Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats.

Amperozide (FG5606), a 5-HT2 receptor antagonist, is well known to suppress alcohol consumption in different rat models of drinking. The present study compared the efficacy of three drugs, FG5974, FG5893, and amperozide, which have differential affinities for 5-HT1A and 5-HT2A receptors, on alcohol drinking in the genetic alcohol-preferring (P) rat. After preference for alcohol vs. water was determined over 10 days when concentrations of alcohol were increased from 3% to 30%, the maximal concentration of alcohol preferred by each animal was selected for drug testing. A 4-day predrug preference test was followed by SC injection of the saline control vehicle or doses of 1.0 and 2.5 mg/kg FG5974, FG5893, or amperozide given at 1600 and 2200 h for 4 days. Alcohol preference testing concluded with a final 4-day interval. A total daily dose of 5.0 mg/kg FG5974 reduced absolute g/kg intake of alcohol and proportional intakes of the P rats significantly; the lower dose of FG5974 also reduced alcohol drinking significantly following treatment. The mixed 5-HT1A agonist/5-HT2A antagonist, FG5893, which suppresses drinking in cyanamide-treated rats, was without effect on alcohol ingested by the P rats. However, amperozide caused a dose-dependent decline in both absolute intakes and proportion of alcohol that was more intense than that of FG5974. The control vehicle failed to alter alcohol drinking and, like the FG compounds, did not affect food intake or body weight. Although the inhibition of alcohol drinking by amperozide corresponds precisely with previous findings, the effect of FG5974 contrasts to results obtained with a structurally analogous drug FG5893. Thus, the genetic strain of rat as well as the nature of the chemical characteristics of a 5-HT agonist/antagonist will determine the differential efficacy of a drug in influencing the volitional drinking of alcohol.