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author:("Lerman, carya")
1.  The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex 
Background
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure.
Methods
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163).
Results
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males.
Conclusions
In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.
Impact
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
doi:10.1158/1055-9965.EPI-12-1234-T
PMCID: PMC3617060  PMID: 23371292
Tobacco; Cotinine; CYP2A6; Polycyclic aromatic hydrocarbons; NNAL
2.  Effects of Smoking Cues and Argument Strength of Antismoking Advertisements on Former Smokers’ Self-efficacy, Attitude, and Intention to Refrain From Smoking 
Nicotine & Tobacco Research  2012;15(2):527-533.
Introduction:
This study examines the impact of smoking cues employed in antismoking advertisements on former smokers. Previous findings indicate that visual smoking cues in antismoking advertisements with weak antismoking arguments can elicit smoking urges in smokers and undermine message effectiveness. This study extends these observations to former smokers asking whether smoking cues in antismoking advertisements influence former smokers’ self-efficacy, attitudes, and intention to refrain from smoking, along with smoking urges and perceived message effectiveness.
Methods:
The study was a mixed 2 (smoking cues; present vs. absent) × 2 (argument strength [AS]; high vs. low) design where smoking cue was a between-subject factor and AS was a within-subject factor. Potential participants recruited via online ads were screened in a phone interview for their eligibility. A total of 105 former smokers (aged 21–65) participated in the study, which was conducted in a laboratory setting. Repeated measure ANOVA and MANOVA were used for the analyses.
Results:
The results showed that the presence of smoking cues in antismoking ads undermines former smokers’ behavioral self-efficacy, attitude, and intention about smoking abstinence, which increased as AS for the ads increased. Former smokers’ reports of smoking urge were not affected by smoking cues or AS. However, consistent with previous findings for smokers, the presence of cues weakened perceived message effectiveness of antismoking ads rated by former smokers.
Conclusions:
The effect of smoking cues on former smokers’ self-efficacy, attitude, and intention to refrain from smoking is problematic. Inclusion of smoking cues in antismoking ads should be undertaken only when accompanied by strong arguments.
doi:10.1093/ntr/nts171
PMCID: PMC3545718  PMID: 22949578
3.  Nicotinic Acetylcholine Receptor Variation and Response to Smoking Cessation Therapies 
Pharmacogenetics and genomics  2013;23(2):94-103.
Objective
Evaluate nicotinic acetycholine receptor (nAChR) single nucleotide polymorphism (SNP) association with seven day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies (RCTs) in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.
Methods
We quantified association of four SNPs at three nAChRs with abstinence in eight RCTs. Participants were 2,633 outpatient treatment-seeking, self-identified European ancestry individuals smoking ≥10 cigarettes per day, recruited via advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment (EOT) and six month (6MO) abstinence, with demographic, behavioral and genetic covariates.
Results
“Risk” alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the placebo pharmacotherapy group (PG) at 6MO [for rs588765 OR (95%CI) 0.41 (0.17–0.99)], and at EOT and at 6MO [for rs1051730, 0.42 (0.19–0.93) and 0.31 (0.12–0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765 2.07 (1.11–3.87) and for rs1051730 2.54 (1.29–4.99)]. We observed significant heterogeneity in rs1051730 effects (F=2.48, P=0.021) between PGs.
Conclusions
chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with placebo treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.
doi:10.1097/FPC.0b013e32835cdabd
PMCID: PMC3563676  PMID: 23249876
logistic regression; mediation analysis; nAChR variation; nicotine dependence; pharmacotherapy; randomized clinical trials
4.  Pharmacogenetics of smoking cessation: role of nicotine target and metabolism genes 
Human genetics  2012;10.1007/s00439-012-1143-9.
