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 pharmacological mechanisms underlying d-fenfluramine- and d-norfenfluramine-induced hypophagia in the rat using highly selective serotonin 5-HT2 receptor antagonists. Administration of d-fenfluramine, and its major metabolite d-norfenfluramine, suppresses food intake in animals. Both compounds stimulate the release of serotonin and are potent inhibitors of the re-uptake of 5-HT into nerve terminals. In addition, d-norfenfluramine also acts as a direct 5-HT(2B/2C) receptor agonist. Pre-treatment with the selective 5-HT2C receptor antagonist, SB-242084 (0.3-3 mg/kg), dose-dependently inhibited both d-fenfluramine- (3 mg/kg) and d-norfenfluramine-induced (2 mg/kg) hypophagia. In contrast, the hypophagic effect of d-fenfluramine and d-norfenfluramine was unaffected by prior treatment with the highly selective 5-HT2B receptor antagonists, SB-215505 (0.3-3 mg/kg) and RS-127445 (1-3 mg/kg) or the 5-HT2A receptor 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 provide unequivocal evidence for an important role of the 5-HT2C receptor in the 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.
Vickers
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SP
Vernalis Research Limited, Oakdene Court, 613 Reading Road, Winnersh RG41 5UA, UK. s.vickers@vernalis.com
Dourish
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CT
Kennett
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GA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D009642:Norfenfluramine / Q000494:pharmacology*; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D005277:Fenfluramine; D009642:Norfenfluramine; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors