Limited access to ethanol in genetic drinking rats is suppressed while feeding is enhanced by the mixed 5-HT1A agonist/5-HT2A antagonist FG5938.

Serotonin (5-HT) receptor agonists, antagonists, and mixed agonist/antagonists have been implicated in the volitional intake of ethanol in the rat and other species. The present experiments were undertaken to determine whether FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate) would alter ethanol drinking in: genetic ethanol preferring (P) rats; and a new strain of high ethanol preferring (HEP) male and female rats derived from crossbreeding of P and a variant strain of Sprague-Dawley animals. After a preference test for solutions of 3 to 30% ethanol vs. water, each rat was given limited access to its maximally preferred concentration daily between 1600 and 1800 h; fluid intakes were recorded every 0.25 h. Once fluid consumption had stabilized over 4 days, saline vehicle, 2.5 mg/kg or 5.0 mg/kg FG5938 was injected subcutaneously 0.5 h prior to ethanol access on each of 3 consecutive days; thereafter, preference testing for ethanol continued for 4 additional days. Whereas the saline vehicle was without effect, FG5938 caused a fivefold decrease in total intake of ethanol from 1.7 to 0.3 g/kg and in proportion of ethanol to total fluid consumed from 0.42 to 0.03. The onset of the significant decline in ethanol drinking occurred during the latter 1.75-h interval. Further, both doses of FG5938, but not saline, increased the intake of food significantly. The decline in ethanol drinking was virtually identical in both P and HEP males and in female HEP rats. These results demonstrate that FG5938 affects ethanol drinking only after 0.5 h of its administration. Finally, it is envisaged that the ingestion of ethanol in genetic high drinking rats is mediated, in part, by central synapses utilizing both 5-HT1A and 5-HT2A receptors.