Many smokers attempt to quit smoking but few are successful in the long term. The heritability of nicotine addiction and smoking relapse have been documented, and research is focused on identifying specific genetic influences on the ability to quit smoking and response to specific medications. Research in genetically modified cell lines and mice has identified nicotine acetylcholine receptor subtypes that mediate the pharmacological and behavioral effects of nicotine sensitivity and withdrawal. Human genetic association studies have identified single nucleotide polymorphisms (SNPs) in genes encoding nicotine acetylcholine receptor subunits and nicotine metabolizing enzymes that influence smoking cessation phenotypes. There is initial promising evidence for a role in smoking cessation for SNPs in the β2 and α5/α3/β4 nAChR subunit genes; however, effects are small and not consistently replicated. There are reproducible and clinically significant associations of genotypic and phenotypic measures of CYP2A6 enzyme activity and nicotine metabolic rate with smoking cessation as well as response to nicotine replacement therapies and bupropion. Prospective clinical trials to identify associations of genetic variants and gene–gene interactions on smoking cessation are needed to generate the evidence base for both medication development and targeted therapy approaches based on genotype.
doi:10.1007/s00439-012-1143-9
PMCID: PMC3864572  PMID: 22290489
5.  Smoking in Response to Negative Mood in Men Versus Women as a Function of Distress Tolerance 
Nicotine & Tobacco Research  2012;14(12):1418-1425.
Introduction:
Negative mood situations often increase smoking behavior and reward, effects that may be greater among women and smokers low in tolerance for distress.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1093/ntr/nts075
PMCID: PMC3509012  PMID: 22416115
6.  Cognitive effects of the acetylcholinesterase inhibitor, donepezil, in healthy, non-treatment seeking smokers: A pilot feasibility study 
Drug and alcohol dependence  2012;126(1-2):263-267.
Background
There is a need to identify medications to aid in smoking cessation. Reducing withdrawal-related cognitive deficits represents a pharmacological target for new pharmacotherapies. Endogenous acetylcholine levels, which are modulated by acetylcholinesterase inhibitors (AChEIs), play an important role in smoking behavior and cognition. This pilot feasibility study tested whether an AChEI, donepezil, enhanced cognitive performance among healthy smokers.
Methods
Eighteen non-treatment seeking daily smokers (6 female) received either donepezil (5mg q.d) or placebo (double-blind; 2:1 allocation ratio) for four weeks. Smoking rate, side effects, and neurocognitive measures of working memory (Letter-N-back) and sustained attention (Penn Continuous Performance Task) were assessed weekly.
Results
For the working memory task, there was a significant group × load × time interaction (p=0.03) indicating that the donepezil group demonstrated an increase in true positives from baseline to week 4 at the highest working memory load (3-back). The placebo group showed no change in accuracy. For the sustained attention task, there was a marginal effect in the same direction for discriminability, or d', p=0.08. There were no significant effects on reaction time during either task. There was also a reduction in cigarettes per day in the placebo group, but not the donepezil group.
Conclusions
AChEIs, such as donepezil, may have pro-cognitive effects among healthy smokers while they continue to smoke as usual. Given the association between cognitive deficits and relapse, AChEIs should be explored as potential therapeutics for smoking cessation.
doi:10.1016/j.drugalcdep.2012.04.019
PMCID: PMC3424358  PMID: 22595038
smoking; nicotine; acetylcholine; cognition; cognitive enhancers; working memory
7.  Primary Care Physicians’ Willingness to Offer a New Genetic Test to Tailor Smoking Treatment, According to Test Characteristics 
Emerging pharmacogenetics research may improve clinical outcomes for common complex conditions typically treated in primary care settings. Physicians’ willingness to offer genetically-tailored treatments to their patients will be critical to realizing this potential. According to recent research, it is likely that genotypes used to tailor smoking will have pleiotropic associations with other addictions and diseases, and may have different frequencies across populations. These additional features may pose an additional barrier to adoption. To assess physicians’ willingness to offer a new test to individually tailor smoking treatment according to specific test characteristics, we conducted a national mailed survey of 2000 U.S. primary care physicians (response rate: 62.3%). Physicians responded to a baseline scenario describing a new test to tailor smoking treatment, and 3 additional scenarios describing specific test characteristics based on published research; there was random assignment to one of two survey conditions in which the test was described as a genetic or non-genetic test. Our findings indicate physicians’ self-reported likelihood (0–100 scale) that they would offer a new test to tailor smoking cessation treatment ranged from 69–78% across all scenarios. Relative to baseline scenario responses, physicians were significantly less likely to offer the test when informed that the same genotypes assessed for treatment tailoring: (1) may also identify individuals predisposed to become addicted to nicotine (p<.001); (2) differ in frequency by race (p<.004); and (3) may have associations with other conditions (e.g., alcohol and cocaine addiction, ADHD and Tourette’s Syndrome) (p<.01). Describing a new test to individually tailor smoking treatment as a “genetic” versus non-genetic test significantly reduced physicians’ likelihood of offering the test across all scenarios, regardless of specific test characteristics (p<.0007). Effective education of primary care physicians will be critical to successful integration of promising new pharmacogenetic treatment strategies for smoking.
