Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors

The present series of studies is the first to investigate the pharmacologic al mechanisms underlying d-fenfluramine- and d-norfenfluramine-induced hypo phagia in the rat using highly selective serotonin 5-HT2 receptor antagonis ts. Administration of d-fenfluramine, and its major metabolite d-norfenflur amine, suppresses food intake in animals. Both compounds stimulate the rele ase of serotonin and are potent inhibitors of the re-uptake of 5-HT into ne rve terminals. In addition, d-norfenfluramine also acts as a direct 5-HT2B/ 2C receptor agonist. Pre-treatment with the selective 5-HT2C receptor antag onist, SB-242084 (0.3-3 mg/kg), dose-dependently inhibited both d-fenfluram ine- (3 mg/kg) and d-norfenfluramine-induced (2 mg/kg) hypophagia. In contr ast, the hypophagic effect of d-fenfluramine and d-norfenfluramine was unaf fected by prior treatment with the highly selective 5-HT2B receptor antagon ists, SB-215505 (0.3-3 mg/kg) and RS-127445 (1-3 mg/kg) or the 5-HT2A recep tor antagonists MDL 100,907 (0.003-0.03 mg/kg) and ketanserin (0.2, 0.5 mg/ kg). In addition, the 5-HT1A receptor antagonist WAY-100635 (0.3, 1 mg/kg) and the 5-HT1B receptor antagonists GR-127935 (1, 2 mg/kg) and SB-224289 (2 -10 mg/kg) did not affect d-fenfluramine-induced hypophagia. These data pro vide unequivocal evidence for an important role of the 5-HT2C receptor in t he mediation of d-fenfluramine and d-norfenfluramine-induced hypophagia in the rat and do not support the involvement of 5-HT1A/1B/2A/2B receptors. (C ) 2001 Elsevier Science Ltd. All rights reserved.