5-HT(2) RECEPTOR BLOCKADE BY AMPEROZIDE SUPPRESSES ETHANOL DRINKING IN GENETICALLY PREFERRING RATS

Previously, it was shown that the unique diphenylbutylpiperazinecarbox amide derivative, amperozide (FG 5606), inhibits the volitional drinki ng of ethanol induced in the rat by the inhibitor of aldehyde dehydrog enase, cyanamide. In this study, the efficacy of this long-acting psyc hotropic agent and potent 5-hydroxytryptamine2 (5-HT2) receptor antago nist was examined in the genetic line of ethanol-preferring (P) and -n onpreferring (NP) rats. In both lines, the pattern of drinking of ethy l alcohol was determined by a standard preference test for 3-30% ethan ol vs. water. Then, the maximally preferred concentration of ethanol w as determined for each individual, which ranged from 9-15% for P rats and 9-13% for NP animals. After a 4-day predrug test, either the salin e control vehicle or amperozide was administered SC b.i.d. at 1600 and 2200 h. The drug was given over a 3-day period in one of three doses: 0.5, 1.0, or 2.5 mg/kg. The intake of ethanol of P rats was reduced s ignificantly in a dose-dependent manner in terms of both absolute g/kg and proportion of ethanol to water during injections of amperozide. T he same doses of amperozide had no effect on the low intake of ethanol in NP rats. The saline control vehicle also did not alter the consump tion of ethanol of P or NP rats. Further, neither the consumption of f ood nor level of body weight was affected by amperozide either during or after its administration. These results demonstrate that in the ind ividual predisposed genetically to drink ethanol amperozide exerts a p alliative effect on the aberrant preference for ethanol consumed in a pharmacologically significant amount. Presently, dopaminergic and sero tonergic synapses in the brain are implicated in the genetic differenc es in the patterns of ethanol consumption that distinguish the P from the NP line of rats. Because amperozide influences the functional acti vity of both dopaminergic and serotonergic neurons in the mesolimbic s ystem, it is envisaged that the drug attenuates ethanol drinking by wa y of its direct action on these neurons.