Decreased ethanol sensitivity and tolerance development in gamma-protein kinase C null mutant mice is dependent on genetic background

Initial sensitivity and tolerance development to the sedative-hypnotic and hypothermic effects of ethanol were investigated in gamma-protein kinase C (PKC) null mutant mice. Null mutants from a C57BL/6J x 129/SvJ mixed geneti c background demonstrated decreased ethanol sensitivity and failed to devel op chronic tolerance after 10 days of ethanol liquid diet. However, when th e null mutation was introgressed onto a C57BL/6J background for six generat ions, the "no tolerance" phenotype for sedative-hypnotic and hypothermic ef fects of ethanol was no longer apparent. Outcrossing the gamma-PKC null mut ation to a C57BL/6J x 129/SvEvTac mixed background restored the "no toleran ce" phenotype to ethanol-induced sedation after chronic ethanol diet; howev er, as measured by hypothermia, tolerance was still evident in the null mut ant mice. These observations and the results of tests of chronic tolerance in the C57BL/6J, 129/SvJ, and 129/SvEvTac background inbred strains indicat e that gamma-PKC plays an important role in initial sensitivity and toleran ce to ethanol. However, the impact of gamma-PKC is modulated by the backgro und genotype. These results stress the importance of including the effect o f genetic background when evaluating the effects of single gene mutations o n quantitative behavioral traits.