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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
2.  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
3.  Influences of polymorphic variants of DRD2 and SLC6A3 genes, and their combinations on smoking in Polish population 
BMC Medical Genetics  2009;10:92.
Polymorphisms in dopaminergic genes may influence cigarette smoking by their potential impact on dopamine reward pathway function. A1 allele of DRD2 gene is associated with a reduced dopamine D2 receptor density, and it has been hypothesised that A1 carriers are more vulnerable to smoking. In turn, the 9-repeat allele of dopamine transporter gene (SLC6A3) has been associated with a substantial reduction in dopamine transporter, what might result in the higher level of dopamine in the synaptic cleft, and thereby protective role of this allele from smoking. In the present study we investigated whether polymorphic variants of DRD2 and SLC6A3 genes and their combinations are associated with the smoking habit in the Polish population.
Genotyping for TaqIA polymorphism of DRD2 and SLC6A3 VNTR polymorphism was performed in 150 ever-smokers and 158 never-smokers. The association between the smoking status and smoking phenotypes (related to the number of cigarettes smoked daily and age of starting regular smoking), and genotype/genotype combinations was expressed by ORs together with 95% CI. Alpha level of 0.05, with Bonferroni correction whenever appropriate, was used for statistical significance.
At the used alpha levels no association between DRD2 and SLC6A3 genotypes and smoking status was found. However, A1 allele carriers reported longer abstinence periods on quitting attempts than non-carriers (p = 0.049). The ORs for heavier smoking were 0.38 (0.17-0.88), p = 0.023, and 0.39 (0.17-0.88), p = 0.021 in carriers compared to non-carriers of A1 or *9 allele, respectively, and the OR for this smoking phenotype was 8.68 (2.47-30.46), p = 0.0005 for the A1-/9- genotype combination, relatively to the A1+/9+. Carriers of *9 allele of SLC6A3 had over twice a lower risk to start smoking before the age of 20 years compared to non-carriers (sex-adjusted OR = 0.44; 95% CI: 0.22-0.89; p = 0.0017), and subjects with A1-/9- genotype combination had a higher risk for staring regular smoking before the age of 20 years in comparison to subjects with A1+/9+ genotype combination (sex-adjusted OR = 3.79; 95% CI:1.03-13.90; p = 0.003).
Polymorphic variants of DRD2 and SLC6A3 genes may influence some aspects of the smoking behavior, including age of starting regular smoking, the level of cigarette consumption, and periods of abstinence. Further large sample studies are needed to verify this hypothesis.
PMCID: PMC2758863  PMID: 19761593
4.  Genetic influence of dopamine receptor, dopamine transporter, and nicotine metabolism on smoking cessation and nicotine dependence in a Japanese population 
BMC Genetics  2014;15(1):151.
This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects’ smoking history on the association.
Genotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence.
This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.
PMCID: PMC4307219  PMID: 25526961
ANKK1/DRD2 TaqIA polymorphism; CYP2A6*4 polymorphism; Nicotine dependence SLC6A3 VNTR polymorphism; Smoking cessation
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.  The Influence of Nicotine Dose and Nicotine Dose Expectancy on the Cognitive and Subjective Effects of Cigarette Smoking 
This study investigated the independent and interactive effects of nicotine dose and nicotine dose expectancy on smoking outcomes using a 2 (given nicotine vs. placebo) × 2 (told nicotine vs. placebo) Balanced Placebo Design (BPD). Smokers (N = 148) completed the Rapid Visual Information Processing Task (RVIP) and measures of smoking urge, mood, and cigarette ratings (e.g., satisfying) after smoking a nicotine or placebo cigarette crossed with instructions that the cigarette contained either nicotine or no nicotine. Nicotine cigarettes (0.6 mg nicotine) produced better sustained attention performance than placebos as indicated by RVIP reaction time, hits, and sensitivity (A′). Nicotine cigarettes also produced better mood and greater rewarding subjective effects of the cigarettes on 11 of 11 dimensions compared to placebos. Nicotine instructions resulted in fewer RVIP false alarms, better mood, and greater rewarding subjective effects of the cigarettes on 9 of 11 dimensions compared to placebo instructions. Nicotine dose by nicotine dose expectancy interactions were also observed for urge and tension-anxiety, such that the dose expectancy manipulation produced differential effects only among those who smoked placebo cigarettes. In contrast a significant interaction for self-reported vigor-activity demonstrated that the dose expectancy manipulation produced effects only among those who smoked nicotine cigarettes. This study provides additional evidence that nicotine improves cognitive performance, and provides initial evidence that denicotinized cigarettes smoked under the guise that they contain nicotine influence cognitive performance, albeit with less robust effects than nicotine. These data may inform the development of expectancy-based interventions for tobacco dependence.
PMCID: PMC3660849  PMID: 21463067
smoking; expectancies; placebo; nicotine; cognitive performance
7.  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
8.  Multivariate Analysis of Dopaminergic Gene Variants as Risk Factors of Heroin Dependence 
PLoS ONE  2013;8(6):e66592.
Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants.
To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients.
303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA).
Findings and conclusions
In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, –521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the –521 C/T (rs1800955) polymorphism in the promoter.
PMCID: PMC3696122  PMID: 23840506
9.  Mood and smoking behavior: The role of expectancy accessibility and gender 
Addictive behaviors  2012;37(12):1349-1352.
Little is known about overall or gender-specific factors that may influence the relationship between negative affect and smoking behavior such as smoking expectancies. This paper presents a secondary analysis from a laboratory studying gender differences in smoking behavior following a musical mood induction [Weinberger, A.H., & McKee, S.A., 2012, Gender differences in smoking following an implicit mood induction. Nicotine & Tobacco Research, 14(5), 621–625]. The current analyses examine the role of expectancies (endorsement and accessibility) in the relationship of gender, affect, and smoking. Ninety adult smokers (50% female) were randomly assigned to a negative mood induction, positive mood induction, or neutral condition while completing a single laboratory session. Expectancy endorsement, expectancy accessibility, affect, and smoking topography were assessed following the mood induction. Female smokers with faster accessibility of negative reinforcement expectancies smoked more cigarettes, had longer puff durations, and had shorter inter-puff intervals. Women with faster expectancy accessibility were also more likely to endorse negative reinforcement smoking expectancies. This study was the first to demonstrate links among gender, mood, and accessibility of smoking-related beliefs. Information about the role of expectancy accessibility in smoking behavior can lead to both a better understanding of gender-specific mechanisms of smoking behavior and new directions for smoking treatment development.
PMCID: PMC3440619  PMID: 22958868
expectancies; accessibility; smoking; negative affect; gender
10.  ‘Smoking Genes’: A Genetic Association Study 
PLoS ONE  2011;6(10):e26668.
Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence) with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A) [rs1801272], CYP2A6*9 (−48T>G) [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T) [rs8192789], CYP2A13*3 (7520C>G), CYP2A13*4 (579G>A), CYP2A13*7 (578C>T) [rs72552266], CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A) [rs1800497], 5HTT LPR, HTR2A −1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126) and ethnically matched never smokers (controls, N = 80). The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both P<0.001). Compared with carriers of variant alleles, the odds ratio (OR) for being a non-smoker in individuals with the wild-type genotype of CYP2A6*12 and DRD2-ANKK1 2137G>A (Taq1A) polymorphisms was 3.60 (95%CI: 1.75, 7.44) and 2.63 (95%CI: 1.41, 4.89) respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65). We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms) are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1).