doi:10.1080/14622200802087580
PMCID: PMC3814125  PMID: 18584467
8.  Content matters: neuroimaging investigation of brain and behavioral impact of televised anti-tobacco public service announcements 
Public service announcements (PSAs) are televised ads that are a key component of public health campaigns against smoking. Understanding the neurophysiological correlates of anti-tobacco ads is an important step towards novel objective methods of their evaluation and design. In the present study, we used Functional Magnetic Resonance Imaging (fMRI) to investigate the brain and behavioral effects of the interaction between content (“argument strength”) and format (“message sensation value”) of anti-smoking ads in human. Seventy-one non-treatment seeking smokers viewed a sequence of sixteen high or 16 low argument strength ads during a fMRI scan. Dependent variables were brain fMRI signal, the immediate recall of the ads, immediate change in Intentions to Quit Smoking and the urine levels of a major nicotine metabolite cotinine at a one-month follow-up. Whole brain ANOVA revealed that argument strength and message sensation value interacted in the inferior frontal, inferior parietal and fusiform gyri, the precuneus and the dorsomedial prefrontal cortex (dMPFC). Regression analysis showed that the activation in the dMPFC predicted lower cotinine levels a month later. These results characterize the key brain regions engaged in the processing of persuasive communications and suggest that brain fMRI response to anti-smoking ads could predict subsequent smoking severity in non-treatment seeking smokers. Our findings demonstrate the importance of the quality of ad content for objective ad outcomes and suggest that fMRI investigation may aid the pre-release evaluation of televised public health announcements.
doi:10.1523/JNEUROSCI.3840-12.2013
PMCID: PMC3773220  PMID: 23616548
9.  Efficacy of Extended Duration Transdermal Nicotine Therapy: A Randomized Trial 
Annals of internal medicine  2010;152(3):144-151.
Background: Tobacco dependence is a chronic, relapsing condition that may require extended treatment.
Objective: To assess whether extended transdermal nicotine therapy increases abstinence from tobacco more than standard duration therapy in adult smokers.
Design: Parallel randomized placebo-controlled trial from September 2004 to February 2008 (small block randomization scheme, not stratified). Study participants and all research personnel except for the database manager were blinded to randomization. (NCT00364156)
Setting: Academic center.
Participants: 568 adult smokers.
Intervention: Participants were randomized to: standard (8 weeks 21mg Nicoderm CQ, 16 weeks placebo) or extended (24 weeks 21mg Nicoderm CQ) therapy.
Measurements: The primary outcome was biochemically-verified point prevalence abstinence at weeks 24 and 52. Secondary outcomes were continuous and prolonged abstinence, lapse and recovery events, cost/additional quitter, and side effects and adherence.
Results: At 24 weeks, extended therapy produced higher rates of point prevalence abstinence (31.6% versus 20.3%; Odds Ratio [OR] = 1.81 [1.23-2.66], p = 0.002), prolonged abstinence (41.5% versus 26.9%; OR = 1.97 [1.38-2.82] p = 0.001), and continuous abstinence (19.2% versus 12.6%; OR = 1.64 [1.04-2.60] p = 0.032), versus standard therapy. Extended therapy reduced the risk for a lapse (Hazard Ratio [HR] = 0.77 [0.63-0.95], p = 0.013) and increased the chances of recovery from lapses (HR = 1.47 [1.17-1.84], p = 0.001). Time to relapse was slower with extended versus standard therapy (HR = 0.50 [0.35-0.73], p < 0.001). At week 52, extended therapy produced higher quit rates for prolonged abstinence only (p = 0.027). There were no group differences in side effects and adverse events at the extended treatment phase assessment.
