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


CONCLUSIONS
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.
Paul T
PT
Harrell
Hui-Yi
HY
Lin
Jong Y
JY
Park
Melissa D
MD
Blank
David J
DJ
Drobes
David E
DE
Evans
D000293:Adolescent; D000328:Adult; D000368:Aged; D004298:Dopamine / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D009538:Nicotine / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012201:Reward; D012907:Smoking / Q000235:genetics* / Q000523:psychology*; D016540:Smoking Cessation / Q000523:psychology; D062789:Tobacco Products; D055815:Young Adult
C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4; D009538:Nicotine; D004298:Dopamine