Submitted on July 22, 2006
Accepted on January 9, 2007
Milnacipran, a serotonin and noradrenalin reuptake inhibitor, induces appetite suppressing effects without inducing hypothalamic stress responses in mice
Katsunori Nonogaki1*, Kana Nozue1, Tomifusa Kuboki2, and Yoshitomo Oka3
1 COE, Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
2 Psychosomatic Medicine, University of Tokyo, Tokyo, Japan
3 Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
* To whom correspondence should be addressed. E-mail: knonogaki-tky{at}umin.ac.jp.
Milnacipran, a selective serotonin (5-hydroxytryptamine; 5-HT) and noradrenalin (NA) reuptake inhibitor increases extracellular 5-HT and NA levels equally in the central nervous system. Here we report that systemic administration of milnacipran (20-60 mg/kg) significantly suppressed food intake after fasting in C57BL6J mice. The appetite suppressing effects of milnacipran were sustained for 5 h. Neither SB242084, a selective 5-HT2C receptor antagonist, nor SB224289, a selective 5-HT1B receptor antagonist, reversed the appetite suppressing effects of milnacipran. Milnacipran 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 pro-opiomelanocortin (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 mRNA levels. Interestingly, milnacipran did not increase plasma corticosterone and blood glucose levels, whereas fenfluramine, 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 milnacipran had no effects on food intake in food restricted wild-type mice and Ay mice. On the other hand, fenfluramine suppressed food intake in food restricted wild type mice, but it had no effects in food restricted Ay mice. These results suggest that inhibition of 5-HT and NA reuptake induces appetite suppressing effects independent of 5-HT2C and 5-HT1B receptors, and increases hypothalamic POMC and CART gene expression without increasing plasma corticosterone and blood glucose levels in mice.
