A polymorphism in GABRA2 is associated with the medial frontal response to alcohol cues in an fMRI study

Abstract

Background: Significant evidence has accumulated to suggest an association between single-nucleotide polymorphisms (SNPs) in the GABRA2 gene and alcoholism. However, research has yet to show an association between these polymorphisms and the human brain's reward system function. In this study, we stratified subjects who had participated in an fMRI study of alcohol cue responses according to their genotype at a SNP in GABRA2 (rs279871) shown to be associated with alcohol dependence (Edenberg et al., 2004).

Methods: Genotyping showed 13 subjects to be homozygous for the high-risk allele (AA), and 23 subjects to be heterozygous (AG). In fMRI, subjects were exposed to the aromas of their preferred alcoholic drink odors (AO), as well as to appetitive control odors (ApCO) under both alcohol intoxication and placebo control conditions.

Results: Homozygous AA subjects had a larger [AO > ApCO] response than did AG subjects in medial frontal cortical areas thought to code reward value. However, AG subjects had a larger [AO > ApCO] effect in the ventral tegmental area. Alcohol intoxication did not alter these group differences.

Conclusions: These are the first data to suggest that GABRA2 genotype could affect the brain's responses to cues associated with alcohol.

Figure 1. Subjective responses to alcohol

Perceived ‘High’ and ‘Intoxication’ during alcohol infusion in fMRI using a modified SHAS scale. Baseline= before the infusion pumps are started; 1= at targeted breath alcohol; 2, 3= between each of the three BOLD scans; 4=following the third (last) BOLD scans. *Significant main effect of genotype (p< 0.05).

Figure 2. Craving

Desire to drink (craving) at baseline (prior to any stimulus exposure) and following combined odor and picture presentation outside the scanner room and just prior to imaging (see text for abbreviations). *Significantly different from baseline (p< 0.001).

Figure 3. Medial Prefrontal Activation [AO > ApCO] Effects

All effects shown are collapsed across alcohol and placebo. A. Location of peak effects as obtained in an SPM factorial model of the [alcohol odor (AO) > appetitive odor control (ApCO)] effect (display threshold, p < 0.005, extent threshold = 25 voxels) and their overlap with the a priori regions of interest (blue= mPFC, green= vmPFC). B. Peak locations for significant group (AA > AG) effects of the [AO > ApCO] BOLD contrast (top= peak voxel effects; bottom= nature of interaction within ROIs). Display threshold as in panel A. mPFC= medial prefrontal cortex; vmPFC= ventromedial prefrontal cortex; x= lateral coordinate in stereotactic space; BOLD=blood oxygen level dependent.

Figure 4. VTA Activation [AO > ApCO] Effects

Peak ventral tegmental area (VTA; green dashed circle) location of the [alcohol odor (AO) > appetitive odor control (ApCO)] response (collapsed across alcohol and placebo), where AG subjects activate more than AA subjects. Display threshold, p< 0.005, extent threshold = 0. BOLD= blood oxygen level dependent.