Genetic and Depressive Traits Moderate the Reward-Enhancing Effects of Acute Nicotine in Young Light Smokers

Abstract

Introduction: Rates of light smoking have increased in recent years and are associated with adverse health outcomes. Reducing light smoking is a challenge because it is unclear why some but not others, progress to heavier smoking. Nicotine has profound effects on brain reward systems and individual differences in nicotine's reward-enhancing effects may drive variability in smoking trajectories. Therefore, we examined whether a genetic risk factor and personality traits known to moderate reward processing, also moderate the reward-enhancing effects of nicotine.

Methods: Light smokers (n = 116) performed a Probabilistic Reward Task to assess reward responsiveness after receiving nicotine or placebo (order counterbalanced). Individuals were classified as nicotine dependence 'risk' allele carriers (rs16969968 A-allele carriers) or non-carriers (non-A-allele carriers), and self-reported negative affective traits were also measured.

Results: Across the sample, reward responsiveness was greater following nicotine compared to placebo (p = 0.045). For Caucasian A-allele carriers but not non-A-allele carriers, nicotine enhanced reward responsiveness compared to placebo for those who received placebo first (p = 0.010). Furthermore, for A-allele carriers but not non-A-allele carriers who received nicotine first, the enhanced reward responsiveness in the nicotine condition carried over to the placebo condition (p < 0.001). Depressive traits also moderated the reward-enhancing effects of nicotine (p = 0.010) and were associated with blunted reward responsiveness following placebo but enhanced reward responsiveness following nicotine.

Conclusion: These findings suggest that individual differences in a genetic risk factor and depressive traits alter nicotine's effect on reward responsiveness in light smokers and may be important factors underpinning variability in smoking trajectories in this growing population.

Implications: Individuals carrying genetic risk factors associated with nicotine dependence(rs16969968 A-allele carriers) and those with higher levels of depressive personality traits, showmore pronounced increases in reward learning following acute nicotine exposure. These findingssuggest that genetic and personality factors may drive individual differences in smoking trajectoriesin young light smokers by altering the degree to which nicotine enhances reward processing.

Clinical trial registration: NCT02129387 (pre-registered hypothesis: www.clinicaltrials.gov).

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Results showed a main effect of Drug (A), where averaged across blocks and order, response bias was significantly higher in the nicotine relative to the placebo condition. There was also a trend-level Drug x Order interaction (B), which was driven by higher response bias in the nicotine relative to the placebo condition in those who received the placebo first, but not in those who received nicotine first. Furthermore, response bias in the placebo condition was higher for those who received nicotine first relative to those who received the placebo first. *p < 0.05.

Figure 2.

Figure shows the significant SNP × Drug × Order interaction in the Caucasian subset of the sample. The Drug x Order interaction was significant in the A-allele carriers (left) but not in the non-A-allele carriers (right). Within the A-allele carriers, there was a significant increase in response bias in the nicotine relative to the placebo condition, but only for individuals who received the nicotine condition first. Furthermore, response bias in the placebo condition was higher for those who received nicotine first compared to those who received the placebo first. These findings suggest Caucasian young light smokers at increased genetic risk for nicotine dependence show greater increases in response bias following nicotine relative to a placebo and also show a greater propensity for prior nicotine exposure to influence reward processing following a placebo. *p < 0.05. SNP, single-nucleotide polymorphism.

Figure 3.

Figure shows the moderating effect of depressive traits (A) and nicotine dependence severity (B) on changes in response bias following nicotine relative to a placebo. For visualization purposes, predicted response bias for individuals with depressive trait scores and nicotine dependence scores at the mean (“Mean”), 1 SD above the mean (“High”) and 1 SD below the mean (“Low”) are plotted. The reward-enhancing effects of nicotine were stronger in young light smokers scoring higher on depressive personality traits and also in those reporting a greater sense of being “hooked” on nicotine.