The voluntary ingestion or self-administration of alcohol (ethanol) in humans and experimental animals is influenced not only by environmental but also by genetic/biological factors. We hypothesize that individual differences in response to the reinforcing/aversive actions of ethanol, in tolerance development, and in ethanol and acetaldelyde metabolism underlies much of the individual differences in genetic vulnerability to developing alcoholism. This applicant institution has unique resources for this kind of research and proposes to establish an Alcohol Research Center that will make these resources more accessible to other investigators. 1) We will establish an Animal Production Core that will make available for others the genetically selected P, NP, HAD and LAD lines of rats. The alcohol-preferring P line of rats has been shown to be a good animal model of alcoholism, useful in the study of the neurobiological basis of alcohol-seeking behavior. 2) We will establish a Molecular Biology Core that will develop methodology to identify the polymorphic alleles of the human alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes. The large collection of human autopsy liver specimens of known phenotypes will be employed to establish the validity of the restriction-fragment-length-polymorphism (RFLP) analyses. The relation of ADH and ALDH polymorphism to alcoholism and to alcohol-induced liver disease, brain damage, and other complications will be studied across populations and in family studies. 3) We will establish a Human Genetics and Database Core that will develop methodology to estimate the heritability of various pharmacodynamic actions of ethanol through comparison studies of monozygotic and dizygotic twins. A number of behavioral, electrophysiological and neuroendocrine responses to ethanol will be assessed. The long-term goal of this core is to enable the testing in humans of hypotheses emerging from work with experimental animals. An example is that the rapid development of acute tolerance and its persistence over a long period of time is an inherited predisposing factor of heavy drinking and alcoholism. 4) We will establish a Neuroendocrine Core to perform analysis of neuropeptides and hormones needed in the proposed human studies, in ongoing animal studies, and in the proposed Pilot Projects. 5) We propose to support, as part of the Center activity, Pilot Projects as a way to recruiting new investigators into the field, and to enhancing collaborative, interdisciplinary research.
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