Limitations: The generalizability of the findings may be limited because participants were treatment-seeking smokers without medical comorbidity and differences in adherence across treatment arms were detected.
Conclusion: Compared to 8 weeks of transdermal nicotine, 24 weeks of transdermal nicotine increased biochemically-confirmed point prevalence abstinence and continuous abstinence at week 24, reduced the risk of smoking lapses, and increased the likelihood of post-lapse recovery to abstinence.
doi:10.7326/0003-4819-152-3-201002020-00005
PMCID: PMC3782858  PMID: 20124230
10.  Nicotine Dependence Pharmacogenetics: Role of Genetic Variation in Nicotine-Metabolizing Enzymes 
Journal of neurogenetics  2009;23(3):252-261.
Nicotine-dependence pharmacogenetics research is an emerging field, and a number of studies have begun to characterize the clinical relevance and predictive power of genetic variation in drug-metabolizing enzymes and drug target genes for response to medication. The present paper focuses on evidence for the role of nicotine-metabolizing enzymes in smoking behavior and response to treatment. Nicotine metabolism is mediated primarily by cytochrome P450 2A6 (CYP2A6). Genetic variation in the CYP2A6 gene has been linked with several smoking behavior phenotypes. Individuals who carry null or reduced activity alleles for CYP2A6 smoke fewer cigarettes per day, are less dependent on nicotine, and may have an easier time quitting smoking. A phenotypic measure of CYP2A6 enzyme activity, defined as the ratio of the nicotine metabolites 3′hydroxycotinine/cotinine, also predicts successful quitting with the transdermal nicotine patch, and counseling alone. Faster metabolizers of nicotine respond more poorly to these treatments; however, they may be excellent candidates for non-nicotine therapies, such as bupropion. Inherited variation in the CYP2B6 enzyme is also associated with response to bupropion treatment and counseling alone for smoking cessation. Inhibition of the CYP2A6 enzyme to slow nicotine metabolism is a promising approach to increase nicotine availability and potentially reduce harm from tobacco smoking.
doi:10.1080/01677060802572887
PMCID: PMC3772540  PMID: 19169923
tobacco; nicotine; addiction; genetics; pharmacogenetics
11.  COMPARATIVE DYNAMICS OF FOUR SMOKING WITHDRAWAL SYMPTOM SCALES 
Addiction (Abingdon, England)  2012;107(8):1501-1511.
Aims
Examine the association of person-specific trajectories of withdrawal symptoms of urge-to-smoke, negative affect, physical symptoms, and hunger during the first 7 days after smoking cessation with abstinence at end of treatment (EOT) and 6 months.
Design
Hierarchical Linear Modeling (HLM) was used to model person-specific trajectory parameters (level, slope, curvature and volatility) for withdrawal symptoms.
Setting
University-based smoking cessation trials.
Participants
Treatment seeking smokers in clinical trials of transdermal nicotine versus nicotine spray (n=514) and bupropion versus placebo (n=421)
Measurements
Self-reported withdrawal symptoms for 7 days after the planned quit date, and 7 day point prevalence and continuous abstinence at EOT and 6 months.
Findings
In regressions that included trajectory parameters for one group of withdrawal symptoms, both urge-to-smoke and negative affect were predictive of abstinence while physical symptoms and hunger were generally not predictive. In stepwise regressions that included the complete set of trajectory parameters across withdrawal symptoms (for urge-to-smoke, negative affect, physical symptoms, and hunger), with a single exception, only the trajectory parameters for urge-to-smoke were predictive. Area under the Receiver Operator Characteristic curve was 0.594 for covariates alone, and 0.670 for covariates plus urge-to-smoke trajectory parameters.
