Direct antagonism of ethanol's effects on GABA(A) receptors by increased atmospheric pressure.
Previous studies have shown that exposure to 12 times normal atmospheric pressure of helium-oxygen gas (heliox) directly antagonizes a range of ethanol's acute and chronic behavioral effects. The present study extends the investigation to the biochemical level by investigating the effects of pressure on ethanol-induced potentiation of GABA(A) receptor function in mouse membrane vesicles (microsacs). Exposure to 12 atmospheric pressure heliox significantly antagonized ethanol (25 to 100 mM) potentiation of GABA-activated 36Cl- uptake, but did not significantly alter baseline GABA(A) receptor function measured by the response of the system to GABA (10 to 100 microM), bicuculline (3 and 100 microM), or picrotoxin (100 microM). These findings add essential support for the hypothesis that hyperbaric exposure is a direct ethanol antagonist that can be used as a tool to help identify ethanol's initial cellular and molecular sites of action that cause its behavioral effects. Taken in context with previous behavioral studies, the present results also provide important new evidence for a cause-effect relationship between ethanol potentiation of GABA(A) receptor function and ethanol's anesthetic and behavioral effects.
Davies
D L
DL
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033, USA.
Alkana
R L
RL
D000435:Alcoholic Intoxication / Q000503:physiopathology; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001274:Atmospheric Pressure; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology
D011963:Receptors, GABA-A; D000431:Ethanol