Nonogaki Katsunori, Ohba Yukie, Wakameda Mamoru, Tamari Tomohiro
Centre of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Int J Neuropsychopharmacol. 2009 May;12(4):547-52. doi: 10.1017/S1461145708009619. Epub 2008 Oct 31.
Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m-chlorophenylpiperazine (mCPP) and fenfluramine. We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor, together with pharmacological inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors in mice. Here, we report that fluvoxamine exerted anorexic effects in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene (2CREnd mice), whereas fluvoxamine had no effect on food intake in age-matched wild-type mice and 5-HT2C receptor mutant mice, which are associated with decreases in hypothalamic proopiomelanocortin (POMC) expression. mCPP suppressed food intake in 5-HT2C receptor mutant mice, 2CREnd mice and age-matched wild-type mice. These results suggest that fluvoxamine-induced feeding suppression requires a perturbation of 5-HT2C receptor and beta-endorphin signalling plus functional hypothalamic POMC activity, whereas mCPP-induced feeding suppression does not always require functional 5-HT2C receptor, beta-endorphin, and POMC activity in mice.
血清素（5-羟色胺；5-HT）2C受体及下游的促黑素细胞激素途径被认为介导了间氯苯哌嗪（mCPP）和芬氟拉明的厌食作用。我们之前报道过，选择性5-羟色胺再摄取抑制剂氟伏沙明与5-HT2C受体的药理学失活共同作用，通过激活小鼠体内的5-HT1B受体来抑制进食。在此，我们报道氟伏沙明在β-内啡肽基因杂合突变的5-HT2C受体突变小鼠（2CREnd小鼠）中发挥厌食作用，而氟伏沙明对年龄匹配的野生型小鼠和5-HT2C受体突变小鼠的食物摄入量没有影响，这些小鼠下丘脑阿片促黑素原（POMC）表达降低。mCPP抑制了5-HT2C受体突变小鼠、2CREnd小鼠及年龄匹配的野生型小鼠的食物摄入量。这些结果表明，氟伏沙明诱导的进食抑制需要5-HT2C受体和β-内啡肽信号传导的扰动以及下丘脑POMC的功能活性，而mCPP诱导的进食抑制在小鼠中并不总是需要功能性的5-HT2C受体、β-内啡肽和POMC活性。
