Genetic differences in sensitivity to ethanol\'s aversive effects may play an important role in the development of alcohol-seeking behavior and alcoholism. The present study examined the development of ethanol-induced conditioned taste aversion in 20 BXD/Ty recombinant inbred strains of mice and their progenitor inbred strains, C57BL/6J (B6) and DBA/2J (D2). Adult male mice were given 1-hr access to a saccharin-flavored solution every 48 hr for 12 days. After all but the first and last saccharin access periods, they received ethanol injections (0, 2, or 4 g/kg, i.p.). Separate groups of unpaired control mice received 4 g/kg of ethanol 1 hr after water access. Saline control mice were also used for examining preference across a wide range of saccharin concentrations (0.019 to 4.864% w/v). As expected, saccharin consumption during taste conditioning declined over conditioning trials in a dose-dependent manner, indicating development of ethanol-induced conditioned taste aversion. Correlational analyses using strain means from recently published papers indicated no significant genetic correlation between taste conditioning and two phenotypes thought to reflect ethanol reinforcement or reward (ethanol drinking, conditioned place preference). However, there were significant genetic correlations between taste conditioning at the high dose and sensitivity to ethanol-induced hypothermia, rotarod ataxia, and acute withdrawal. Quantitative trait locus (QTL) analyses of strain means indicated that taste aversion was associated (p < 0.01) with genetic markers on nine chromosomes (1, 2, 3, 4, 6, 7, 9, 11, and 17). These QTLs were located near several candidate genes, including genes encoding several different acetylcholine receptor subunits, the delta opioid receptor, and two serotonin receptors (1B and 1D). QTLs for saccharin preference were located on several of the same chromosomes (2, 3, 4, 6, and 11). Two of these saccharin QTLs overlap candidate genes influencing sensitivity to sweet or bitter taste stimuli. In general, these findings support the conclusion that multiple genes influence ethanol-induced conditioned taste aversion. Some of these genes appear to influence taste sensitivity, whereas others appear to mediate sensitivity to aversive pharmacological effects of ethanol.
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