title: Milnacipran, a serotonin and norepinephrine reuptake inhibitor, induces appetite-suppressing effects without inducing hypothalamic stress responses in mice.
abstract: Milnacipran, a selective serotonin (5-HT) and norepinephrine (NE) 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 A(y) mice, which have ectopic expression of the agouti protein. Moreover, milnacipran significantly increased hypothalamic proopiomelanocortin (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 A(y) mice. On the other hand, fenfluramine 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-HT1B receptors, and increases hypothalamic POMC and CART gene expression without increasing plasma corticosterone and blood glucose levels in mice.
authors.affiliation: Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku Univ Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, Japan. knonogaki-tky@umin.ac.jp
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nonogaki
authors.forename: Kana
authors.initials: K
authors.lastname: Nozue
authors.forename: Tomifusa
authors.initials: T
authors.lastname: Kuboki
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D001066:Appetite / Q000187:drug effects* / Q000502:physiology; D001067:Appetite Depressants / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D005277:Fenfluramine / Q000494:pharmacology; D005508:Food Deprivation; D007031:Hypothalamus / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013312:Stress, Physiological
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001067:Appetite Depressants; D001786:Blood Glucose; D003345:Corticosterone; D003521:Cyclopropanes; D005277:Fenfluramine; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors