QUANTITATIVE TRAIT LOCI INVOLVED IN GENETIC PREDISPOSITION TO ACUTE ALCOHOL-WITHDRAWAL IN MICE

Alcohol dependence (alcoholism) is accompanied by evidence of toleranc e, withdrawal (physiological dependence), or compulsive behavior relat ed to alcohol use. Studies of strain and individual differences using animal models for acute physiological dependence liability are useful means to identify potential genetic determinants of liability in human s. Behavioral and quantitative trait analyses were conducted using ani mal models for high risk versus resistance to acute physiological depe ndence. Using a two-step genetic mapping strategy, loci on mouse chrom osomes 1, 4, and 11 were mapped that contain genes that influence alco hol withdrawal severity. In the aggregate, these three risk markers ac counted for 68% of the genetic variability in alcohol withdrawal. Cand idate genes in proximity to the chromosome 11 locus include genes enco ding the alpha(1), alpha(6), and gamma(2) subunits of type-A receptors for the inhibitory neurotransmitter, GABA. In addition, suggestive li nkage is indicated for two loci on mouse chromosome 2, one near Gad1 e ncoding glutamic acid decarboxylase, and the other near the El2 locus which influences the seizure phenotype in the neurological mutant, str ain El. The present analyses detect and map some of the loci that incr ease risk to develop physiological dependence and may facilitate ident ification of genes related to the development of alcoholism, Syntenic conservation between human and mouse chromosomes suggests that human h omologs of genes that increase risk for physiological dependence may l ocalize to 1q21-q32, 2q24-q37/11p13, 9p21-p23/1p32-p22.1, and 5q32-q35 .