Decreased Ethanol Sensitivity and Tolerance Development in gamma-Protein Kinase C Null Mutant Mice Is Dependent on Genetic Background

Abstract

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 genetic background demonstrated decreased ethanol sensitivity and failed to develop chronic tolerance after 10 days of ethanol liquid diet. However, when the null mutation was introgressed onto a C57BL/6J background for six generations, the "no tolerance" phenotype for sedative-hypnotic and hypothermic effects of ethanol was no longer apparent Outcrossing the gamma-PKC null mutation to a C57BL/6J x 129/SvEvTac mixed background restored the "no tolerance" phenotype to ethanol-induced sedation after chronic ethanol diet; however, as measured by hypothermia, tolerance was still evident in the null mutant mice. These observations and the results of tests of chronic tolerance in the C57BL/6J, 129/SvJ, and 129/SvEvTac background inbred strains indicate that gamma-PKC plays an important role in initial sensitivity and tolerance to ethanol. However, the impact of gamma-PKC is modulated by the background genotype. These results stress the importance of including the effect of genetic background when evaluating the effects of single gene mutations on quantitative behavioral traits.

A role for corticotropin releasing factor (CRF) in ethanol consumption, sensitivity, and reward as revealed by CRF-deficient mice

“…However, one potential limitation of these findings is the fact that the mice used in the present study were from a mixed C57BL/6J 129S genetic background. Many behavioral phenotypes, including ethanol consumption patterns, of mice with targeted embryonic gene deletions can depend largely on the genetic background of the strain used (Gerlai 1996;Bowers et al 1999;Phillips et al 1999). In the present study, CRF-deficient mice consumed approximately the same amount of ethanol as wild-type mice from a pure C57BL/6J background under identical experimental conditions (Koenig and Olive 2002).…”

Microarray Analysis of the Effects of a γ-protein Kinase C Null Mutation on Gene Expression in Striatum: A Role for Transthyretin in Mutant Phenotypes

“…Because homozygous mutants have decreased viability when bred on a pure inbred background (Wehner, unpublished data), F1 c-PKC homozygous null mutant mice and wild type mice were generated from crosses of heterozygotes of two congenic strains (B6.cPKC) and (S6.cPKC). Mice were genotyped prior to use as described by Bowers et al (1999). After weaning, mice were housed in like-sex groups of 2-5 composed of all genotypes and were maintained on a 12-hour light/dark cycle (lights on at 0700).…”

“…Mutants also do not develop significant tolerance to chronic treatment with ethanol (Bowers et al 1999). The reduced sensitivity to ethanol and impaired tolerance development seen in the null mutants is dependent on genetic background (Bowers et al 1999(Bowers et al , 2000b. This suggests that the effects of the null mutation can be compensated for in some backgrounds.…”

“…These differences appear to be mediated by altered CNS sensitivity because ethanol metabolism is not different between wild types and mutants, and the ability of ethanol to enhance GABAergic mediated Cl -flux through GABA-A receptors is reduced in the mutants throughout the brain (Harris et al 1995;Proctor et al 2003). Mutants also do not develop significant tolerance to chronic treatment with ethanol (Bowers et al 1999). The reduced sensitivity to ethanol and impaired tolerance development seen in the null mutants is dependent on genetic background (Bowers et al 1999(Bowers et al , 2000b.…”

Protein kinase C regulation of GABAA receptors

“…3). PKCg null mice show reduced sensitivity to the acute effects of ethanol on loss of the righting reflex and body temperature, but have normal responses to pentobarbital and flunitrazepam [5,77]. This is associated with decreased in vitro sensitivity of GABA A receptors to ethanol, but not to muscimol, pentobarbital or flunitrazepam.…”