PMCID: PMC3202555  PMID: 22046326
11.  The impact of genetic variation in DRD2 and SLC6A3 on smoking cessation in cohort of participants one year after enrollment in a lung cancer screening study 
Smoking cessation strategies continue to have disappointing results. By determining the interindividual genetic differences that influence smoking behaviors, we may be able to develop tailored strategies that increase the likelihood of successful cessation. This study attempts to determine genetic influences on the relationship between the dopamine pathway and smoking cessation by examining associations with a variable number tandem repeat variation in SLC6A3 and the DRD2 variants TaqIA (A2 vs. A1), TaqIB (B2 vs. B1), C957T (C vs. T), and -141C Ins/Del (C vs. Del). Baseline smokers in the Pittsburgh Lung Screening Study who provided information on smoking status one year later were evaluated. We frequency-matched those who were not abstinent at one year to those who were abstinent at one year by gender, decade of age, and time of enrollment (three month intervals) in a three to one ratio (N=881). Logistic regression was used to identify the effect of genotype on abstinence at one year. In a model containing the matching variables and other genotypes, DRD2 TaqIA was significantly associated with being abstinent at one year (p=0.01). Compared to participants who were homozygous TaqIA major allele (A2A2), participants who carried at least one minor allele (A1) were less likely to quit (Odds Ratio: 0.47, 95% CI: 0.24–0.94). The other dopamine receptor genotypes and the SLC6A3 genotype were not associated with smoking status at one-year. The association between DRD2 TaqIA and smoking cessation supports the hypothesis that genetic variation in the dopamine pathway influences smoking cessation.
PMCID: PMC2730224  PMID: 18563706
tobacco use cessation; genotype; case-control study; dopamine
12.  Sex, ADHD symptoms, and smoking outcomes: An integrative model 
Medical Hypotheses  2012;78(5):585-593.
Both females and individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) have been found to be at increased risk for a range of smoking outcomes, and recent empirical findings have suggested that women with ADHD may be particularly vulnerable to nicotine dependence. On a neurobiological level, the dopamine reward processing system may be implicated in the potentially unique interaction of nicotine with sex and with ADHD status. Specifically, nicotine appears to mitigate core ADHD symptoms through interaction with the dopamine reward processing system, and ovarian hormones have been found to interact with nicotine within the dopamine reward processing system to affect neurotransmitter release and functioning.
This article synthesizes data from research examining smoking in women and in individuals with ADHD to build an integrative model through which unique risk for cigarette smoking in women with ADHD can be systematically explored. Based upon this model, the following hypotheses are proposed at the intersection of each of the three variables of sex, ADHD, and smoking: 1) Individuals with ADHD have altered functioning of the dopamine reward system, which diminishes their ability to efficiently form conditioned associations based on environmental contingencies; these deficits are partially ameliorated by nicotine; 2) Nicotine interacts with estrogen and the dopamine reward system to increase the positive and negative reinforcement value of smoking in female smokers; 3) In adult females with ADHD, ovarian hormones interact with the dopamine reward system to exacerbate ADHD-related deficits in the capacity to form conditioned associations; and 4) During different phases of the menstrual cycle, nicotine and ovarian hormones may interact differentially with the dopamine reward processing system to affect the type and value of reinforcement smoking provides for women with ADHD.
Understanding the bio-behavioral mechanisms underlying cigarette addiction in specific populations will be critical to developing effectively tailored smoking prevention and cessation programs for these groups. Overall, the goal of this paper is to examine the interaction of sex, smoking, and ADHD status within the context of the dopamine reward processing system not only to elucidate potential mechanisms specific to female smokers with ADHD, but also to stimulate consideration of how the examination of such individual differences can inform our understanding of smoking more broadly.
PMCID: PMC3321070  PMID: 22341778
13.  Waterpipe Smoking And The DRD2/ANKK1 Genotype 
Waterpipe smoking is increasingly a worldwide phenomenpn. Few studies have been conducted on the epidemiology of waterpipe smoking behavior and its genetic determinants. A polymorphism (TaqI) in the 3′ untranslated region of the dopamine receptor gene (DRD2), later localized to the neighboring ANKK1 gene, has been previously linked to cigarette smoking. Since all tobacco products' share the ability of stimulating the dopaminergic reward system, variation in the DRD2 genotype might be associated with waterpipe smoking addiction.
This study aims to explore genetic variations in DRD2 gene and waterpipe smoking, motives and addiction in Egyptian rural males.
