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Differences in GABA activity between ethanol withdrawal seizure prone and resistant mice
D J Feller1, R A Harris, J C Crabbe
1Research Service, VA Medical Center, Portland, OR 97201.
European Journal of Pharmacology
|November 22, 1988
Summary
Genetically selected mice show differences in ethanol withdrawal seizures. While withdrawal seizure prone (WSP) mice are more sensitive to certain drugs, the underlying GABA-chloride channel receptor density and affinity do not differ between WSP and WSR mice.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Genetic selection created distinct mouse lines (WSP and WSR) differing in ethanol withdrawal seizure severity.
- Ethanol withdrawal is a significant clinical concern, necessitating research into its underlying mechanisms.
Purpose of the Study:
- To investigate the role of the GABA-chloride channel in the differential ethanol withdrawal seizure behavior observed between WSP and WSR mice.
- To determine if differences in GABA-chloride channel binding sites or function explain the varying seizure susceptibility.
Main Methods:
- Behavioral testing using subconvulsant doses of picrotoxin, bicuculline, and pentylenetetrazole to assess seizure exacerbation.
- Radioligand binding assays using [35S]t-butylbicyclophosphorothionate (TBPS) to measure GABA-chloride channel binding site density and affinity in specific brain regions.
- Characterization of [3H]flunitrazepam binding and GABA's potentiation of this binding in whole brain samples.
Main Results:
- Naive WSP mice exhibited greater sensitivity to the proconvulsant effects of picrotoxin, bicuculline, and pentylenetetrazole compared to WSR mice.
- No significant differences were found between WSP and WSR mice in the density or affinity of [35S]TBPS binding sites in the frontal cortex, cortex, cerebellum, or hippocampus.
- Similarly, no differences were observed in [3H]flunitrazepam binding properties or GABA's ability to enhance this binding.
Conclusions:
- Behavioral data strongly suggest a functional difference in the GABA-chloride channel contributes to the distinct ethanol withdrawal seizure phenotypes of WSP and WSR mice.
- These observed behavioral differences are not attributable to alterations in the overall density or affinity of the studied GABA-chloride channel binding sites.