The research theme of the Indiana Alcohol Research Center (IARC) is Genetic Determinants of Alcohol Ingestion. We hypothesize that between-individual variability in response to ethanol, much of which being genetic, is an underlying factor of individual differences in ethanol ingestive behavior and susceptibility to alcoholism and the complications of alcohol abuse. The IARC has unique resources to pursue this kind of research. A team of investigators with broad-based expertise will adc3 ~:ss this theme in experimental animals and humans. The human research components will examine the effect of repeated exposure to alcohol on measures of adaptation to ethanol, the sensitivity of individuals with family history of alcoholism to the rate of change of blood alcohol concentrations, and the genetic associations of measures of personality and affective state with risk of alcoholism. These studies will employ young subjects with and without a family history of alcoholism, and twins for the studies of risk-relevant personality and affective dimensions. The animal components will examine the differences in mRNA and protein expression of the limbic system of rats selected for alcohol preference and non-preference, the potential genetic influence on susceptibility to fetal alcohol syndrome in mice, and will continue selective breeding for and phenotypic characterization of alcohol-preference in mice. The pilot projects will examine genetic susceptibility to alcoholic liver injury, effect of alcohol on the blood vessel wall and its role in hepatocarcinogenesis, PET imaging of dopaminergic systems, and models of loss of control drinking. Core laboratory functions will include the production of selective bred high and low alcohol-preferring rats for research, provision of genotyping services, and support for high throughput screening of mRNA expression using microarrays and proteomic analysis of gene products. We will also expand current education and outreach activities of the Center through a new Translational Research and Science Education component.