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 excessiv e drinking of ethyl alcohol. Recently, the 5-HT2 antagonist amperozide was found to reduce selectively the high intake of alcohol in the cya namide-induced drinking rat without any adverse side effects. The purp ose of the present study was to determine the action on alcohol drinki ng of the novel second-generation amperozide-like drug, which is a mix ed 5-HT1 agonist/5-HT2 antagonist, FG 5893 ophenyl)butyl]-l-piperaziny l]-3-pyridinecarboxylic acid methyl ester). To induce preference for a lcohol in Sprague-Dawley rats, the enzyme aldehyde dehydrogenase was i nhibited 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 pref erence test was used in which water and a maximally preferred concentr ation of alcohol were offered to each animal. Following control tests of alcohol preference for 3 days, either a saline control vehicle or F G 5893 in a dose of 0.5, 1.0, or 2.5 mg/kg was administered subcutaneo usly at 1600 and 2200 for 3 consecutive days. Whereas control injectio ns of saline were without effect on alcohol consumption, all doses of FG 5893 significantly reduced the 24-h intake of alcohol in terms of b oth absolute g/kg and proportion of alcohol to total fluid intake. Fur ther, the 1.0 and 2.5 mg/kg doses of FG 5893 continued to suppress alc ohol consumption over two 4-day tests immediately following the inject ion sequence and after a 40-day interval. Neither body weights nor int akes of food of the rats were affected by FG 5893 either during or aft er its administration. Thus, it is proposed that this putative anxioly tic and antidepressant drug causes a prolonged modification in the fun ction of serotonergic synapses in the mesolimbic system of the brain. Because FG 5893 possesses combined 5-HT1A agonist and 5-HT2 antagonist characteristics, it is envisaged that the addictive property of alcoh ol may in part involve a concurrent perturbation in the function of th ese two subtypes of scrotonergic receptors.