Antagonism of alcohol hypnosis by blockade of prostaglandin synthesis and activity: genotype and time course effects

Pretreatment of mice with prostaglandin synthetase inhibitors (PGSI's) antagonizes alcohol-induced behaviors. This study examined genetic and time course factors of this effect and studied the effects of a putative prostaglandin antagonist (SC-19220) on ethanol sleep time. Long Sleep (LS) and Short Sleep (SS) mice, lines bred for differential response to an hypnotic dose of ethanol, showed a four-fold difference in their dose-response curves for indomethacin antagonism of ethanol-induced hypnosis. Females of both lines required higher amounts of indomethacin relative to males. Indomethacin pretreated animals regained the righting response at a higher blood ethanol concentration than did saline pretreated animals. In addition, indomethacin pretreatment failed to alter the rate of ethanol disappearance from blood. In general, both lines showed effects with low doses of indomethacin at early time points and with high doses of indomethacin at later time points. Indomethacin did not antagonize ethanol-induced hypnosis if given after ethanol. In C3H mice, pretreatment with low doses of SC-19220, a dibenzoxazepine derivative, produced a significant decrease in ethanol sleep time, moderate doses produced no effect, and high levels increased sleep time. These results further substantiate and expand our previous reports. Possible mechanisms for the biphasic effects of indomethacin treatment are presented and discussed.