The lifetime prevalence of alcohol abuse and alcoholism is 5-10% for men and 3-5% for women among U.S. and European adults. It is evident that there is a substantial genetic component to alcoholism predisposition, and that multiple genes as well as environmental factors influence this disease. In addition to the initial effects of ethanol, with continued ethanol use other factors come into play that profoundly affect the pattern of ethanol use and the likelihood that ethanol use will, for some individuals, progress from casual use to alcoholism. Among these is the capacity of ethanol to produce physical dependence. When ethanol is eliminated, as its depressant effects disappear, characteristic symptoms of hyperexcitability first wax and then wane, including tremor, autonomic nervous system overactivity and, in extreme cases, convulsions. These withdrawal symptoms define a preexisting state of physical dependence on the drug.

No animal model exactly duplicates clinically defined alcoholism, but many animal models for specific factors, such as the withdrawal syndrome, have been developed. Alcohol withdrawal convulsions occur in all species studied, including humans, and provide a quantitative index of the severity of withdrawal in mice. The well-documented difference in susceptibility to withdrawal after chronic ethanol exposure between the C57BL/6J and DBA/2J mouse strains provides an excellent starting point for dissecting genetic influences involved in physical dependence on ethanol. A quantitative trait locus (QTL) identifies the genomic location of a gene(s) affecting a trait of interest. Genome-wide QTL mapping studies have been carried out to dissect the multifactorial nature of withdrawal after chronic ethanol exposure using recombinant inbred strains and F2 mice derived from the C57BL/6J and DBA/2J progenitor strains.

To induce physical dependence, we used a standard paradigm in which mice were exposed to ethanol vapor for 72 hours. The mice were then tested hourly for handling-induced convulsions (HICs) for 10 hours and at hours 24 and 25. Ethanol withdrawal severity was first computed as the area under the 25-hour HIC curve. Separate regression residuals were then calculated that corrected for individual differences in blood ethanol concentration at the time of withdrawal and baseline HIC severity (i.e., before ethanol exposure). Statistical mapping yielded significant evidence (P<.00005) for QTLs on chromosomes 19 and distal 1 that account for 45% of the genetic variance in ethanol withdrawal severity.

The results also provide supporting evidence for a sex-limited QTL on chromosome 13, and a QTL on proximal chromosome 1, that may account for an additional 30% of the genetic variance. The distal chromosome 1 QTL is a locus of major effect, and experiments using chromosome 1 congenic strains more precisely mapped this QTL. The QTLs map near candidate genes involved in neurosteroid biosynthesis and signal transduction. Syntenic homology between human and mouse chromosomes suggests that genes related to physical dependence on ethanol may localize to human chromosome regions 10q23-q26, 1q31-q43, 2q11-q32, and 5p15/5q14-q21.

This work is supported by P50AA10760, RO1AA06243, RO1AA11114, and the VA.