Role of 5-HT2C receptors in the hypophagic effect of m-CPP, ORG 37684 and CP-94,253 in the rat

Compounds that stimulate 5-HT(2C) and/or 5-HT(1B) receptors induce hypophagia, but the relative role of these receptors in the control of feeding behaviour remains to be unequivocally demonstrated. The objectives of the present study were: (a) comparison of the hypophagic effect of the mixed 5-HT(2C/1B) receptor agonist, m-CPP, with that of ORG 37684 and CP-94.253, a relatively selective 5-HT(2C) and 5-HT(1B) receptor agonist, respectively (b) verification of the contribution of 5-HT(2C) receptors to the hypophagic effect of these compounds by antagonism experiments, and (c) to test whether cotreatment with ORG 37684 and CP-94,253 leads to a more pronounced reduction of food intake as compared with treatment with either compound alone. Food intake was measured in a free feeding experimental protocol employing female Wistar rats. m-CPP was more potent in suppressing food intake than ORG 37684 and CP-94,253 (ED(50) values for the first hour of access: 0.45, 1.84 and 3.48 mg/kg ip, respectively). The 5-HT(2C) receptor antagonists, metergoline and SB 242,084, completely reversed the hypophagic effect of ORG 37684, but not that of CP-94,253 and m-CPP. The hypophagic effect of ORG 37684 was potentiated by a low (inactive) dose of CP-94.253 (ED(50): 4.95 and 2.44 mg/kg ip after vehicle and CP-94,253 pretreatment, respectively) and vice versa (ED(50) values: 4.02 and 0.62 mg/kg ip). It is concluded that the hypophagic effect of ORG 37684-but not that of m-CPP and CP-94,253 is exclusively mediated by activation of 5-HT(2C) receptors. The results further indicate that simultaneous activation of 5-HT(2C) and 5-HT(1B) receptors underlies the higher potency of m-CPP in reducing food intake, as compared with other, more selective, compounds. (C) 2001 Elsevier Science Inc. All rights reserved.