This proposal for an International Collaborative U01 exchanges novel alcohol administration techniques between investigators at the Indiana University School of Medicine and the Technical University of Dresden, Germany, then undertakes research that contributes new knowledge complementing ongoing existing activities at both institutions. The Computer-Assisted Self-administration of Ethanol (CASE) system, invented, developed and validated by the Co-PIs, will be used prospectively in Germany to assess the initial drinking trajectories of 80 adolescents, recruited for a differential risk history of familial alcoholism. The sample will be assessed for symptoms of alcohol use disorders and recent drinking history prior to CASE assessments of alcohol self administration for enjoyment, conducted at ages 16 and 18. The initial slope of drinking trajectories will be computed from changes in CASE performance, and tested for association with the other risk factors. Dresden will also assess the effects alcohol on frontal lobe measures of impulsivity in half the sample population, using the Stop-Signal task performed during fMRI scanning. The time-course of brain exposure to alcohol in the fMRI camera will be nearly identical in every subject, accomplished by an autoclamping system, developed in Indiana. In Indianapolis, the aim is to assess the capacity of CASE to differentiate liking from wanting alcohol as bases for alcohol self-administration behavior in preparation for drug-development studies. Two CASE paradigms will be compared; one assessing the hedonic impact of alcohol self-administration; the other quantifying the willingness to work for more alcohol. A crossover design in a sample population of 80 young adult drinkers will be employed. CASE performance in each paradigm will be assessed for differential sensitivity to subjective perceptions at the end of a priming interval, and to risk factors for alcohol dependence that include differential history of familial alcoholism, personal recent drinking history, and an inventory of alcohol use disorder symptoms. Indiana will also genotype both German and American sample populations and seek associations between SNP haplotypes in the alcohol dehydrogenase cluster and alcohol metabolism and other risk factors. PUBLIC HEALTH RELEVANCE: This original application directly addresses research priorities valued in PAR-08-004; pharmacodynamics, alcohol genetics and epigenetics, biomarkers of risk, effects of exposure on the adolescent that elucidate the relationship between drinking onset, and the development of alcohol use disorders. The partnership is real and well balanced, and the U01 leadership plan incorporates the collaborative resources of NIAAA.