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RATIONALE: The possible role of compensatory changes in 5-HT2C receptors in the reduced hypophagic action of d-fenfluramine in 5-HT1B knockout (KO) mice was assessed by comparing their response to d-fenfluramine and the 5-HT2C receptor agonist mCPP. In addition we measured 5-HT(2C/A) receptor binding in 5-HT1B KO and wild-type (WT) mice and examined the effects of 5-HT1B receptor antagonists on d-fenfluramine-induced hypophagia in WT mice. METHODS: Hypophagic responses to d-fenfluramine (1-30 mg/kg) and mCPP (1-5.6 mg/kg) were measured using a behavioural satiety sequence paradigm. The effects of the 5-HT1B receptor antagonists GR 127,935 and SB 224289 in opposing the hypophagic action of d-fenfluramine were evaluated in WT mice. The binding of [3H]-mesulergine was compared in the brains of both mouse strains. RESULTS: The hypophagic effects of moderate doses of d-fenfluramine and mCPP were attenuated in 5-HT1B KO mice. Pretreatment of WT mice with the 5-HT(1B/1D) receptor antagonist GR 127,935, or food-deprived WT mice with the 5-HT1B receptor antagonist SB 224289, did not reproduce the reduction in sensitivity to the effects of d-fenfluramine on feeding behaviour observed in 5-HT1B KO mice. Estimates of 5-HT2C receptor binding were similar in 5-HT1B KO and WT mice. CONCLUSIONS: The hypophagic effect of d-fenfluramine in mice is unlikely to be mediated by the 5-HT1B receptor. Instead, the evidence suggests that an adaptive change in 5-HT2C receptor function occurs in 5-HT1B receptor KO mice and contributes to their reduced response to d-fenfluramine.

Original publication

DOI

10.1007/s00213-004-1864-0

Type

Journal article

Journal

Psychopharmacology (Berl)

Publication Date

10/2004

Volume

176

Pages

39 - 49

Keywords

Animals, Binding Sites, Cerebral Cortex, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Evaluation, Preclinical, Eating, Ergolines, Fenfluramine, Genotype, Injections, Intraperitoneal, Injections, Subcutaneous, Isomerism, Mianserin, Mice, Mice, Knockout, Piperazines, Piperidones, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Satiation, Satiety Response, Serotonin 5-HT2 Receptor Agonists, Species Specificity, Spiperone, Spiro Compounds, Time Factors, Tritium, United Kingdom