Milnacipran, a serotonin and norepinephrine reuptake inhibitor, induces appetite-suppressing effects without inducing hypothalamic stress responses in mice

Milnacipran, a selective serotonin (5-HT) and norepirrephrine (NE) reuptake inhibitor, increases extracellular 5-HT and NA levels equally in the central nervous system. Here, we report that systen-fic administration of milnacipran (20-60 mg/kg) significantly suppressed food intake after fasting in C57BL6J nrice. The appetite-suppressing effects of milnacipran were sustained for 5 h. Neither S13242084, a selective 5-HT2C receptor antagonist, nor S13224289, a selective 5-HTIB receptor antagonist, reversed the appetite-suppressing effects of milnacipran. Miltracipran suppressed food intake and body weight in wild-type mice and in AY mice, which have ectopic expression of the agouti protein. Moreover, milnacipran significantly increased hypothalamic proopionrelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA levels, while having no effect on hypothalamic neuropeptide Y, ghrelin, corticotropin-releasing hormone (CRH), and suppressor of cytokine signaling-3 rnRNA levels. Interestingly, milnacipran did not increase plasma corticosterone and blood glucose levels, whereas fenflurairrine, which inhibits 5-HT reuptake and stimulates 5-HT release, significantly increased plasma corticosterone and blood glucose levels in association with increased hypothalamic CRH mRNA levels. The appetite-suppressing effects of rnilnacipran had no effects on food intake in food-restricted, wild-type nrice and A(y) mice. On the other hand, fenflurarnine suppressed food intake in food-restricted wild-type mice, but it had no effects in food-restricted A(y) mice. These results suggest that inhibition of 5-HT and NA reuptake induces appetite-suppressing, effects independent of 5-HT2C and 5-HTIB receptors, and increases hypothalamic POMC and CART gene expression without increasing plasma corticosterone and blood glucose levels in mice.