High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption

C57BL/6J (B6) inbred mice are well known to drink large amounts of alcohol (ethanol) voluntarily and to have only modest ethanol-induced withdrawal un der fixed dose conditions. In contrast, DBA/2J (D2) mice are "teetotallers" and exhibit severe ethanol withdrawal. Speculation that an inverse genetic relationship existed between these two traits was substantiated by meta-an alysis of existing data collected in multiple genetic models, including lar ge panels of standard and recombinant inbred strains, their crosses, and se lectively bred mouse lines. Despite methodological differences among labora tories in measurement of both preference drinking and withdrawal, a nearly universal finding was that genotypes consuming large amounts of 10% ethanol (calculated as g/kg/day) during two-bottle choice preference drinking were genetically predisposed to low withdrawal scores in independent studies af ter either acute or chronic ethanol treatment. Conversely, low-drinking gen otypes had higher withdrawal severity scores. The genetic relationship appe ars to be strongest in populations derived from B6 and D2, where data from more genotypes (BXD RIs, B6D2F(2)s, BXD RI F(1)s, and B6D2F(2)-derived sele ctively bred lines) were available for analysis. Gene mapping studies in th ese populations identified four chromosome regions [on Chromosomes (Chrs) 1 , 2, 4, and 15] where genes might potentially influence both traits. Among genotypes with greater genetic diversity (for example, a panel of standard inbred strains or selectively bred lines), the relationship was less pronou nced. Thus, reduced susceptibility to the development of high alcohol use m ay be supported by increased genetic susceptibility to ethanol withdrawal s ymptoms.