Material and Methods
The subjects (N=154) were selected from participants in a household smoking prevalence survey if they were adults, males, currently smoking waterpipe and not smoking cigarettes. Participants were interviewed about their smoking behaviors. Blood samples were genotyped by polymerase chain reaction (PCR). Subjects were subsequently classified as either the A1 (presence of at least one A1 allele) or A2 group (A2 homozygotes).
The prevalence of Al genotype was 34.4 % in current waterpipe users, and was associated with the maximum duration before smokers experienced craving to smoke: after adjusting for age of smoking initiation, smoking for addictive motives, and average daily tobacco consumption, the A1 carriers were more likely to experience craving within a shorter duration after abstinence (the first 24 hours) compared to subjects with A2/A2 genotype (Odds ratio [OR] 2.70, 95% confidence interval [CI]: 1.18 – 6.23). In addition, the frequent visitors of shisha cafes were more likely to be younger, heavy smokers and carriers of A1 allele (OR, 2.52, 95% CI: 1.06-6.02).
Conclusion and Recommendations
This study revealed that the maximum duration before experiencing craving to smoke waterpipe and frequency of visiting cafes to smoke may be influenced by an inherited variations in the DRD2 genotype.
PMCID: PMC3622212  PMID: 21244814
DRD2 gene; genetic; smoking; tobacco addiction; waterpipe
14.  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
15.  Ventral Striatal Dopamine Release in Response to Smoking a Regular vs a Denicotinized Cigarette 
Prior studies have demonstrated that both nicotine administration and cigarette smoking lead to dopamine (DA) release in the ventral striatum/nucleus accumbens. In tobacco-dependent individuals, smoking denicotinized cigarettes leads to reduced craving, but less pleasure, than smoking regular cigarettes. Using denicotinized cigarettes and 11C-raclopride positron emission tomography (PET) scanning, we sought to determine if nicotine is necessary for smoking-induced DA release. Sixty-two tobacco-dependent smokers underwent 11C-raclopride PET scanning, during which they smoked either a regular or denicotinized cigarette (double-blind). Change in 11C-raclopride binding potential (BP) in the ventral striatum from before to after smoking was determined as an indirect measure of DA release. Cigarette craving, anxiety, and mood were monitored during scanning. Smoking a regular cigarette resulted in a significantly greater mean reduction in ventral striatal 11C-raclopride BP than smoking a denicotinized cigarette. Although both groups had reductions in craving and anxiety with smoking, the regular cigarette group had a greater improvement in mood. For the total group, change in BP correlated inversely with change in mood, indicating that greater smoking-induced DA release was associated with more smoking-related mood improvement. Thus, nicotine delivered through cigarette smoking appears to be important for ventral striatal DA release. Study findings also suggest that mood improvement from smoking is specifically related to ventral striatal DA release.
PMCID: PMC2777990  PMID: 18563061
dopamine; nicotine; tobacco; ventral striatum; positron emission tomography; 11C-raclopride
16.  The CHRNA3 rs578776 Variant is Associated with an Intrinsic Reward Sensitivity Deficit in Smokers 
A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS−) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS− group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS− group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.
PMCID: PMC3779859  PMID: 24065931
nAChR; DRD2; nicotine; reward sensitivity; ERP; LPP; smoking cessation; genetics
17.  Dopamine DRD2 polymorphism alters reversal learning and associated neural activity 
In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIa polymorphism is associated with reduced expression of dopamine (DA) D2 receptors in the striatum. Recently, it was observed that carriers of the A1 allele (A1+ subjects) showed impaired learning from negative feedback in a reinforcement learning task. Here, using functional MRI, we investigated carriers and non-carriers of the A1 allele while they performed a probabilistic reversal learning task. A1+ subjects showed subtle deficits in reversal learning. In particular, these deficits consisted of an impairment in sustaining the newly rewarded response after a reversal and in a generally decreased tendency to stick with a rewarded response. Both genetic groups showed increased fMRI signal in response to negative feedback in the rostral cingulate zone (RCZ) and anterior insula. Negative feedback that incurred a change in behavior additionally engaged the ventral striatum and a region of the midbrain consistent with the location of dopaminergic cell groups. The response of the RCZ to negative feedback increased as a function of preceding negative feedback. However, this graded response was not observed in the A1+ group. Furthermore, the A1+ group also showed diminished recruitment of the right ventral striatum and the right lateral orbitofrontal cortex (lOFC) upon reversals. Taken together, these results suggest that a genetically driven reduction in DA D2 receptors leads to deficient feedback integration in RCZ. This in turn was accompanied by impaired recruitment of the ventral striatum and the right lOFC upon reversals, which might explain the behavioral differences between the genetic groups.