Conclusion
Among a number of different withdrawal symptoms (urge-to-smoke, negative affect, physical symptoms, and hunger) urge-to-smoke trajectory parameters (level, slope, and volatility) over the first 7 days of smoking cessation show the strongest prediction of both short and long term relapse. Other withdrawal symptoms increase the predictive ability by negligible amounts.
doi:10.1111/j.1360-0443.2012.03838.x
PMCID: PMC3394903  PMID: 22321019
smoking cessation; withdrawal symptoms; urge-to-smoke; negative affect; physical symptoms; hunger; nicotine replacement therapy; bupropion
12.  DRD1 Associations with Smoking Abstinence Across Slow and Normal Nicotine Metabolizers 
Pharmacogenetics and Genomics  2012;22(7):551-554.
Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence, but further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cutoff). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system. Gene × NMR interaction P-values were adjusted for multiple correlated tests, and we used a Bonferroni-corrected α-level of 0.004 to determine system-wide significance. Three SNPs in DRD1 (rs11746641, rs2168631, rs11749035) had significant interactions (0.001 ≤ adjusted P-values ≤ 0.004), with increased odds of abstinence within slow metabolizers (ORs=3.1–3.5, 95% CI 1.7–6.7). Our findings support the role of DRD1 in nicotine dependence, and identify genetic and nicotine metabolism profiles that may interact to impact nicotine dependence.
doi:10.1097/FPC.0b013e3283539062
PMCID: PMC3376177  PMID: 22495174
Genetic association studies; heterogeneity; smoking abstinence; nicotine metabolism; nicotine metabolite ratio; DRD1
13.  µ-opioid Receptor Availability in the Amygdala is Associated with Smoking for Negative Affect Relief 
Psychopharmacology  2012;222(4):701-708.
Rationale
The perception that smoking relieves negative affect contributes to smoking persistence. Endogenous opioid neurotransmission, and the µ-opioid receptor (MOR) in particular, plays a role in affective regulation and is modulated by nicotine.
Objectives
We examined the relationship of µ-opioid receptor binding availability in the amygdala to the motivation to smoke for negative affect relief and to the acute effects of smoking on affective responses.
Methods
Twenty-two smokers were scanned on two separate occasions after overnight abstinence using [11C]carfentanil positron emission tomography imaging: after smoking a nicotine-containing cigarette and after smoking a denicotinized cigarette. Self-reports of smoking motives were collected at baseline, and measures of positive and negative affect were collected pre- and post- cigarette smoking.
Results
Higher MOR availability in the amygdala was associated with motivation to smoke to relieve negative affect. However, MOR availability was unrelated to changes in affect after smoking either cigarette.
Conclusions
Increased MOR availability in amygdala may underlie the motivation to smoke for negative affective relief. These results are consistent with previous data highlighting the role of µ-opioid receptor neurotransmission in smoking behavior.
doi:10.1007/s00213-012-2673-5
PMCID: PMC3670416  PMID: 22389047
Smoking motivation; µ-opioid receptor; amygdala; affect regulation
14.  Gender Stratified Gene and Gene–Treatment Interactions in Smoking Cessation 
The pharmacogenomics journal  2011;12(6):521-532.
We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni corrected α-level of 5 × 10−4 to determine system-wide significance. Four SNPs (rs12021667, rs12027267, rs6702335, rs12039988; r2>0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (OR=0.5; 95% CI 0.3–0.6) at end of treatment (adjusted P<6 × 10−5). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P=3.9 × 10−5); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR=0.04; 95% CI 0.01–0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.
doi:10.1038/tpj.2011.30
PMCID: PMC3208134  PMID: 21808284
Genetic association studies; heterogeneity; smoking cessation
15.  Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation 
Neuropsychopharmacology  2012;37(7):1683-1688.
Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22–0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted.
doi:10.1038/npp.2012.13
PMCID: PMC3358736  PMID: 22373943
nicotine; addiction; craving; pharmacogenetics; galanin receptor; behavioral science; neurogenetics; pharmacogenetics / pharmacogenomics; psychiatry & behavioral sciences; nicotine; addiction; craving; pharmacogenetics; galanin receptor 1
16.  Narrative Health Communication and Behavior Change: The Influence of Exemplars in the News on Intention to Quit Smoking 
The Journal of communication  2012;62(3):473-492.
