Suppression of alcohol consumption by fenfluramine in Fawn-Hooded rats with serotonin dysfunction

Abstract

The high preference for alcohol intake observed in Fawn-Hooded rats has been attributed to the central serotonin (5-HT) dysfunction in this strain. To further characterize the involvement of 5-HT in alcohol-seeking behavior in Fawn-Hooded rats, the effect of both acute and subchronic administration of fenfluramine, a 5-HT releaser, on alcohol intake and preference was determined. Rats were individually housed and provided free access to a solution of 10% alcohol, food, and water. After establishing a stable baseline, rats were injected twice daily for 1 day or for 5 consecutive days either with saline or 0.1, 0.25, 0.5, and 1.0 mg/kg of fenfluramine at 0930 h and 1600 h, and their consumption of alcohol, food, and water was measured for 24 h. Another group of rats scheduled with a limited access (1 h/day) to alcohol and free access to food and water were injected with either saline or 0.25, 0.5, 0.75, and 1.0 mg/kg fenfluramine 20 min before exposure to alcohol, and their alcohol consumption was measured at the end of 1 h exposure. Further, to determine the effect of fenfluramine on alcohol metabolism, rats were injected with 1.0 mg/kg fenfluramine or saline and 15 min later with 2.5 g/kg alcohol (16%, v/v). Blood alcohol levels were then measured at 1, 3, and 5 h after alcohol administration. Our results demonstrate that both acute and subchronic administration of fenfluramine dose-dependently attenuate alcohol intake and increased water intake without a significant effect on food intake. Fenfluramine did not affect the pharmacokinetics of alcohol, indicating a central effect. These findings provide more support for the involvement of the serotonergic system in excessive alcohol consumption and indicate that fenfluramine exerts an attenuating effect on alcohol intake by enhancing the activation of serotonergic systems in the brain.