Although LR has received much attention as an endophenotype, it is worth noting that some inconsistencies in the alcohol challenge literature have led others to propose a more nuanced “differentiator model” [63] that takes into account subjective and motor responses across the rise and fall of blood alcohol levels. Under this model, individuals at risk for developing an AUD (by virtue of family history) are hypothesized to show acute sensitization to alcohol as blood/breath alcohol level rises, and acute tolerance as blood/breath alcohol level falls. Thus, these individuals are at risk because of two processes: they experience more pleasurable and excitatory effects of alcohol during initial intoxication, and fewer of the sedative effects of alcohol as blood alcohol level declines. A modified version of the differentiator model [64] suggests that these effects are most pronounced at peak breath alcohol concentration. Recent longitudinal work is consistent with this modified differentiator model; individuals who were more sensitive to the stimulant and rewarding effects of alcohol and who were less sensitive to the sedating effects of alcohol at peak breath alcohol concentration in an alcohol challenge study had the highest number of AUD symptoms six years later [65].
