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Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward.

ABSTRACT: Cigarette smoking is influenced by nicotine’s effects on dopaminergic activity in the mesocorticolimbic pathway. This activity appears to be moderated by genetic variation, specifically a variable number tandem repeat (VNTR) polymorphism in the third exon of the dopamine receptor gene (DRD4).We examined whether this polymorphism along with three DRD4 single-nucleotide polymorphisms (SNPs: rs936460, rs936461, and rs12280580) moderate the influence of nicotine on subjective responses to cigarettes.White, non-Hispanic smokers (n?=?96, cigarettes/day ?15) attended two double-blind, counterbalanced experimental sessions, each preceded by overnight smoking abstinence. Participants smoked four nicotine (8.9 mg) or placebo (1.0 mg) cigarettes per session, with each cigarette followed by completion of the modified Cigarette Evaluation Questionnaire (mCEQ).We examined the mCEQ composite score via 2?×?2?×?4 ANOVAs with genotype (major homozygotes versus minor carriers) as the between-subject factor and nicotine content and smoking bout as within-subject factors. Although DRD4 VNTR variation did not moderate overall nicotine response, there was a moderation of nicotine response over successive cigarettes. Smokers with fewer than seven repeats for the DRD4 VNTR reported markedly reduced craving, increased satisfaction, and a greater calming effect in response to earlier smoked nicotine cigarettes, whereas those with seven or more repeats did not. In addition, minor carriers for all three DRD4 SNPs displayed blunted overall response to nicotine.These findings provide support for DRD4 variation as an informative predictor of subjective responses to nicotine. We discuss how these data may lead to improved tailoring of smoking cessation pharmacotherapies.

SUBMITTER: Harrell PT

PROVIDER: S-EPMC5808950 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward.

Harrell Paul T PT Lin Hui-Yi HY Park Jong Y JY Blank Melissa D MD Drobes David J DJ Evans David E DE

Psychopharmacology 20160101 2

<h4>Rationale</h4>Cigarette smoking is influenced by nicotine’s effects on dopaminergic activity in the mesocorticolimbic pathway. This activity appears to be moderated by genetic variation, specifically a variable number tandem repeat (VNTR) polymorphism in the third exon of the dopamine receptor gene (DRD4).<h4>Objective</h4>We examined whether this polymorphism along with three DRD4 single-nucleotide polymorphisms (SNPs: rs936460, rs936461, and rs12280580) moderate the influence of nicotine o ...[more]

PMID: 26497691

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Project description:BackgroundIdentifying e-cigarette product characteristics that moderate the effects of non-tobacco flavors and nicotine on user appeal can inform regulations issued in tandem with e-cigarette nicotine and flavor policies aimed to protect young adult health. An e-cigarette device's electrical power affects the amount of solution aerosolized per puff, leading to more concentrated or diluted aerosol, which may alter product appeal. This laboratory experiment tested whether e-cigarette device power moderated the independent and interactive effects of non-tobacco flavors and nicotine on appeal in young adults.MethodIn a within-subject design single-visit protocol, young adult e-cigarette users (N = 100) administered standardized doses of e-cigarette solutions varying in flavor (fruit, menthol, tobacco) and nicotine (nicotine-containing [6 mg/mL], nicotine-free). Solutions were administered via a variable-voltage tank-style device at low (7.3 W[3.3 V@1.5 Ω resistance]) and high (12.3 W[4.3 V@1.5 Ω resistance]) power settings. Participants rated each dose's appeal (0-100 scale).ResultsThe high (vs. low) power setting attenuated the appeal-enhancing effects of menthol (vs. tobacco) flavors (Menthol × Power, estimate = -5.44, P = .03). Power did not moderate the appeal-enhancing effects of fruit flavors. High (vs. low) power amplified the appeal-reducing effects of nicotine-containing (vs. nicotine-free) solutions (Nicotine × Power, estimate = 6.69, P < .001) and augmented the extent to which fruit and menthol flavors suppressed nicotine's appeal-reducing effects (Flavor × Nicotine × Power, estimates = 9.40-14.85, Ps≤0.03).ConclusionE-cigarette device power appears to moderate flavor- and nicotine-induced changes in product appeal in nuanced ways, including by augmenting the ability of non-tobacco flavors to mask nicotine's appeal-reducing effects. Regulatory restrictions on high-powered e-cigarette devices warrant consideration in efforts to protect young adult health.

