression and greater after overnight abstinence in those with lower distress tolerance. Reward and affect relief, but not reinforcement, were greater during speech preparation among those high in anxiety sensitivity.
Low distress tolerance may enhance acute smoking reinforcement due to abstinence, while depression history may broadly increase acute smoking reinforcement regardless of mood. Neither smoking reward nor affect help explain these individual differences in smoking reinforcement.
PMCID: PMC2882096  PMID: 20217051
Smoking; Reinforcement; Nicotine; Depression history; Distress tolerance; Anxiety sensitivity; Negative affect; Mood; Withdrawal
Drug and alcohol dependence  2008;99(1-3):47-57.
Initial sensitivity to nicotine’s effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.
PMCID: PMC2648532  PMID: 18775605
nicotine; sensitivity; nonsmokers; reward; reinforcement; sex differences; cross-tolerance; parental smoking history
Behavioural pharmacology  2008;19(5-6):630-640.
Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 μg/kg) was administered via nasal spray followed by mood, nicotine reward (e.g. “liking”) and perception (e.g. “feel effects”) measures, physiological responses, sensory processing (pre-pulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine vs. placebo spray choice procedure. For the dopamine D4 receptor (DRD4 VNTR), presence of the 7 repeat allele was associated with greater aversive responses to nicotine (decreases in “vigor”, positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased “feel effects” and greater startle response, but in men only. Also observed in men but not women were other genetic associations, such as greater “feel effects” and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T SNP) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3’ VNTR (SLC6A3), and the mu opioid receptor A118G SNP (OPRM1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine prior to the onset of dependence and may do so differentially between men and women.
PMCID: PMC2743299  PMID: 18690117
nicotine; sensitivity; genetics; dopamine; reward; reinforcement

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