PMCID: PMC2694507  PMID: 19321766
fMRI; reversal learning; dopamine; DRD2/ANKK1-TaqIa polymorphism; ACC; ventral striatum
18.  Behavioral phenotypes of impulsivity related to the ANKK1 gene are independent of an acute stressor 
The A1 allele of the ANKK1 TaqIA polymorphism (previously reported as located in the D2 dopamine receptor (DRD2) gene) is associated with reduced DRD2 density in the striatum and with clinical disorders, particularly addiction. It was hypothesized that impulsivity represents an endophenotype underlying these associations with the TaqIA and that environmental stress would moderate the strength of the gene-behavior relationship.
TaqIA genotyping was conducted on 72 healthy young adults who were randomly allocated to either an acute psychosocial stress or relaxation induction condition. Behavioral phenotypes of impulsivity were measured using a card-sorting index of reinforcement sensitivity and computerized response inhibition and delay discounting tasks.
Separate analyses of variance revealed associations between the A1 allele and two laboratory measures of impulsivity. The presence of the TaqIA allele (A1+) was associated with slower card-sorting in the presence of small financial reinforcers, but was overcome in a second administration after either a five-minute rest or psychosocial stress induction. A1+ participants also demonstrated significantly poorer response inhibition and faster response times on a computerized stop inhibition task, independent of acute stress exposure.
These findings indicate the A1 allele is associated with an endophenotype comprising both a "rash impulsive" behavioral style and reinforcement-related learning deficits. These effects are independent of stress.
PMCID: PMC2607297  PMID: 19025655
19.  Genetic polymorphism of dopamine D2 receptors in Parkinson's disease and interactions with cigarette smoking and MAO-B intron 13 polymorphism 
Genetic polymorphisms of dopamine D2 receptors (DRD2) may be susceptibility factors for Parkinson's disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinson's disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinson's disease were investigated and tested for interactive effects with smoking and the monoamine oxidase B (MAO-B) intron 13 polymorphism previously found to be related to smoking. Study subjects were 152 cases of idiopathic Parkinson's disease and 231 controls. The smoking history of all genotyped subjects was known. Subjects of genotype B12 were more frequent among cases than controls (27% and 23.8%, respectively), and were more frequent among "ever smokers" than "never smokers", among controls (27.8% and 17.2%, respectively), although these associations were not statistically significant. Neither TaqIA or TaqIB genotypes modified the inverse relation of smoking and Parkinson's disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinson's disease were found; although the MAO-B/DRD2 interaction did not reach statistical significance after Bonferroni correction for multiple comparisons, these results are suggestive of a possible synergism between MAOB and DRD2 genes with respect to Parkinson's disease.

PMCID: PMC1737136  PMID: 10990520
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
Psychopharmacology  2010;210(1):1-12.
We assessed the reinforcing effects of nicotine and non-nicotine components of cigarette smoke, by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized (“denic”) cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component. Sixteen smokers participated in 7 sessions, consisting of: 1) a baseline smoking assessment, which was used to tailor the nicotine dose per infusion to that of puffs from subjects’ preferred brands of cigarettes; 2) two sessions in which participants were trained to discriminate IV nicotine vs. saline infusions and denic smoke vs. sham (air) puffs; and 3) four sessions assessing choice behavior after different satiation conditions. Results showed that subjects self-administered more puffs of denic smoke than any other alternative, including IV nicotine. IV nicotine, however, was preferred over IV saline and sham puffs. Preference for denic smoke vs. IV nicotine was highly correlated with subjective ratings of “comfort” associated with the two alternatives. Satiation with smoke diminished the number of denic puffs taken during choice periods, while prior administration of nicotine did not affect the number of puffs taken. Smoking withdrawal symptoms were alleviated both by nicotine administration and by denic smoke. These results show that in established smokers, non-nicotine aspects of cigarette smoking have potent reinforcing effects. While current smoking cessation pharmacotherapies primarily address the nicotine component of cigarette addiction, future cessation strategies should also be designed to target non-nicotine factors.