Project description:Exposure to social stress is a well-established risk factor for the development and recurrence of depression. Reduced neural responsiveness to monetary reward has been associated with greater symptoms following stress exposure. However, it remains unclear whether reduced reward responsiveness serves as a mediator or moderator of the effects of stress on internalizing symptoms or whether similar patterns emerge with responses to social reward. We addressed this issue by measuring lifetime stress exposure and event-related potentials (ERPs) to social reward in 231 emerging adults (M = 18.16, SD = 0.41 years old). Participants completed the Stress and Adversity Inventory (STRAIN) to assess severity of lifetime stressors and self-report measures of current internalizing symptoms. In addition, participants completed the Island Getaway task in which the reward positivity (RewP) ERP was recorded in response to social acceptance, adjusting for responses to rejection (RewP residual). In this task, participants vote to accept or reject peers and receive reward/acceptance and rejection feedback. Stressors were divided into social and non-social stress severity scores. Analyses were conducted to test social reward responsiveness as a mediator or moderator of the effects of social and non-social stress on internalizing symptoms. Both social and non-social stress exposure over the life course predicted symptoms of depression (ps < 0.001) and social anxiety (ps < 0.002). The effect of social stress on depression was moderated by the residual RewP to social reward, adjusting for responses to social rejection (p =0.024), such that greater lifetime social stress exposure and a relatively blunted RewP to social reward were associated with greater depressive symptoms. Social reward responsiveness did not mediate effects of stress on internalizing symptoms. Reduced processing of social reward may be a vulnerability for depression that increases risk for symptoms following exposure to social stress. Blunted social reward responsiveness appears to be a relatively unique vulnerability for depression, rather than social anxiety. Results support the utility of ERP measures in measuring individual differences in social reward processing that can be applied to better understand neural processes involved in the development of depression, and highlight the importance of considering specific dimensions of stressful life experiences.

Project description:BackgroundWhile the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.MethodsIn a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).ResultsThe pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.ConclusionsBecause the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).ImpactDopaminergic pathways may be salient during early smoking and the development of ND.

Project description:Technological advances have led to the discovery of genetic variants that contribute to many illnesses including nicotine dependence. A multi-stage model of the development of nicotine dependence underlies these genetic studies, and it includes a progression through several stages of smoking behavior from never smoking to nicotine dependence. The final step in this model of dependence is the progression from established smoking behavior to the development of nicotine dependence. Contrasting individuals who smoke only a few cigarettes per day, or "chippers", to heavy smoking, nicotine dependent subjects, focuses a genetic study on the transition from smoking to nicotine dependence. This approach has identified distinct genetic variants that contribute to nicotine dependence on chromosome 15 in the region of the alpha5-alpha3-beta4 family of nicotinic receptor genes. This region of association includes an amino acid change in the alpha5 nicotinic receptor protein, which is most likely a biological variant altering the risk of developing dependence. There is also evidence that other variants alter alpha5 nicotinic receptor gene expression and potentially the risk of smoking. The discovery of these genetic variants and their contribution to the development of nicotine dependence highlight some of the many challenges in genetic studies. The first is that the prevalence of risk alleles can vary across populations so that a genetic risk factor can have a larger or small effect in a population depending on its frequency. The second challenge is that the risk that each genetic variant contributes in the development of a disorder is small and so it is many genes along with environmental risk factors that contribute to the development of a disorder. Interestingly, recent genetic studies of lung cancer and chronic obstructive pulmonary disease demonstrate that this same region has an important genetic influence on these disorders. Finally, there are differences in the risk of developing nicotine dependence based on gender and socioeconomic status. As our understanding of the genetic contributions of nicotine dependence increases, we may improve and personalize our treatments for smoking cessation and enhance our knowledge of other smoking related diseases in those who are at high risk for the many adverse consequences of smoking.

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Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward.

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Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward.

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