AIMS Many patients taking risperidone for the treatment of psychiatric disorders experience substantial body weight gain. Researchers have speculated that risperidone induces obesity by modulating central signals; however, the precise central mechanisms involved remain to be fully elucidated. METHODS Twenty-four C57BL/6J mice were divided into four groups: a control group; a risperidone-treated group; a lorcaserin-treated group; and a combined risperidone + lorcaserin-treated group. The mice were received the corresponding treatments for 4 weeks, and their brains were collected for in situ hybridization analysis. A subset of C57BL/6J mice was administrated with risperidone or placebo, and brains were collected 60 minutes post-treatment for determination of c-fos activity. In addition, brains of NPY-GFP mice treated with or without risperidone were collected to perform colocalization of NPY and c-fos, as well as NPY and 5-HT2c receptor using immunohistochemistry. RESULTS There was significantly elevated c-fos expression in the hypothalamic arcuate nucleus (Arc) of risperidone-treated mice. More than 68% c-fos-positive neurons were NPY-expressing neurons. Furthermore, in situ hybridization revealed that Arc NPY mRNA expression was significantly increased in the risperidone-treated group compared with control group. Moreover, we identified that 95% 5-HT2c receptors were colocalized with NPY positive neurons, and increased Arc NPY mRNA expression induced by risperidone was markedly reduced by cotreatment with lorcaserin, a specific 5-HT2c receptor agonist. CONCLUSION Our findings provide critical insight into the mechanisms underlying antipsychotic-induced obesity, which may assist the development of therapeutic strategies to address metabolic side effects of risperidone.

中文翻译：

---

利培酮通过下丘脑弓状核 5-HT2c 受体-NPY 通路刺激食物摄入并诱导体重增加。

目的 许多服用利培酮治疗精神疾病的患者体重明显增加。研究人员推测，利培酮通过调节中枢信号诱发肥胖；然而，所涉及的确切中心机制仍有待充分阐明。方法 24只C57BL/6J小鼠分为四组：对照组；利培酮治疗组；氯卡色林治疗组；和利培酮+氯卡色林联合治疗组。小鼠接受相应治疗4周，取脑进行原位杂交分析。给一部分 C57BL/6J 小鼠施用利培酮或安慰剂，并在治疗后 60 分钟收集大脑以确定 c-fos 活性。此外，收集用或不用利培酮治疗的 NPY-GFP 小鼠的大脑，以使用免疫组织化学对 NPY 和 c-fos 以及 NPY 和 5-HT2c 受体进行共定位。结果 利培酮治疗小鼠的下丘脑弓状核 (Arc) 中 c-fos 表达显着升高。超过 68% 的 c-fos 阳性神经元是表达 NPY 的神经元。此外，原位杂交显示，与对照组相比，利培酮治疗组的 Arc NPY mRNA 表达显着增加。此外，我们发现 95% 的 5-HT2c 受体与 NPY 阳性神经元共定位，并且通过与 lorcaserin（一种特定的 5-HT2c 受体激动剂）共同处理，利培酮诱导的 Arc NPY mRNA 表达增加显着降低。