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Fyn-kinase as a determinant of ethanol sensitivity: relation to NMDA-receptor function
T Miyakawa1, T Yagi, H Kitazawa
1Laboratory for Neurobiology of Emotion, Brain Science Institute, RIKEN, Hirosawa, Wako-shi, Saitama-ken 351-01, Japan.
Abstract:
Animals vary in their sensitivity to ethanol, a trait at least partly determined by genetic factors. In order to identify possible responsible genes, mice lacking Fyn, a non-receptor type tyrosine kinase, were investigated. These mice were hypersensitive to the hypnotic effect of ethanol. The administration of ethanol enhanced tyrosine phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of control mice but not in Fyn-deficient mice. An acute tolerance to ethanol inhibition of NMDAR-mediated excitatory postsynaptic potentials in hippocampal slices developed in control mice but not in Fyn-deficient mice. These results indicate that Fyn affects behavioral, biochemical, and physiological responses to ethanol.
Insights
Mice lacking Fyn, a tyrosine kinase, showed increased sensitivity to ethanol
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Ethanol sensitivity in animals has a genetic basis.
- Fyn is a non-receptor tyrosine kinase implicated in cellular signaling.
Purpose of the Study:
- To investigate the role of Fyn in ethanol sensitivity and its underlying mechanisms.
Main Methods:
- Comparison of ethanol responses in wild-type and Fyn-deficient mice.
- Biochemical analysis of N-methyl-D-aspartate receptor (NMDAR) phosphorylation.
- Electrophysiological assessment of NMDAR function in hippocampal slices.
Main Results:
- Fyn-deficient mice exhibited hypersensitivity to ethanol's hypnotic effects.
- Ethanol-induced NMDAR tyrosine phosphorylation in the hippocampus was dependent on Fyn.
- Acute tolerance to ethanol's effects on NMDARs was impaired in Fyn-deficient mice.
Conclusions:
- Fyn kinase plays a critical role in modulating behavioral, biochemical, and physiological responses to ethanol.
- Fyn signaling pathway is essential for the development of acute tolerance to ethanol.