Hyperbaric ethanol antagonism in mice: Studies on oxygen, nitrogen, strain and sex

Abstract

Male and female C57BL/6J and male BALBc/J mice were injected with 3.6 g/kg ethanol or saline and exposed to 1-10 atmospheres absolute (ATA) air, to 1 ATA 80% helium-20% oxygen, or to 12 ATA helium-oxygen having oxygen partial pressures between 0.5 and 18 times normal. Hyperbaric helium-oxygen significantly reduced sleep-time and increased wake-up brain ethanol concentrations in all mice tested. The degree of antagonism was not enhanced by increasing the oxygen partial pressure. Hyperbaric air increased sleep-time and decreased wake-up brain ethanol concentration in C57 mice. Hyperbaric air induced a pressure-related lethal effect beginning at 6 ATA in intoxicated BALBs. These findings demonstrate that hyperbaric ethanol antagonism extends across strains and sexes, that the degree of antagonism cannot be enhanced by increasing the oxygen partial pressure, and that air is not suitable as an antagonistic hyperbaric gas. The findings are consistent with membrane theories of anesthesia.

Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

“…This provides normal oxygenation and avoids complications from higher oxygen partial pressures. In addition, we replace the nitrogen in our gas mixture with helium to avoid the depressant effect of nitrogen at increased atmospheric pressure (Alkana and Malcolm 1982a).…”

Ethanol Withdrawal in Mice Precipitated and Exacerbated by Hyperbaric Exposure

“…In previous studies we observed that exposure to 12 atmospheres absolute (ATA) of a mixture of helium and oxygen antagonizes the acute depressant effect of ethanol in mice (5,(9)(10)(11)(12). The antagonismn does not reflect changes in the absorption, distribution, or elimination of ethanol; increases in the partial pressure of oxygen or helium; or alterations in body temperature.…”

“…Studies involving acute exposure to ethanol support the contention that hyperbaric exposure acts as a direct antagonist to ethanol at the membrane level. As mentioned above, indirect mechanisms have been eliminated as critical factors mediating the antagonism (S, [9][10][11]. In addition, the characteristics of hyperbaric ethanol antagonism mimic those of classical pharmacological agonist-antagonist relationships in that the degree of antagonism is directly related to pressure and inversely related to the dose of ethanol (5).…”

Molecular targets and mechanisms for ethanol action in glycine receptors

“…These studies at 12 ATA and lower demonstrate that pressure antagonism meets the key criteria for a direct mechanism (Syapin et al , 1988;Bejanian et al , 1993;Davies et al , 1994;Syapin et al , 1996;Davies et al , 1999;Davies and Alkana, 2001;Malcolm and Alkana, 1982;Alkana and Malcolm, 1982b;Alkana and Malcolm, 1982a;Davies et al , 2003) and selectivity (Alkana et al , 1995;Davies and Alkana, 1998;Davies et al , 1996;Davies and Alkana, 1998;Davies et al , 2001;Davies et al , 1999;Davies et al , 2003), necessary for it to be used in a manner analogous to a traditional pharmacological antagonist to help identify initial molecular sites of ethanol action and to test cause-effect relationships (Davies and Alkana, 2001). From this perspective, the sites of pressure antagonism are the same as the sites of ethanol action.…”

“…Studies show that exposure to 4–12 times normal atmospheric pressure (ATA) is a direct ethanol antagonist that blocks and reverses a broad spectrum of ethanol’s acute and chronic behavioral effects (Alkana and Malcolm, 1981;Alkana and Malcolm, 1982a;Malcolm and Alkana, 1982;Alkana et al , 1992;Nielsen et al , 1987;Bejanian et al , 1993;Davies et al , 1994;Davies et al , 1999;Davies and Alkana, 2001), as well as its effects at the biochemical (Davies and Alkana, 1998;Davies et al , 1999;Davies and Alkana, 2001) and molecular (Davies et al , 2003;Davies et al , 2004;Perkins et al , 2008) levels.…”