PT  - JOURNAL ARTICLE
AU  - D L Davies
AU  - M Bejanian
AU  - E S Parker
AU  - J Mørland
AU  - M B Bolger
AU  - R D Brinton
AU  - R L Alkana
TI  - Low level hyperbaric antagonism of diazepam's locomotor depressant and anticonvulsant properties in mice.
DP  - 1996 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 667--675
VI  - 276
IP  - 2
4099  - http://jpet.aspetjournals.org/content/276/2/667.short
4100  - http://jpet.aspetjournals.org/content/276/2/667.full
SO  - J Pharmacol Exp Ther1996 Feb 01; 276
AB  - Exposure to 12 atmospheres absolute (12 ATA) helium oxygen gas (heliox) (low level hyperbaric exposure) antagonizes the behavioral effects of ethanol and n-propanol, but not morphine. These and other results indicate that the mechanism of the antagonism is direct (pharmacodynamic) and selective. Our study further investigates the selectivity of low level hyperbaric antagonism by testing its effectiveness against diazepam, a high affinity binding drug that acts via allosteric modulation of GABAA receptors. C57BL/6J mice received injections i.p. of vehicle or diazepam, and were then exposed to 1 ATA air, 1 ATA heliox or 12 ATA heliox. Exposure to 12 ATA heliox antagonized the locomotor depressant effect of 4 and 6 mg/kg, but not 8 mg/kg diazepam. Hyperbaric exposure also antagonized the anticonvulsant effect of 8 and 24 mg/kg, but not 4 mg/kg, diazepam vs. 300 mg/kg isoniazid. Exposure to 12 ATA heliox did not significantly affect blood concentrations of diazepam or its metabolite n-desmethyl diazepam. The pharmacological characteristics of the antagonism (direct, surmountable, rightward shift in diazepam's dose-response curve) closely matched those seen in previous studies for hyperbaric antagonism of ethanol. The results add to the evidence that low level hyperbaric exposure is a direct, mechanistic antagonist that selectively antagonizes drugs that act via perturbation or allosteric modulation of receptor function. Moreover, the results suggest that allosteric coupling pathways, which transduce binding events on ligand-gated ion channels, may represent initial sites of action for ethanol.