ALCOHOL INTAKE IN HIGH ALCOHOL-DRINKING (HAD) RATS IS SUPPRESSED BY FG5865, A NOVEL 5-HT1A AGONIST 5-HT2 ANTAGONIST

Both the 5-HT2 antagonist, FG5606 (amperozide), and the mixed 5-HT1 ag onist/5-HT2 antagonist, FG5893, attenuate significantly the volitional intake of alcohol in the cyanamide treated rat. The purpose of the pr esent study was to investigate the effect on alcohol drinking in the s electively bred, high alcohol drinking (HAD) rat of a new and novel 5- HT1A agonist/5-HT2 antagonist, FG5865 ophenyl)butyl]-1-piperazinyl]-3- pyridinecarboxylic acid methyl ester), which shares pharmacological pr operties with FG5893. Initially, a standard three bottle preference te st for water vs. 3% to 30% alcohol solutions was given over 11 days to determine the maximally preferred concentration for each animal. Then water and this solution, which ranged between 9% and 20% with an over all mean absolute intake of 6.3 +/- 0.5 g/kg per day, was offered over three consecutive 4-day test sequences: (1) predrug control; (2) SC i njections b.i.d. of either 1.0 mg/kg or 2.5 mg/kg FG5865 or saline con trol vehicle; and (3) postdrug. Whereas saline failed to alter alcohol consumption of the HAD rats, FG5865 caused a significant dose depende nt reduction by as much as 75% in the intakes of alcohol during its ad ministration in terms of both g/kg (p < 0.01) and proportion of alcoho l to total fluid intake (p < 0.01). During the administration of 2.5 m g/kg FG5865, alcohol drinking declined from 6.5 +/- 0.3 g/kg to as low as 2.3 +/- 0.2 g/kg per day. Neither the body weight of the HAD anima ls nor their intake of food was affected by either dose of FG5865. The se results uphold the concept that the 5-HT1A and 5-HT2 receptor subty pes in the brain play a part in the aberrant drinking of alcohol of th e HAD rat. Because FG5865 influences the activity of serotonergic neur ons in the mesolimbic system of the rat, it is envisaged that the drug suppresses alcohol drinking by way of its action on these neurons.