Prostaglandin synthesis inhibitors antagonize behavioral responses to ethanol. The dose of inhibitor (e.g., indomethacin or aspirin) required to block ethanol's effects is directly proportional to the ethanol sensitivity of the organism. Animals selectively bred for differential response to ethanol provide a useful tool in exploring the biochemical substrates of ethanol-related behavior. This study shows that ethanol increases brain prostaglandin levels in a dose-, sex-, and genotype-dependent manner consistent with the hypothesis that part of ethanol's mechanism of action is to increase the production of prostaglandins.