Indomethacin pretreatment blocks the effects of high concentrations of ethanol

Previous reports from our laboratory have indicated that the responses to ethanol following intraperitoneal (i.p.) injection increase as the concentration of the ethanol solution increases. We have also presented evidence which indicates that pretreatment with drugs such as indomethacin (a prostaglandin synthetase inhibitor) decreases the response of mice to ethanol injected i.p. The results reported here corroborate our earlier findings in that the sleep time response of C57BL and DBA mice was greater following injection with a 40% (w/v) ethanol solution than that seen following i.p. injection with a 20% (w/v) ethanol solution. The increase in sleep time does not appear to be due to alterations in the rates of absorption or elimination of ethanol. Pretreatment with indomethacin reduced sleep time in those animals injected with the 40% solution but was without effect in the animals injected with the 20% solution. Both C57BL and DBA mice pretreated with indomethacin exhibited an increase in waking blood and brain ethanol, an indicant of altered central nervous system sensitivity. In addition, both DBA and C57BL mice exhibited an increase in the linear rate of ethanol elimination if pretreated with indomethacin before injection with the 40% ethanol solution. Indomethacin did not affect ethanol elimination rates of animals injected with the 20% ethanol solution. These data indicate that high concentrations of ethanol when injected into the peritoneal cavity promote the production of prostaglandins which serve to enhance the behavioral response to ethanol. This enhancement may be due to altered pharmacokinetics as well as central nervous system effects.