Antagonism of ethanol by pretreatment or posttreatment with RO 15-4513 and indomethacin alone or in combination.
RO 15-4513, an inverse agonist at the GABA/benzodiazepine receptor Cl- channel complex, antagonizes multiple effects of ethanol. Prostaglandin synthesis inhibitors, such as indomethacin, also antagonize several effects of alcohols. However, prostaglandin synthesis inhibitors and RO 15-4513 each provide only partial antagonism of ethanol, typically seen as a dose-related effect with a maximum efficacy of approximately 50%. The purpose of this study was to: (1) compare the relative efficacy of these compounds for antagonizing ethanol; (2) compare the effectiveness of preethanol treatment versus postethanol treatment with each drug; and (3) compare the effect of RO 15-4513 and indomethacin in combination with the effects of each drug alone. The results show that indomethacin significantly decreased duration of loss of the righting reflex when administered either pre- or postethanol. Conversely, RO 15-4513 decreased duration of loss of the righting reflex only when given preethanol. When coadministered, RO 15-4513 and indomethacin did not show additive or synergistic effects. Compounds from these two drugs classes should continue to prove useful in elucidating ethanol's mechanisms of action.
Elmer
G I
GI
Southwest Institute on Drug and Alcohol Studies, Albuquerque, New Mexico 87190-3991, USA.
George
F R
FR
D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D011292:Premedication; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology
D001386:Azides; D018118:Chloride Channels; D018079:Receptors, GABA; D001569:Benzodiazepines; D000431:Ethanol; C042957:Ro 15-4513; D007213:Indomethacin