Serotonin 1B and 2C receptor interactions in the modulation of feeding behaviour in the mouse

Rationale: This study was conducted to examine the functional relationship between 5-HT1B receptors (5-HT1B-R) and 5-HT2C receptors (5-HT2C-R) in the control of food intake. Objectives: The aim of this study was to compare the hypophagic effect of the 5-HT2C/1B-R agonist m-chlorophenylpiperazine (mCPP) with that of the selective 5-HT1B-R agonist CP-94,253 in both wild-type (WT) and 5-HT2C knockout (KO) mice. Methods: The hypophagic effects of mCPP (1, 3 and 5.6 mg/kg) and CP-94,253 (5, 10 and 20 mg/kg) were assessed in WT and 5-HT2C KO mice using the behavioural satiety sequence paradigm. The effects of pretreatment with the selective 5-HT2C-R antagonist SB 242,084 (0.5 and 1.5 mg/kg) were assessed in WT mice given mCPP or CP-94,253. Results: The 5-HT2C/1B receptor agonist mCPP and the selective 5-HT1B receptor agonist CP-94,253 both suppressed food intake in WT mice. 5-HT2C KO mice were insensitive to the hypophagic effects of mCPP but were more sensitive to CP-94,253-induced hypophagia than WT controls. mCPP induced a significant increase in postprandial activity in 5-HT2C KO mice but this effect was absent in 5-HT2C KO mice given CP-94,253. Data from WT mice pretreated with the 5-HT2C receptor antagonist SB 242,084 and then challenged with either mCPP or CP-94,253 were similar to those obtained from 5-HT2C KO mice. Conclusions: 5-HT2C-R and 5-HT1B-R activation are each sufficient to induce a hypophagic response. However, concurrent 5-HT2C-R inactivation can potentiate the hypophagic response to 5-HT1B-R activation, consistent with an inhibitory role for the 5-HT2C-R in behaviour mediated by activation of other 5-HT receptors. These results also confirm that 5-HT1B-R activation alone cannot account for the hyperactive response of 5-HT2C KO mice to mCPP.