Differential neural response to alcohol priming and alcohol taste cues is associated with DRD4 VNTR and OPRM1 genotypes

Abstract

Background: Studies suggest that polymorphisms in the D4 dopamine receptor (DRD4) and opioid receptor, mu 1 (OPRM1) genes are involved in differential response to the effects of alcohol and to alcohol cues. However, to date, the mechanisms that underlie these differences remain largely unknown.

Methods: Using functional magnetic resonance imaging, hemodynamic response in mesocorticolimbic structures after exposure to alcohol tastes was contrasted with a control taste and compared between DRD4 variable number of tandem repeats (VNTR) genotypes and OPRM1 A118G genotypes. Additionally, the effects of a priming dose of alcohol on this response were examined.

Results: The results indicated that DRD4 VNTR >7 repeat individuals (DRD4.L) had significantly greater response to alcohol cues in the orbitofrontal cortex, anterior cingulate gyrus, and striatum compared with individuals with <7 repeats (DRD4.S) prior to a priming dose of alcohol (p < 0.05), but not after a priming dose. In the OPRM1 comparisons, results showed that individuals with at least 1 copy of the OPRM1 + 118 G allele had greater hemodynamic response in mesocorticolimbic areas both before and after priming compared with those who were homozygous for the OPRM1 + 118 A allele. For the DRD4.L and OPRM1 + 118 G groups, brain response in the striatum was highly correlated with measures of alcohol use and behavior such that greater activity corresponded with greater frequency and quantity of alcohol use.

Conclusions: The DRD4 VNTR and OPRM1 A118G polymorphisms are associated with functional neural changes in mesocorticolimbic structures after exposure to alcohol cues. This provides evidence for the contributions of the DRD4 and OPRM1 genes in modulating neural activity in structures that are involved in the motivation to drink.

Figures

Fig. 1

Schematic of a single taste cue trial. A single trial consisted of a continuous delivery of either alcohol or litchi juice presented for 24 seconds at the beginning of each trial (interspersed with 2 visual prompts to allow subjects to swallow). The total amount of liquid delivered during this period was 1 ml. The taste delivery was followed by a 16-second washout period. This was followed by an urge question presented on the screen for 2 seconds to which the subjects were asked to rate their current subjective urge to drink alcohol (“Please rate your urge to drink alcohol right now?”) using a scale of 1 (no urge at all) to 4 (very high urge) using a button box. Each trial ended with a 2-second “Ready” prompt screen. The active and baseline regressors are also indicated. Because tastes were not detected until mid-way through the 1 ml stimulus delivery (typically after the first swallow prompt) and took longer to dissipate, we modeled the active period to encompass the period between the initial swallow and the end of the washout period.

Fig. 2

Schematic of the fMRI protocol. During the fMRI session, subjects underwent 2 sets of scanning. The first set of scans (“predrink scans”) were without alcohol priming and consisted of anatomical scans and a counterbalanced order of 2 fMRI runs. These scans were followed by a break from scanning (“priming”), where subjects were taken out of the magnet and allowed to stretch while consuming a priming dose of alcohol within 10 minutes followed by another 10 minutes to allow absorption. Subjects were then breathalyzed and their BACs recorded. They were immediately placed back into the scanner for the second set of scans (“postdrink scans”), which was identical to the first set.

Fig. 3

Greater activity in the DRD4.L subjects compared with control subjects. The DRD4.L subjects had significantly greater BOLD response compared with the controls in response to alcohol taste cues in the all areas before priming. After priming, the DRD4.L subjects did not have increased response in the ROIs compared with the controls (p < 0.05). The right side of the image reflects right-hemispheric activation. The colorscale represents z-scores.

Fig. 4

Greater activity in the OPRM.G subjects compared with controls. The OPRM1.G subjects had significantly greater BOLD response compared with the controls in response to alcohol taste cues in the ventral striatum, ventromedial PFC, and OFC before the priming dose of alcohol (p < 0.05). After the priming dose, striatal, ventromedial PFC, and OFC areas had greater response in the OPRM1.G group compared with the control group (p < 0.05). The right side of the image reflects left-hemispheric activation. The colorscale represents z-scores.