Fluvoxamine, a selective serotonin reuptake inhibitor, and 5-HT _2C receptor inactivation induce appetite-suppressing effects in mice via 5-HT_1B receptors

Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the appetite-suppressing effects of 5-HT drugs such as m-chlorophenylpiperazine (mCPP) and fenfluramine. Here, we report that fluvoxamine (3-30 mg/kg), a selective serotonin reuptake inhibitor (SSRI), in the presence of SB 242084 (1-2 mg/kg), a selective 5-HT_2C receptor antagonist, exerts appetite-suppressing effects while fluvoxamine or SB 242084 alone has no effect. The appetite-suppressing effects were attenuated in the presence of SB 224289 (5 mg/kg), a selective 5-HT_1B receptor antagonist. Moreover, CP 94253 (5-10 mg/kg), a selective 5-HT_1B receptor agonist, exerted appetite-suppressing effects and significantly increased hypothalamic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) gene expression and decreased hypothalamic orexin gene expression. These results suggest that fluvoxamine and inactivation of 5-HT_2C receptors exert feeding suppression through activation of 5-HT_1B receptors, and that 5-HT_1C receptors up-regulate hypothalamic POMC and CART gene expression and down-regulate hypothalamic orexin gene expression in mice.