This study investigated psychological mechanisms underlying the effect of narrative health communication on behavioral intention. Specifically, the study examined how exemplification in news about successful smoking cessation affects recipients’ narrative engagement, thereby changing their intention to quit smoking. Nationally representative samples of U.S. adult smokers participated in 2 experiments. The results from the 2 experiments consistently showed that smokers reading a news article with an exemplar experienced greater narrative engagement compared to those reading an article without an exemplar. Those who reported more engagement were in turn more likely to report greater smoking cessation intentions.
doi:10.1111/j.1460-2466.2012.01644.x
PMCID: PMC3377164  PMID: 22736808
exemplar; exemplification; news; narrative engagement; smoking cessation intention
17.  Extended Duration Therapy with Transdermal Nicotine may Attenuate Weight Gain Following Smoking Cessation 
Addictive Behaviors  2011;37(4):565-568.
Aim
People who quit smoking often gain 11–12 pounds, on average, which can frequently lead to a relapse to smoking. This study evaluated whether extended vs. standard duration treatment with nicotine patch helps those able to quit smoking to reduce cessation-induced weight gain and explored nicotine patch adherence as a mediator of treatment effects.
Design and Setting
We examined data from a completed randomized placebo-controlled clinical trial of extended (24 weeks) vs. standard (8 weeks plus 16 weeks of placebo) transdermal nicotine patch therapy. Changes in measured weight over 24 weeks were compared across the two treatment arms, controlling for gender, baseline smoking rate, and previous weight. Adherence to patch use was assessed using self-report of daily use over 24 weeks.
Participants
139 clinical trial participants who were confirmed to be abstinent at weeks 8 and 24.
Findings
Compared to participants who received 8 weeks of nicotine patch therapy, participants who received 24 weeks of treatment showed significantly less weight gain from pre-treatment to week 24 (β = −4.76, 95% CI: −7.68 to −1.84, p = .002) and significantly less weight gain from week 8 to week 24 (β = −2.31, 95% CI: −4.39 to −0.23, p = .03). Extended treatment increased patch adherence which, in turn, reduced weight gain; patch adherence accounted for 20% of the effect of treatment arm on weight gain.
Conclusion
Compared to 8 weeks of transdermal nicotine therapy, 24 weeks of patch treatment may help to reduce the weight gain that is typical among smokers who are able to achieve abstinence from tobacco use. Extended treatment increased nicotine patch adherence which, in turn, reduced weight gain.
doi:10.1016/j.addbeh.2011.12.009
PMCID: PMC3288882  PMID: 22244706
18.  Dopamine genes and nicotine dependence in treatment seeking and community smokers 
We utilized a cohort of 828 treatment seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent’s smoking behavior. 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex and study site. SNP P values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3 and NR4A2 SNPs with adjusted P values < 0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic and literature analyses. Each independent signal among the top-ranked SNPs accounted for ~1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
doi:10.1038/npp.2009.52
PMCID: PMC3558036  PMID: 19494806
dopamine transporter; Fagerström Test for Nicotine Dependence; single nucleotide polymorphism; candidate gene association scan; gene-gene interaction
19.  Nicotine Receptor Subtype-Specific Effects on Auditory Evoked Oscillations and Potentials 
PLoS ONE  2012;7(7):e39775.
Background
Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity.
Methodology/Principal Findings
We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma.
Conclusions/Significance
These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2 receptors. Event-related gamma is strongly influenced by activation of α4β2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes.
doi:10.1371/journal.pone.0039775
PMCID: PMC3401200  PMID: 22911690
20.  Association of the Nicotine Metabolite Ratio and CHRNA5/CHRNA3 Polymorphisms With Smoking Rate Among Treatment-Seeking Smokers 
Nicotine & Tobacco Research  2011;13(6):498-503.
Introduction:
Genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in the CHRNA5/A3/B4 gene cluster with heaviness of smoking. The nicotine metabolite ratio (NMR), a measure of the rate of nicotine metabolism, is associated with the number of cigarettes per day (CPD) and likelihood of cessation. We tested the potential interacting effects of these two risk factors on CPD.
