Since the discovery of different typologies for alcohol-use disorders in the 1980s, two major patterns have emerged. One type is oftentimes called alcohol abuse, whereas the other is associated with alcohol dependence. The abuse typology is associated with antisocial behavior and has an estimated high heritability, whereas the dependence- based typology is associated with stressful life events, bad marriage, difficult job, etc. This latter type is also supposed to have some degree of heritability, but this is difficult to assess because not all susceptible genotypes are subjected to stressful events. Attempts to develop animal models of the stress-related disorder have yielded inconsistent results. This is because the stressors tend to be short in duration and not always similar to human life events;or, the measure of alcohol drinking may not capture the kind of consumption seen in humans prior, during or following the stressful events. The primary aim of this proposal is to develop a model of stress-related change (increase or decrease) in alcohol consumption in a genetic reference population of mice subjected to several weeks of unpredictable environmental perturbations, termed chronic mild stress (CMS). The approach is a systems biology/systems genetics analysis of alcohol consumption within the framework of other physiological changes caused by CMS. Alcohol consumption will be assessed by the drinking in the dark (DID) paradigm and will be measured prior to CMS, during CMS and following CMS. The physiological measures include hypothalamus-pituitary-adrenal axis function, i.e., fecal corticosterone determinations during all phases of the experiment, thymus and adrenal weights. All endpoints will be subjected to multivariate analysis and genetic analysis to identify polymorphic genes that influence alcohol drinking and the other indices. Gene expression by microarray analysis will be performed on hippocampus, hypothalamus and adrenal glands to identify genes whose expression is altered by CMS and which genes that change expression are related to the other parameters, especially DID. At the end of the work, we will identify genes and gene networks related to stress-related alcohol consumption and that are syntenic with the human genome.
This research is aimed directly at developing an animal model of stress-related alcohol-use disorders. Previous attempts to develop such have yielded inconsistent results, likely because of methodological problems with administering stress, measuring alcohol consumption and not including multiple genotypes. In this work we will identify genes and gene networks related to this disorder and which share common functions in humans.