Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice.
BACKGROUND
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.
Lee
Michelle D
MD
Department of Psychology, University of Sussex, Brighton, Sussex, BN1 9QG, UK.
Somerville
Elizabeth M
EM
Kennett
Guy A
GA
Dourish
Colin T
CT
Clifton
Peter G
PG
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004435:Eating / Q000187:drug effects; D004873:Ergolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D005277:Fenfluramine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005838:Genotype; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007536:Isomerism; D008803:Mianserin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010881:Piperidones / Q000008:administration & dosage / Q000493:pharmacokinetics; D044302:Receptor, Serotonin, 5-HT1B / Q000172:deficiency* / Q000235:genetics*; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C / Q000008:administration & dosage; D012527:Satiation / Q000187:drug effects* / Q000502:physiology; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology; D058826:Serotonin 5-HT2 Receptor Agonists; D013045:Species Specificity; D013134:Spiperone / Q000494:pharmacology; D013141:Spiro Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium; D006113:United Kingdom
D004873:Ergolines; D010879:Piperazines; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; C108518:SB 22489G; D058826:Serotonin 5-HT2 Receptor Agonists; D013141:Spiro Compounds; D014316:Tritium; D008803:Mianserin; D005277:Fenfluramine; D013134:Spiperone; C015068:1-(3-chlorophenyl)piperazine; C031649:mesulergine