title: 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.
abstract: 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.
authors.affiliation: Alcohol and Brain Research Laboratory, Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA. ddavies@hsc.usc.edu
authors.forename: D L
authors.initials: DL
authors.lastname: Davies
authors.forename: R L
authors.initials: RL
authors.lastname: Alkana
mesh_terms: D000435:Alcoholic Intoxication / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001274:Atmospheric Pressure; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004357:Drug Synergism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005838:Genotype; D006371:Helium / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000008:administration & dosage; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000927:Anticonvulsants; D002712:Chlorides; D011963:Receptors, GABA-A; D006371:Helium; D000431:Ethanol; C038949:heliox; D010100:Oxygen