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

RATIONALE: 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: To compare the hypophagic effect of the 5-HT(2C/1B)-R agonist m-chlorophenylpiperazine (mCPP), with that of the selective 5-HT1B-R agonist CP-94,253 in both wildtype (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 pre-treatment with the selective 5-HT2C-R antagonist SB 242,084 (0.5 and 1.5 mg/kg) were assessed in two groups of WT mice, with each group given only mCPP or CP-94,253. RESULTS: The 5-HT(2C/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 post-prandial activity in 5-HT2C KO mice, but this effect was absent in 5-HT2C KO mice who were given CP-94,253. Data from WT mice, who were pre-treated 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 the 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.

mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor subtypes.

The serotonin receptor agonist mCPP induces hyperlocomotion in 5-HT2C receptor knockout (KO) mice or in the presence of a 5-HT2C receptor antagonist. In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice. We also assess the ability of agonists at these receptors to induce hyperactivity in wildtype (WT) mice pre-treated with a selective 5-HT2C receptor antagonist. As previously reported, mCPP (3 mg/kg) induced hyperactivity in 5-HT2C KO mice. A combination of the 5-HT1B receptor agonist CP-94,253 (20 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg) induced marked hyperactivity in WT but not in 5-HT2C KO mice, nor in mice treated with the selective 5-HT2C receptor antagonist, SB 242084 (1.5 mg/kg). Neither CP-94,253 nor 8-OH-DPAT had any intrinsic effect on locomotion in WTs. mCPP-induced hyperactivity was attenuated in 5-HT2C KO mice by the 5-HT1B receptor antagonist SB 224289 (2.5 mg/kg), and the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg) and M100907 (0.01 mg/kg) but not by the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg). The 5-HT(2A/2B/2C) receptor agonist, Ro 60-0175 (3 mg/kg), induced a modest increase in locomotor activity in WT mice pre-treated with SB 242084. However, the combination of Ro 60-0175 with CP-94,253 induced a substantial increase in activity in 5-HT2C KO mice, an effect comparable to mCPP-induced hyperactivity. Thus, joint activation of 5-HT1A and 5-HT1B receptors stimulates locomotion in WT mice but this response is dependent on a functional 5-HT2C receptor population and hence is absent in 5-HT2C KO mice. By contrast, mCPP-induced hyperactivity depends on the inactivation of a separate 5-HT2C receptor population and is mediated by 5-HT2A and 5-HT1B receptor activation.