Indomethacin significantly reduces mortality due to acute ethanol overexposure

Previous studies in our laboratory have demonstrated that indomethacin, a potent prostaglandin synthetase inhibitor, significantly antagonizes the depressant, activating, and hypothermic responses to ethanol. In this study, male SS mice, a line selectively bred for low sensitivity to the hypnotic effects of ethanol, were pretreated with indomethacin or vehicle up to 24 hr prior to administration of an LD69 dose of ethanol. Indomethacin pretreatment significantly reduced the mortality rate independent of pretreatment time and produced an increase in the number of animals exhibiting a depressed behavioral response as measured by loss of the righting reflex. These results suggest that indomethacin antagonized the effects of ethanol to an extent such that a lethal dose was transformed into a depressant dose. These data are consistent with our hypothesis that pretreatment with prostaglandin synthetase inhibitors serves to shift the ethanol dose response curve to the right, suggesting that the arachidonic acid cascade is an important system in the mechanism of ethanol's actions.