Thermogenic effect of YM348, a novel 5-HT2C-receptor agonist, in rats

We have investigated the effect of S-2-(7-ethyl-1H-furo2,3-g]indazol-1-yl)-1-methylethylamine (YM348), a novel 5-HT(2C)-receptor agonist, on body temperature and energy expenditure in Wistar rats. m-Chlorophenylpiperazine (mCPP) and S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (RO 60-0175) were used as reference 5-HT(2C)-receptor agonists. Administration of YM348, mCPP and RO 60-0175 dose-dependently and significantly increased body temperature in rats. YM348- or RO 60-0175-induced hyperthermia was significantly attenuated by the non-selective 5-HT(2)-receptor antagonist methysergide and the selective 5-HT(2C)-receptor antagonist SB242084, but not by the selective 5-HT(2A)-receptor antagonist MDL100907. mCPP-induced hyperthermia was significantly attenuated by methysergide, SB242084 and MDL100907. In addition to the increase in body temperature, YM348, mCPP and RO 60-0175 produced dose-related and significant increases in energy expenditure. YM348-, mCPP- and RO 60-0175-induced increases in energy expenditure were significantly attenuated by methysergide and SB242084 but not by MDL100907. These results suggested that 5-HT(2C)-receptor stimulation increased body temperature and energy expenditure and that the 5-HT(2C)-receptor was the target receptor in the thermogenic effect of YM348 in Wistar rats.