The mixed 5-HT 1A/2A receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT1A and 5-HT2A receptors in the brain. For example, amperozide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate). exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15% had stabilized for 4 days, saline or FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT1A and 5-HT2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.