The role of prostaglandin synthetase in the rate depressant effects and narcosis caused by ethanol.
Ethanol is proposed to exert its pharmacological effects by increasing membrane fluidity. Support for this hypothesis comes from strong correlations between in vitro effects of ethanol and pharmacological effects and genetic variation seen in vivo. Because arachidonate acid (AA) cascade is a membrane-bound system activated by disruptions in the cell membrane, it is possible that ethanol-induced membrane fluidization increases the formation of AA metabolites such as prostaglandins. The studies reported here were designed to characterize systematically the ability of various prostaglandin endoperoxide synthetase (PES; prostaglandin synthetase or cyclooxygenase) inhibitors to antagonize the effects of ethanol. A wide range of chemically diverse PES inhibitors significantly antagonized the rate-depressant effects and acute narcosis caused by ethanol. The ability of these compounds to antagonize the effects of ethanol was significantly correlated with two measures of PES activity; in vitro inhibition of the PES enzyme and in vivo anti-inflammatory activity. These significant potency correlations between the ability of PES inhibitors to antagonize in vivo acute ethanol hypnosis and their ability to inhibit in vitro and in vivo conversion of AA to AA metabolites strongly suggest an underlying functional relationship. These results obtained from two divergent dependent measures of the effects of ethanol, duration of loss of the righting reflex and rate depressant effects, extend the range of ethanol-related behaviors that PES inhibitors effectively antagonize and provide substantive evidence in support of a mechanistic role for PES and related metabolites in the central effects of ethanol.
Elmer
G I
GI
Preclinical Pharmacology Branch, National Institute on Drug Abuse, Baltimore, Maryland.
George
F R
FR
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D012018:Reflex / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000431:Ethanol; D011451:Prostaglandin-Endoperoxide Synthases