Frequently, studies of a genetic association lack mechanistic, translational data that link genetic variation with downstream changes in biological and behavioral phenotypes and the course of a disorder or treatment response. The present investigation was designed to translate the effects of variation in the CNR1 gene across different levels of phenotypes, from changes in receptor binding to neuronal activation after an alcohol cue challenge, to the subjective effects of alcohol consumption, and, ultimately, to treatment outcome differences. Based on previous studies suggesting that rs2023239 was the locus with the strongest association with substance abuse25 and in the region associated with differential brain activation to rewarding stimuli,29 this variation was advanced for more in-depth analysis. Analyses at the molecular level using human postmortem tissue suggest that the SNP was associated with greater CB1 receptors in critical prefrontal structures and, hence, might alter the response of the mesocorticolimbic circuitry that underlies drug-seeking behavior.
