Although genetic background alters responses to ethanol, there has not yet been a methodical quantification of differences in ethanol-related behaviors between inbred and hybrid mice commonly used in gene-targeting studies. Here, we compared C57BL/6NTac × 129S6/SvEvTac F1 hybrid mice (B6129S6) with C57BL/6NTac inbred mice (B6NT), and C57BL/6J × 129X1/SvJ (B6129X1) and C57BL/6J × 129S4/SvJae F1 hybrids (B6129S4) with C57BL/6J mice (B6J), in five commonly used tests: continuous access two-bottle choice drinking, intermittent limited-access binge drinking, ethanol clearance, ethanol-induced loss of the righting reflex, and conditioned place preference (CPP) for ethanol. We found that inbred B6J and B6NT mice showed greater ethanol preference and consumption than their respective hybrids when ethanol was continuously available. Within the intermittent limited-access drinking procedure, though all lines showed similar intake over eight drinking sessions, the average of all sessions showed that B6NT mice drank significantly more ethanol than B6129S6 mice. In addition, B6J mice consumed more ethanol than B6129X1 mice, although they drank less than B6129S4 mice. No differences in ethanol LORR duration were observed between inbred and hybrid mice. Although ethanol clearance was similar among B6J mice and their respective hybrids, B6NT mice cleared ethanol more rapidly than B6129S6 mice. All lines developed CPP for ethanol. Our findings indicate that it may not be necessary to backcross hybrids to an inbred B6 background to study many ethanol-related behaviors in gene-targeted mice.

Neuronal signal transduction by the JNK MAP kinase pathway is altered by a broad array of stimuli including exposure to the widely abused drug ethanol, but the behavioral relevance and the regulation of JNK signaling is unclear. Here we demonstrate that JNK signaling functions downstream of the Sterile20 kinase family gene tao/Taok3 to regulate the behavioral effects of acute ethanol exposure in both the fruit fly Drosophila and mice. In flies tao is required in neurons to promote sensitivity to the locomotor stimulant effects of acute ethanol exposure and to establish specific brain structures. Reduced expression of key JNK pathway genes substantially rescued the structural and behavioral phenotypes of tao mutants. Decreasing and increasing JNK pathway activity resulted in increased and decreased sensitivity to the locomotor stimulant properties of acute ethanol exposure, respectively. Further, JNK expression in a limited pattern of neurons that included brain regions implicated in ethanol responses was sufficient to restore normal behavior. Mice heterozygous for a disrupted allele of the homologous Taok3 gene (Taok3Gt) were resistant to the acute sedative effects of ethanol. JNK activity was constitutively increased in brains of Taok3Gt/+ mice, and acute induction of phospho-JNK in brain tissue by ethanol was occluded in Taok3Gt/+ mice. Finally, acute administration of a JNK inhibitor conferred resistance to the sedative effects of ethanol in wild-type but not Taok3Gt/+ mice. Taken together, these data support a role of a TAO/TAOK3-JNK neuronal signaling pathway in regulating sensitivity to acute ethanol exposure in flies and in mice.