PMCID: PMC4154143  PMID: 20358364
nicotine; addiction; reinforcement; self-administration
22.  Mood, nicotine, and dose expectancy effects on acute responses to nicotine spray 
Nicotine & Tobacco Research  2009;11(5):540-546.
We recently showed effects of nicotine dose and nicotine expectancy on some responses to cigarette smoking, with generally no influence of induced mood on these effects. The present study extended this line of research to Nicotrol nasal spray, to determine whether formulation (spray vs. smoking) alters responses.
Smokers abstained overnight before each of two virtually identical sessions, involving negative or positive mood induction. They were randomized to one of five groups, four comprising the 2 × 2 balanced placebo design, varying actual and expected dose of nicotine in the nasal spray, and the fifth group a no-spray control. Dependent measures included self-reported affect, craving, withdrawal, and spray ratings of “liking” and “how much nicotine.” Analyses were limited to those whose nicotine expectancies were manipulated successfully (N = 48).
The following results matched those from our smoking study: expecting nicotine increased liking; expected, but not actual, nicotine dose increased dose perception; neither actual nor expected nicotine dose had much influence on affect or withdrawal; and mood had no influence on these effects. However, both actual and expected nicotine dose decreased craving in response to spray, contrary to our prior study with smoking.
Formulation made little difference in some effects of nicotine and expectancies, but other effects differed by formulation. Some of these findings, particularly for craving reduction, may have implications for enhancing the acute therapeutic effects of nasal spray and, perhaps, other medications in smokers trying to maintain abstinence after quitting.
PMCID: PMC2671464  PMID: 19351782
23.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
To evaluate associations of treatment and an ‘additive genetic efficacy score’ (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled in two randomized clinical trials of smoking cessation therapies.
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (HR = 1.29, 95%CI 1.17–1.41, p=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
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
25.  Cognitive Reappraisal and Expressive Suppression Emotion Regulation Strategies in Cigarette Smokers 
Nicotine & Tobacco Research  2010;12(11):1156-1161.
Negative affect is an important psychological factor in the promotion and maintenance of cigarette smoking, though the underlying factors that account for this relationship remain to be determined. One possible mechanism may be smokers’ emotion regulation strategies. Preliminary research among adolescents and young adults suggests that greater utilization of expressive suppression versus cognitive reappraisal is associated with higher rates of smoking initiation. There is limited research, however, on the role of emotion regulation strategies in smoking maintenance in adult smokers.
Data from participants in a laboratory study (N = 121) were used to examine whether utilization of cognitive reappraisal and/or expressive suppression were related to smoking characteristics and subjective (i.e., mood, urge to smoke ratings) and behavioral reactions (i.e., Emotional Stroop Task performance, smoking behavior) to a mood induction procedure. Data were evaluated for the full sample and subsample who endorsed current depressive symptoms (n = 46).
Frequent reappraisal was associated with weaker expectancies that smoking alleviates unpleasant feelings, greater positive mood, and fewer depressive symptoms. In contrast, frequent suppression was related to longer smoking history and greater attentional bias to smoking cues on an Emotional Stroop Task. Among the depressed subsample, reappraisal moderated the effect of mood condition on smoking duration, number of cigarette puffs, and carbon monoxide boost.
These results provide preliminary support that emotion regulation strategies may be associated with motivational correlates of smoking as well as actual smoking behavior among depressed smokers.
PMCID: PMC2964920  PMID: 20829326

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