Background genotype modulates the effects of gamma-PKC on the development of rapid tolerance to ethanol-induced hypothermia

The role of gamma-PKC in initial sensitivity and in the development of rapi d tolerance to the hypothermic effects of ethanol were investigated in gamm a-PKC null mutant mice. Effects of the single gene mutation were evaluated on three different generic backgrounds. Null mutants from a C57BL/6f X 129/ Svf mixed genetic background failed to develop rapid tolerance after 4 days of ip. ethanol injections. However, when the null mutation was introgresse d onto a C57BL/6f background for six generations to create a congenic line, the expression of rapid tolerance unexpectedly reoccurred in the null muta nt mice. Subsequent outcrossing of the gamma-PKC null mutation to a C57BL/6 f X 129/SvEvTac mixed background did not restore the "no tolerance" phenoty pe. These observations, taken together with similar results reported previo usly concerning the development of chronic tolerance to ethanol in these sa me genotypes,(1) indicate that the gene coding for gamma-PKC has pleiotropi c effects in the expression of both rapid and chronic tolerance to ethanol- induced hypothermia. However, the impact of gamma-PKC is modulated by the b ackground genotype. These results stress the necessity of understanding int eractions with genetic background when interpreting the effects of single g ene mutations on complex behavioral traits.