Document Detail

Direct evidence for a cause-effect link between ethanol potentiation of GABA(A) receptor function and intoxication from hyperbaric studies in C57, LS, and SS mice.
MedLine Citation:
PMID:  11505039     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: This article uses a direct ethanol antagonist, increased atmospheric pressure, to further test the causative link between ethanol potentiation of gamma-aminobutyric acid (GABA) type A receptor function and ethanol's behavioral effects. This was done by determining whether initial biochemical findings in long-sleep (LS) mice extended to other genotypes and whether the previously reported insensitivity of short-sleep (SS) mice to pressure antagonism of ethanol-induced loss of righting reflex extended to a nonselected ethanol-induced behavior. METHODS: The effects of 12 times normal atmospheric pressure of helium-oxygen gas (heliox) versus ethanol (25-200 mM) potentiation of GABA-activated Cl- uptake in brain membranes (microsacs) from C57, LS, and SS mice were tested by using a 36Cl- flux assay. The effects of pressure versus ethanol's (2 g/kg) anticonvulsant effect in SS mice were tested by using time to onset of isoniazid-induced myoclonic seizures. RESULTS: Exposure to 12 times normal atmospheric pressure heliox antagonized ethanol potentiation of GABA-activated Cl- uptake in all three genotypes across a range of ethanol concentrations that cause ethanol's behavioral and anesthetic effects. Pressure did not affect baseline receptor function. The threshold for initiating ethanol potentiation differed between genotypes in accordance with their behavioral sensitivities to ethanol (C57 and LS, < or =25 mM; SS, >50 mM). Pressure antagonized ethanol's anticonvulsant effect in SS mice. CONCLUSIONS: The results add important direct evidence supporting the hypothesis that ethanol potentiation of GABA(A) receptor function is an initial action of ethanol causing its behavioral effects. These findings also provide insight into possible effects of selective breeding on GABA(A) receptor function.
D L Davies; R L Alkana
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Alcoholism, clinical and experimental research     Volume:  25     ISSN:  0145-6008     ISO Abbreviation:  Alcohol. Clin. Exp. Res.     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-08-15     Completed Date:  2001-09-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7707242     Medline TA:  Alcohol Clin Exp Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1098-106     Citation Subset:  IM    
Alcohol and Brain Research Laboratory, Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA.
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MeSH Terms
Alcoholic Intoxication / genetics*,  physiopathology
Anticonvulsants / pharmacology
Atmospheric Pressure*
Brain / metabolism
Cell Membrane / metabolism
Chlorides / metabolism
Drug Synergism
Ethanol / administration & dosage,  pharmacology*
Helium / administration & dosage
Mice, Inbred C57BL
Oxygen / administration & dosage
Receptors, GABA-A / drug effects*,  physiology*
Grant Support
Reg. No./Substance:
0/Anticonvulsants; 0/Chlorides; 0/Receptors, GABA-A; 58933-55-4/heliox; 64-17-5/Ethanol; 7440-59-7/Helium; 7782-44-7/Oxygen

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