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-pyridinecarboxylic 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. Neither body weights nor intakes of food of the rats were affected by FG 5893 either during or after its administration. Thus, it is proposed that this putative anxiolytic and antidepressant drug causes a prolonged modification in the function of serotonergic synapses in the mesolimbic system of the brain. Because FG 5893 possesses combined 5-HT_1A agonist and 5-HT₂ antagonist characteristics, it is envisaged that the addictive property of alcohol may in part involve a concurrent perturbation in the function of these two subtypes of serotonergic receptors.