5-HT2 receptor blockade by amperozide suppresses ethanol drinking in genetically preferring rats

Previously, it was shown that the unique diphenylbutylpiperazinecarboxamide derivative, amperozide (FG 5606), inhibits the volitional drinking of ethanol induced in the rat by the inhibitor of aldehyde dehydrogenase, cyanamide. In this study, the efficacy of this long-acting psychotropic agent and potent 5-hydroxytryptamine2 (5-HT2) receptor antagonist was examined in the genetic line of ethanol-preferring (P) and -nonpreferring (NP) rats. In both lines, the pattern of drinking of ethyl alcohol was determined by a standard preference test for 3-30% ethanol vs. water. Then, the maximally preferred concentration of ethanol was 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 saline 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 significantly in a dose-dependent manner in terms of both absolute g/kg and proportion of ethanol to water during injections of amperozide. The 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 consumption of ethanol of P or NP rats. Further, neither the consumption of food nor level of body weight was affected by amperozide either during or after its administration. These results demonstrate that in the individual predisposed genetically to drink ethanol amperozide exerts a palliative effect on the aberrant preference for ethanol consumed in a pharmacologically significant amount. Presently, dopaminergic and serotonergic synapses in the brain are implicated in the genetic differences in the patterns of ethanol consumption that distinguish the P from the NP line of rats. Because amperozide influences the functional activity of both dopaminergic and serotonergic neurons in the mesolimbic system, it is envisaged that the drug attenuates ethanol drinking by way of its direct action on these neurons.