Food Intake and Body Weight Experimental Findings in Rodents

The effect of chronic alterations in caloric intake produced by 5-HT drugs must result in changes in body weight and composition. Thus, a general increase in 5-HT function or selective activation of 5-HT receptors involved in satiety must produce losses in body mass or at least prevent the body weight gain associated with hyperphagia produced by obesity inducing diets. In rodent models of obesity it appears that direct agonism of 5-HT2C receptors does indeed affect weight gain. Vickers et al. (Vickers et al. 2000, 2003), for example, have shown the inhibitory effects of the preferential 5-HT2C receptor agonist mCPP on rodent body weight gain. As mCPP also agonizes several other 5-HT receptors (e.g., 5-HT2A and 5-HT2B receptors), therefore it is theoretically possible that the drug-induced attenuation of body weight gain could be due to activation of any of these receptors. However, using selective antagonists it has been demonstrated that mCPP-induced hypophagia results specifically from activation of the 5-HT2C receptor (Kennett and Curzon 1988b, 1991; Kennett et al. 1997).

The effects of several more selective 5-HT2C receptor agonists on rodent body weight have recently been studied. Vickers et al. (Vickers et al. 2000) infused Ro 60-0175 (26 mg/kg/day) into the animals via implanted mini-pumps for 14 days, which produced a significant reduction in body weight gain. The animals treated with Ro 60-0175 weighed 10% less than controls at the end of the study. Similarly, YM348, another potent and highly selective 5-HT2C receptor agonist, also produced an attenuation of body weight gain over a 2-week treatment period (at doses of 3 and 20 mg/kg/day) (Hayashi et al. 2004). Those animals treated with the higher dose of YM348 weighed 21.5% less than controls at the end of the study. Multiple doses of the novel selective 5-HT2C receptor agonist lorcaserin-APD356 (4.5, 9, 18, and 36 mg/kg) have recently been shown to inhibit the development of dietary-induced obesity (Bjenning et al. 2004). Lorcaserin-APD356 significantly reduced body weight gain in both male and female rats. The reduction in body weight gain was associated with robust hypophagia in the early phase of dosing.

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