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Randomized Controlled Trial
. 2014 Jul;16(7):939-47.
doi: 10.1093/ntr/ntu010. Epub 2014 Mar 22.

Effects of nicotine deprivation and replacement on BOLD-fMRI response to smoking cues as a function of DRD4 VNTR genotype

Xiaomeng Xu  1 , Uraina S Clark  2 , Sean P David  3 , Richard C Mulligan  4 , Valerie S Knopik  5 , John McGeary  6 , James MacKillop  7 , Jeanne McCaffery  8 , Raymond S Niaura  9 , Lawrence H Sweet  10
Affiliations
Randomized Controlled Trial

Effects of nicotine deprivation and replacement on BOLD-fMRI response to smoking cues as a function of DRD4 VNTR genotype

Xiaomeng Xu et al. Nicotine Tob Res. 2014 Jul.

Abstract

Introduction: Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms.

Methods: Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥ 1 copy of ≥ 7 repeats] or short [S: 2 copies ≤ 6 repeats] genotype) of 6 a priori regions of interest.

Results: Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch.

Conclusions: Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.

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Figures

Figure 1.
Figure 1.
Main effect of patch (across all participants) in right and left ventral striatum (VS) and left amygdala (Amyg).
Figure 2.
Figure 2.
Patch × genotype interaction in left amygdala (increased left amygdala activation represents increased cue reactivity).
See this image and copyright information in PMC

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