Methods:
Pretreatment data from three prior clinical trials were pooled for analysis. One thousand and thirty treatment seekers of European ancestry with genotype data for the CHRNA5/A3/B4 SNPs rs578776 and rs1051730 and complete data for NMR and CPD at pretreatment were included. Data for the third SNP, rs16969968, were available for 677 individuals. Linear regression models estimated the main and interacting effects of genotype and NMR on CPD.
Results:
We confirmed independent associations between the NMR and CPD as well as between the SNPs rs16969968 and rs1051730 and CPD. We did not detect a significant interaction between NMR and any of the SNPs examined.
Conclusions:
This study demonstrates the additive and independent association of the NMR and SNPs in the CHRNA5/A3/B4 gene cluster with smoking rate in treatment-seeking smokers.
doi:10.1093/ntr/ntr012
PMCID: PMC3103715  PMID: 21385908
21.  Smoking Cues, Argument Strength, and Perceived Effectiveness of Antismoking PSAs 
Nicotine & Tobacco Research  2011;13(4):282-290.
Introduction:
The study examines the effectiveness of antismoking public service announcements (PSAs) among adult smokers as a function of smoking cues and the argument strength of the PSAs. Consistent with the previous cue-reactivity studies, smoking cues are defined as one of the following visual scenes: (a) objects associated with smoking, (b) holding or handling cigarettes, and (c) actual smoking behaviors. Argument strength indicates smoker's judgments of perceived strength and persuasiveness of the arguments extracted from the PSAs.
Methods:
Data were collected through a web-based experiment of a random sample of general population of smokers (n = 566 adults aged 19 years or older). Each participant was shown 4 PSAs randomly selected from a set of 60. Data were analyzed using multilevel modeling to assess the effects of smoking cues and argument strength. Effectiveness measures include perceived persuasiveness, transportation, valenced thought, negative emotion, and smoking-related thoughts.
Results:
Argument strength is a significant predictor of outcome variables. Although there were no significant main effects of smoking cues on any outcome variables, smoking cues were found to interact with argument strength such that the association between argument strength and outcome variables became weaker for PSAs in the smoking cue condition compared with those in the no-cue condition.
Conclusions:
The interaction between smoking cues and argument strength suggests that smoking cues in antismoking PSAs undermine a significant part of what makes PSAs effective—their arguments against smoking. In designing antismoking messages, the inclusion of smoking cues should be weighed carefully.
doi:10.1093/ntr/ntq255
PMCID: PMC3066405  PMID: 21330273
22.  Nicotine metabolite ratio predicts smoking topography and carcinogen biomarker level 
Background
Variability in smoking behavior is partly attributable to heritable individual differences in nicotine clearance rates. This can be assessed as the ratio of the metabolites cotinine (COT) and 3'-hydroxycotinine (3HC) (referred to as the nicotine metabolism ratio, NMR). We hypothesized that faster NMR would be associated with greater cigarette puff volume and higher levels of total NNAL, a carcinogen biomarker.
Methods
Current smokers (n=109) smoked one of their preferred brand cigarettes through a smoking topography device and provided specimens for NMR and total NNAL assays.
Results
Faster nicotine metabolizers (third and fourth quartiles versus first quartile) based on the NMR exhibited significantly greater total puff volume and total NNAL; the total puff volume by daily cigarette consumption interaction was a significant predictor of total NNAL level.
Conclusion
A heritable biomarker of nicotine clearance predicts total cigarette puff volume and total NNAL.
Impact
If validated, the NMR could contribute to smoking risk assessment in epidemiological studies and potentially in clinical practice.
doi:10.1158/1055-9965.EPI-10-0674
PMCID: PMC3077576  PMID: 21212060
23.  Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials 
Neuropsychopharmacology  2011;37(3):641-650.
Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
doi:10.1038/npp.2011.232
PMCID: PMC3260990  PMID: 22048466
varenicline; bupropion; pharmacogenetics; nicotine; nicotinic receptor; CYP2B6; pharmacogenetics/pharmacogenomics; addiction and substance abuse; clinical pharmacology/clinical trials; neuropharmacology; varenicline; bupropion; nicotine; smoking cessation; nicotinic receptors
25.  Facilitating Clinical Implementation of Pharmacogenomics 
doi:10.1001/jama.2011.1010
PMCID: PMC3189505  PMID: 21771991

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