ABSENCE OF FENFLURAMINE-INDUCED ANOREXIA AND REDUCED C-FOS INDUCTION IN THE HYPOTHALAMUS AND CENTRAL AMYGDALOID COMPLEX OF SEROTONIN 1B RECEPTOR KNOCK-OUT MICE

Fenfluramine, a serotonin releaser and uptake inhibitor, has been wide ly prescribed as an appetite suppressant. Despite its popular clinical use, however, the precise neural pathways and specific 5-HT receptors that account for its anorectic effect have yet to be elucidated. To t est the hypothesis that stimulation of 5-HT1B receptors is required fo r the anorectic effect of fenfluramine, we assessed food intake in wil d-type and 5-HT1B knock-out mice. Next, to determine possible brain st ructures and pathways that may contribute to the 5-HT1B-mediated effec ts of fenfluramine, we studied by immunohistochemistry the induction o f the immediate early gene c-fos. Although the effect of fenfluramine on locomotion was indistinguishable between both wild-type and 5-HT1B. knock-out mice, the anorectic effect of the drug was absent in only t he knock-out mice. Furthermore, the induction of c-Fos immunoreactivit y found in the paraventricular nucleus of the hypothalamus (PVN) of wi ldtype mice was substantially reduced in the knock-outs. Induction in the central amygdaloid nucleus (CeA) and in the bed nucleus of the str ia terminalis (BNST), although robust in wildtype animals, was complet ely absent in knock-out animals. The mixed 5-HT1A/1B agonist RU24969 w as able to mimic both the hypophagia and c-fos induction elicited by f enfluramine in wildtype mice, but not in the 5-HT1B knock-out mice: Ou r results thus demonstrate that stimulation of 5-HT1B receptors is req uired for fenfluramine-induced anorexia and suggest a role for the PVN , CeA, and BNST in mediating this effect.