Alcohol drinking in rats is attenuated by the mixed 5-HT1 agonist/5-HT2 antagonist FG 5893

Over the last three decades, the neurotransmitter serotonin (5-HT) has been implicated in the etiological mechanisms underlying the excessive drinking of ethyl alcohol. Recently, the 5-HT2 antagonist amperozide was found to reduce selectively the high intake of alcohol in the cyanamide-induced drinking rat without any adverse side effects. The purpose of the present study was to determine the action on alcohol drinking of the novel second-generation amperozide-like drug, which is a mixed 5-HT1 agonist/5-HT2 antagonist, FG 5893 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3-pyridinecarb oxylic acid methyl ester). To induce preference for alcohol in Sprague-Dawley rats, the enzyme aldehyde dehydrogenase was inhibited by cyanamide administered in the absence of alcohol in a dose of 10 mg/kg twice a day over three days. A standard three-bottle preference test was used in which water and a maximally preferred concentration of alcohol were offered to each animal. Following control tests of alcohol preference for 3 days, either a saline control vehicle or FG 5893 in a dose of 0.5, 1.0, or 2.5 mg/kg was administered subcutaneously at 1600 and 2200 for 3 consecutive days. Whereas control injections of saline were without effect on alcohol consumption, all doses of FG 5893 significantly reduced the 24-h intake of alcohol in terms of both absolute g/kg and proportion of alcohol to total fluid intake. Further, the 1.0 and 2.5 mg/kg doses of FG 5893 continued to suppress alcohol consumption over two 4-day tests immediately following the injection sequence and after a 40-day interval.(ABSTRACT TRUNCATED AT 250 WORDS)