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

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Abstract

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.

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Acknowledgements

M.D.L. was supported by BBSRC (UK) LINK project grant 85/LKD12007. We are very grateful to Professor Rene Hen for providing our initial breeding stocks of 5-HT1B KO and WT mice.

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  1. Michelle D. Lee

    Present address: Department of Psychology, University of Swansea, Swansea, SA2 8PP, UK

Authors and Affiliations

  1. Department of Psychology, University of Sussex, Brighton, Sussex, BN1 9QG, UK

    Michelle D. Lee, Elizabeth M. Somerville & Peter G. Clifton

  2. Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh, Wokingham, RG41 5UA, UK

    Guy A. Kennett & Colin T. Dourish

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  1. Michelle D. Lee
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  2. Elizabeth M. Somerville
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  3. Guy A. Kennett
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  5. Peter G. Clifton
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Correspondence to Peter G. Clifton.

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Lee, M.D., Somerville, E.M., Kennett, G.A. et al. Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice. Psychopharmacology 176, 39–49 (2004). https://doi.org/10.1007/s00213-004-1864-0

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  • DOI: https://doi.org/10.1007/s00213-004-1864-0

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