Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice

Rationale: d-Fenfluramine stimulates the release of serotonin (5-HT) and is a potent inhibitor of the re-uptake of 5-HT into nerve terminals. Administ ration of d-fenfluramine suppresses food intake in both animals and humans. Objective: We have investigated the role of the 5-HT2c receptor in mediati ng the effect of d-fenfluramine on mouse food intake and the behavioural sa tiety sequence. Methods: Mutant mice lacking serotonin 5HT(2C) receptors an d wild-type animals were habituated to a daily presentation of wet mash. An imals were non-deprived and received d-fenfluramine (3-30 mg/kg) 30 min pri or to being assessed for the presence of stereotypy and presented with wet mash. The behaviour of animals was observed for the subsequent 40 min and f ood intake was recorded. Results: d-Fenfluramine dose-dependently inhibited the consumption of a palatable wet mash by the mice. d-Fenfluramine (3 mg/ kg) significantly reduced the amount of wet mash consumed by wild-type mice and induced a temporal advance in the behavioural satiety sequence consist ent with an enhancement of satiety. Mutant mice were less sensitive to the satiating effects of 3 mg/kg d-fenfluramine. Hence, this dose of d-fenflura mine had a reduced effect on both food consumption and the behavioural sati ety sequence in the 5-HT2C mutant mice. In contrast, mutant mice showed an increased sensitivity to the stereotypy induced by high doses of d-fenflura mine (10, 30 mg/kg) compared to that of wildtype littermates. Conclusion: T hese data demonstrate a role for the 5-HT2C receptor in mediating d-fenflur amine-induced satiety.