The incentive salience of alcohol: translating the effects of genetic variant in CNR1

Abstract

Context: The gene that codes for cannabinoid receptor 1 (CNR1) represents an important target for investigations designed to elucidate individual differences in the etiology of alcohol dependence.

Objective: To achieve a better understanding of the role of the CNR1 gene in the etiology and treatment of alcohol dependence.

Design: The present investigation spans multiple levels of analysis, including receptor binding in postmortem brain tissue, neuroimaging, human laboratory models, and analyses of treatment outcome data.

Results: Findings indicate that the C allele of rs2023239 is associated with greater CB1 binding in the prefrontal cortex, greater alcohol cue-elicited brain activation in the midbrain and prefrontal cortex, greater subjective reward when consuming alcohol, and more positive outcomes after treatment with a medication that targets the mesocorticolimbic neurocircuitry. In addition, there were strong correlations between cue-elicited brain activation and alcohol consumption measures in individuals with the C allele.

Conclusion: Individuals with the C allele may be more susceptible to changes in the mesocorticolimbic neurocircuitry that is involved in the attribution of incentive salience after repeated exposure to alcohol.

Figure 1

Depiction of the cannabinoid receptor type 1 gene (CNR1) genomic region, the location of rs2023239, and linkage disequilibrium (LD) throughout the region. A, The location of the CNR1 gene on chromosome arm 6q15. B, The location of the coding region (box indicated by the arrow), potential noncoding exons, and the untranslated region as depicted by Zhang et al. The regions of significant LD are depicted by the hashed rectangles. The asterisk shows the location of a predicted recombination hotspot. bp indicates base pair.

Figure 2

Cannabinoid receptor type 1 (CB1) receptor levels by genotype. Tritium-labeled CP55,940 binding in postmortem prefrontal cortex, Brodmann areas 9 (BA 9) and 10 (BA 10), comparing individuals with the TT genotype with those with the CT genotype for rs2023239. Those with the CT genotype have significantly greater CB1 receptor binding (*P < .01). Error bars represent SE.

Figure 3

Functional magnetic resonance imaging differences between cannabinoid receptor type 1 gene (CNR1) genotype groups. Greater activity is seen in the CT group compared with the TT group during the alcohol vs control condition. The peak loci of activation in each region are listed below each corresponding contrast map in terms of z scores and Talairach coordinates corresponding to the voxel with the maximum signal intensity. Significance was determined at P < .05. The color scale represents z scores. Left hemispheric activations are depicted on the left side of the images. NAcc/VS indicates nucleus accumbens/ventral striatum; OFC, orbitofrontal cortex; VMPFC, ventromedial prefrontal cortex; and VTA, ventral tegmental area.

Figure 4

Short-term effects of alcohol on subjective reward for each genotype group. Individuals with the CT genotype demonstrated significantly greater mean subjective reward (A) and positive affect (B) after alcohol consumption. In a replication and extension of this work, genotype was a significant moderator of the effect of medication on subjective high such that individuals with the CT genotype reported subjective high in the cyproheptadine hydrochloride (control) condition (C) but not in the olanzapine condition (D). Error bars represent SE.

Figure 5

Cue-elicited craving and treatment outcome for the genotype × medication groups. When treated with olanzapine, there were no significant differences between individuals with the CT genotype and those with the TT genotype in mean cue-elicited craving (A). When treated with placebo, individuals with the CT genotype demonstrated significantly greater mean cue-elicited craving (B). During a 12-week trial, individuals with the CT and TT genotypes drank at similar levels when treated with olanzapine (C). In contrast, individuals with the CT genotype drank significantly more during placebo treatment (D). Error bars represent SE.