Genetic animal models of alcoholism

Genetic studies with animals have several advantages. Many genetically specified populations are maintained and can be created through application of breeding strategies. Although animal studies are limited in their ability to model human traits (e.g. we have no animal equivalent of lower versus higher socioeconomic status), tolerance, dependence and withdrawal, compulsive self-administration, and sensitivity to the rewarding effects of alcohol have all been modeled in rodents. Animal researchers have chosen to model discrete subsets of the relevant human behaviors. The oldest behavior genetic technique is that of selective breeding. For example, lines of mice selected strictly for alcohol withdrawal severity also differ in severity of withdrawal from barbiturates, benzodiazepines, and nitrous oxide. This suggests that there are genes that confer risk or protection from drug withdrawal in general, which may model a genetic basis for polydrug abuse in humans. The other classic behavior genetic technique employed has been the comparison of inbred mouse strains. It has recently become possible to detect the influence of specific polygenes and to assign a tentative map location, called a quantitative trait locus (QTL). Many drug and alcohol response QTLs have been mapped. A recent analysis of acute ethanol withdrawal confirmed the effects of three QTLs. One is in the chromosomal region known to house genes coding for certain subunits of the GABA-A receptor. Such genes are attractive candidates, as GABA is the principal inhibitory brain neurotransmitter. Another technique for novel gene discovery that is seeing increasing use is based on differential gene expression. Using clones on DNA chips, or filters, hybridization analyses comparing ethanol exposed and control tissue can reveal which genes are regulated by ethanol treatment. Finally, the production of transgenic mice with either overexpression or deletion of specifically targeted genes is increasing. Although such knockout preparations are powerful, they are limited by the loss of the gene throughout development. This problem should soon be overcome with the successful production of conditional and tissue-specific knockouts. An additional concern with targeted mutants is the importance of the background strain. Conclusions: Besides improving our understanding of how alcohol works, animal genetic studies can provide new methods for identifying individual humans who may be at genetic risk. Ideally, this information will also help to generate new pharmacotherapies to address this disease.