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Decreased ethanol sensitivity and tolerance development in gamma-protein kinase C null mutant mice is dependent on
B J Bowers1, E H Owen, A C Collins
1Institute for Behavioral Genetics, University of Colorado, Boulder 80309, USA.
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.
Insights
Gamma-protein kinase C (PKC) null mutant mice show altered ethanol sensitivity and tolerance. Genetic background significantly modulates these effects, highlighting its importance in behavioral trait studies.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Ethanol's effects, including sedation and hypothermia, are complex and influenced by genetic factors.
- Protein kinase C (PKC) signaling pathways are implicated in neuronal function and behavioral responses to ethanol.
- Understanding the role of specific PKC isoforms, like gamma-PKC, is crucial for elucidating ethanol's mechanisms of action.
Purpose of the Study:
- To investigate the role of gamma-protein kinase C (PKC) in initial sensitivity and tolerance development to ethanol's sedative-hypnotic and hypothermic effects.
- To determine how different genetic backgrounds influence the phenotype of gamma-PKC null mutant mice regarding ethanol response.
Main Methods:
- Utilized gamma-PKC null mutant mice on mixed genetic backgrounds (C57BL/6J x 129/SvJ and C57BL/6J x 129/SvEvTac).
- Administered ethanol via a liquid diet for 10 days to assess chronic tolerance development.
- Evaluated sedative-hypnotic and hypothermic responses to ethanol in null mutants and control mice across different inbred strains (C57BL/6J, 129/SvJ, 129/SvEvTac).
Main Results:
- Gamma-PKC null mutants on a C57BL/6J x 129/SvJ background showed decreased initial ethanol sensitivity and failed to develop chronic tolerance.
- Introgression of the null mutation onto a C57BL/6J background diminished the 'no tolerance' phenotype.
- Outcrossing to a C57BL/6J x 129/SvEvTac background restored the 'no tolerance' phenotype for sedation but not hypothermia, indicating differential effects based on genetic background.
Conclusions:
- Gamma-PKC plays a significant role in both initial sensitivity and the development of tolerance to ethanol's effects.
- The impact of gamma-PKC on ethanol response is substantially modulated by the genetic background of the mice.
- These findings underscore the necessity of considering genetic background when studying the behavioral effects of gene mutations.
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