Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice

Lee, Michelle D, Somerville, Elizabeth M, Kennett, Guy A, Dourish, Colin T and Clifton, Peter G (2004) Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice. Psychopharmacology, 176 (1). pp. 39-49. ISSN 0033-3158

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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-HT2C/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-HT1B/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.

Item Type: Article
Additional Information: E.M.Somerville took the lead in the interpretation of the result of the binding study and co-authored the paper in collaboration with P.G.Clifton and M.D.Lee. This study explores the effects of knocking out one receptor on a second receptor for the same neurotransmitter using the analysis of behaviour and receptor binding.
Schools and Departments: School of Life Sciences > Neuroscience
Depositing User: Liz Somerville
Date Deposited: 06 Feb 2012 19:34
Last Modified: 23 Mar 2012 15:07
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