Effect of the TaqIA polymorphism on ethanol response in the brain

Acute ethanol administration increases striatal dopamine release and decreases cerebral glucose metabolism. The A1 allele of the ANKK1 TaqIa polymorphism is associated with lower dopaminergic tone and greater risk for alcoholism, but the mechanisms are unclear. We hypothesized that ethanol would be more reinforcing in men with the A1 allele (A1+) than in men without it (A1-), as indicated by decreased anxiety and fatigue and altered activity in associated brain regions. In a pilot study, A1+ and A1- men (6/group) drank ethanol (0.75 ml/kg) or placebo beverages on each of 2 days. Positron emission tomography with [F-18]fluorodeoxyglucose (FDG) was used to assess regional cerebral glucose metabolism as a measure of relative brain activity while participants performed a vigilance task. Significant findings were as follows: Ethanol decreased anxiety and fatigue in A1+ men but increased them in A1- men. Ethanol increased activity in the striatum and insula of A1+ men, but reduced activity in the anterior cingulate of A1- men. Reduced anxiety and fatigue in A1+ men were significantly associated with greater activity within a right orbitofrontal region previously implicated in cognitive control, and less activity in structures associated with anxiety (amygdala), fatigue (thalamus), and craving/reinforcement (striatum). In contrast, anxiety and fatigue changes were unrelated to brain activity in A1- men. Although these results require replication in a larger sample, alcohol-induced negative reinforcement may explain the greater risk for alcoholism associated with the A1 allele.