Behavioral Genomics of Alcohol Neuroadaptation

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The Portland Alcohol Research Center (PARC) focuses on the etiology and prediction of risk of alcohol abuse, alcoholism, and specific alcohol-related health problems (e.g., withdrawal seizures). The genetic risk and protective markers that we are studying will be of utility in the future for prevention of alcoholism. The first theme of the PARC is to use behavioral genomics strategies, through studies of gene mapping and expression, and development of new genetic animal models, to identify genes underlying ethanol neuroadaptation. The other main PARC theme is exploring mechanisms underlying and traits related to ethanol neuroadaptation. Two specific hypotheses have developed from the synthesis of PARC and related projects' findings. The first is the intriguing idea that withdrawal and drinking may be influenced by some of the same genes. The second emergent hypothesis is that high impulsivity is a significant genetic risk factor for high alcohol drinking. Five research components, four core components, and a pilot project component address these themes and hypotheses. An Education and Outreach component trains pre and postdoctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. Three research projects focus intensively on mapping quantitative trait loci (QTLs) for alcohol preference and withdrawal genes in mice. During the current period of funding, we have pursued one QTL and have successfully mapped the first quantitative trait gene (QTG) for an alcohol-related behavioral response, Mpdz, which influences alcohol withdrawal severity. Our gene finding approaches are evolving to include a major emphasis on mapping QTGs whose effects on the trait are derived from differences in regulation of gene expression. This effort has led to a significant expansion in our bioinformatics efforts. A fourth, new component is developing novel mouse models for impulsive behavior, establishing their genetic basis, and relating them to alcohol consumption. The fifth component, also new, takes advantage of access to a large colony of rhesus monkeys, all of whom have been genotyped in a full-genome linkage scan, and were tested at 3 months old for temperament-related traits (e.g., anxiety). These animals will be given an alcohol challenge at 1 year old to determine individual differences in alcohol-induced ataxia and anxiolysis. Our hope is to test them eventually for alcohol self-administration, and retrospectively to discover predictors of alcohol selfadministration. The other new feature in the renewal is a pilot project that will perform the first clinical study in the PARC, a clinical trial of metoclopramide, to see whether impulsivity predicts response.