In the Duke Neurogenetics Study, rs61826952 minor allele carriers had decreased VS activity to positive versus negative feedback in a number-guessing fMRI task. Increased VS activity and dopamine release to non-alcohol reward have been associated with substance use initiation and problematic drinking 25,83-85. In contrast, studies of AD reported relatively reduced VS activity to non-alcohol reward 86,87 and heightened activity to alcohol cues 88. These apparently disparate findings can be integrated with stage-based theories of addiction, which hypothesize that initial problematic use is associated with the positively reinforcing aspects of a substance, while later compulsive use is driven by negative reinforcement and diminished cognitive control, resulting from changes in neural plasticity induced by chronic alcohol use 89 (see also Wetherill et al accompanying paper). Thus, results from the college-based Duke Neurogenetics Study suggested that the minor allele of rs61826952 may protect from AD by reducing VS-related reward drive, thereby diminishing the likelihood of initiating problematic drinking behavior.
