Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward

Abstract

Rationale: 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).

Objective: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Figure 1

Linkage disequilibrium plot of the included DRD4 SNPs and Variable Number Tandem Repeat (rs1805186).

Figure 2

Average modified Cigarette Evaluation Questionnaire scores as a function of nicotine content for long allele carriers vs. short homozygotes. The genotype X nicotine content X cigarette bout interaction was significant, F(2, 299) = 4.18, p = .011 with an indication of a linear contrast, F(1, 94) = 6.80, p = .011. Comparisons between nicotine and placebo indicated by * p < .05, ** p < .01, and *** p < .001.

Figure 3

Average modified Cigarette Evaluation Questionnaire scores as a function of nicotine content for major homozygotes vs. minor allele carriers at Single Nucleotide Polymorphisms rs936460, rs936461, and rs12280580. The genotype X nicotine content interactions were significant: rs936460, F(1, 78) = 5.64, p = .020, rs936461, F(1, 78) = 7.71, p = .007, and rs12280580, F(1, 77) = 11.02, p = .001. Comparisons between nicotine and placebo indicated by *** p < .001.