Effects of a Drd2 deletion mutation on ethanol-induced locomotor stimulation and sensitization suggest a role for epistasis.

Interpretation of studies using single gene mutants is complicated by possible epistatic interactions with genetic background. Dopamine D2 receptor (Drd2) knockout mice on a C57BL/6 (B6) background show decreased basal locomotion, ethanol preference and ethanol-induced ataxia. Epistatic interactions were studied by examining the effect of this null mutation on several traits on a B6 or 129S6 x 129S2 (129) background. Modification of the null mutant effect on ethanol preference by ethanol-induced locomotor sensitization was also examined in B6 background mice. B6 knockout mice exhibited enhanced ethanol-induced locomotor stimulation and sensitization. The reduced ethanol consumption observed in ethanol-naive B6 Drd2 knockout mice was absent in ethanol-sensitized knockout mice. Ethanol-induced locomotor stimulation was not enhanced in 129 knockout mice, and locomotor sensitization was only modestly increased. However, 129 null mutant mice exhibited reduced basal locomotion and diminished ethanol-induced ataxia, similar to our previous results in B6 mice. The impact of the Drd2 null mutation on a subset of ethanol-related behavioral traits is subject to epistatic influences.