Ethanol enhances GABAA receptor function in short sleep and long sleep mouse brain membranes.
BACKGROUND
SS and LS mice have been used to explore the genetic and neurochemical bases for differences in sensitivity to ethanol. The present study investigated the effects of ethanol on GABAA receptor function in microsacs from these genotypes. The purpose was to test a key element of the hypothesis that differences between these lines in sensitivity to ethanol-induced enhancement of GABAA receptor function underlie their selected differences in sensitivity to ethanol-induced loss of righting reflex (LORR).


METHODS
The effects of ethanol on GABA-activated 36Cl- uptake in brain membranes (microsacs) isolated from male SS and LS mice were tested using a chloride flux filtration assay.


RESULTS
Ethanol significantly enhanced GABA-activated 36Cl- uptake in SS microsacs at concentrations of 100-300 mM. Ethanol did not significantly affect GABA-activated chloride uptake in this preparation at concentrations of 25 and 50 mM. Ethanol significantly enhanced GABA-activated 36Cl- uptake in LS microsacs at concentrations of 25-100 mM, but not at 200 mM.


CONCLUSIONS
The present studies are the first to show a statistically significant effect of ethanol on GABA-activated chloride uptake in both SS and LS mice with a clear difference between the genotypes in threshold. The relative threshold differences between SS and LS microsacs in sensitivity to ethanol indicate that selection for resistance to ethanol-induced LORR in SS mice has shifted the ethanol-GABAA receptor concentration-response curve to the right. The findings add key evidence that supports a cause-effect relationship between sensitivity to ethanol-induced potentiation of GABAA receptor function and genetically determined sensitivity to ethanol's behavioral effects.
Davies
D L
DL
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90089-9121, USA. ddavies@hsc.usc.edu
Alkana
R L
RL
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity
D002492:Central Nervous System Depressants; D018118:Chloride Channels; D011963:Receptors, GABA-A; D000431:Ethanol