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Published on: June 23, 2023
Acute functional tolerance to ethanol mediated by protein kinase Cepsilon
Melisa J Wallace1, Philip M Newton, Miho Oyasu
1Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
Summary
Protein kinase C epsilon (PKCepsilon) is crucial for developing acute functional tolerance (AFT) to ethanol
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Low response to ethanol correlates with higher alcoholism risk.
- Acute functional tolerance (AFT) to ethanol is a key factor in determining ethanol response.
- Protein kinase C epsilon (PKCepsilon) deficiency leads to increased intoxication and reduced ethanol self-administration.
Purpose of the Study:
- To investigate the role of PKCepsilon in the development of acute functional tolerance (AFT) to ethanol's motor-impairing effects.
- To explore the relationship between PKCepsilon, GABA(A) receptor sensitivity, and AFT.
- To differentiate the mechanisms of AFT and chronic ethanol tolerance.
Main Methods:
- Comparison of AFT in PKCepsilon knockout mice (-/-) and wild-type littermates (+/+).
- Assessment of GABA(A) receptor phosphorylation and ethanol sensitivity following acute ethanol exposure.
- Evaluation of chronic tolerance development and ethanol preference in both genotypes.
Main Results:
- PKCepsilon knockout mice exhibited significantly reduced AFT to ethanol's motor impairment compared to wild-type mice.
- In wild-type mice, ethanol exposure increased PKCepsilon phosphorylation and GABA(A) receptor resistance to ethanol, correlating with AFT.
- PKCepsilon knockout mice showed no alteration in GABA(A) receptor sensitivity after acute ethanol exposure.
- Both genotypes developed comparable chronic tolerance to ethanol, which did not affect ethanol preference.
Conclusions:
- Ethanol activates a PKCepsilon signaling pathway essential for GABA(A) receptor resistance and AFT.
- AFT to ethanol can be genetically separated from chronic tolerance, with PKCepsilon not regulating the latter.
- PKCepsilon's role in modulating ethanol preference is distinct from its involvement in AFT and chronic tolerance.
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