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 similar to 50%. The purpose of this study was to: (i) 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.