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Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice
Michelle D Lee1, Elizabeth M Somerville, Guy A Kennett
1Department of Psychology, University of Sussex, Brighton, Sussex, BN1 9QG, UK.
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.
Insights
Reduced appetite effects of d-fenfluramine in serotonin 1B receptor knockout mice are linked to adaptive changes in serotonin 2C receptor function. This suggests 5-HT2C receptor adaptations, not 5-HT1B receptor mediation, underlie altered responses to d-fenfluramine.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Investigating the role of serotonin receptors in appetite regulation.
- Examining compensatory mechanisms in genetically modified mouse models.
- Assessing the impact of serotonin 1B receptor deficiency on drug responses.
Purpose of the Study:
- To determine if 5-HT2C receptor changes mediate d-fenfluramine's reduced effect in 5-HT1B KO mice.
- To compare responses to d-fenfluramine and mCPP in 5-HT1B KO and wild-type mice.
- To evaluate the influence of 5-HT1B receptor antagonists on d-fenfluramine's hypophagic action.
Main Methods:
- Behavioral satiety sequence paradigm to measure hypophagia.
- Administration of d-fenfluramine and the 5-HT2C agonist mCPP.
- Assessment of 5-HT2C/5-HT2A receptor binding and effects of 5-HT1B antagonists.
Main Results:
- Hypophagic effects of d-fenfluramine and mCPP were reduced in 5-HT1B KO mice.
- 5-HT1B receptor antagonists did not replicate the reduced sensitivity seen in KO mice.
- 5-HT2C receptor binding was similar between 5-HT1B KO and WT mice, suggesting functional adaptation.
Conclusions:
- The hypophagic effect of d-fenfluramine is not primarily mediated by the 5-HT1B receptor.
- Adaptive changes in 5-HT2C receptor function in 5-HT1B KO mice contribute to their blunted response to d-fenfluramine.
- This highlights the complex interplay between serotonin receptor subtypes in regulating feeding behavior.
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