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Risperidone stimulates food intake and induces body weight gain via the hypothalamic arcuate nucleus 5-HT2c receptor-NPY pathway


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.

Type Journal
ISBN 1755-5949 (Electronic) 1755-5930 (Linking)
Authors Wan, X. Q.; Zeng, F.; Huang, X. F.; Yang, H. Q.; Wang, L.; Shi, Y. C.; Zhang, Z. H.; Lin, S.
Responsible Garvan Author A/Prof Yanchuan Shi
Publisher Name CNS Neuroscience & Therapeutics
Published Date 2020-05-31
Published Volume 26
Published Issue 5
Published Pages 558-566
Status Published in-print
DOI 10.1111/cns.13281
URL link to publisher's version