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. Administration of d-fenfluramine suppresses food intake in both animals and humans. Objective: We have investigated the role of the 5-HT2c receptor in mediating the effect of d-fenfluramine on mouse food intake and the behavioural satiety sequence. Methods: Mutant mice lacking serotonin 5HT(2C) receptors and wild-type animals were habituated to a daily presentation of wet mash. Animals were non-deprived and received d-fenfluramine (3-30 mg/kg) 30 min prior 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 food 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 consistent 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-fenfluramine had a reduced effect on both food consumption and the behavioural satiety sequence in the 5-HT2C mutant mice. In contrast, mutant mice showed an increased sensitivity to the stereotypy induced by high doses of d-fenfluramine (10, 30 mg/kg) compared to that of wildtype littermates. Conclusion: These data demonstrate a role for the 5-HT2C receptor in mediating d-fenfluramine-induced satiety.