title: Rikkunshito and isoliquiritigenin counteract 5-HT-induced 2C receptor-mediated activation of pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus.
abstract: Anorexia deteriorates the quality of life in patients with anorexia nervosa, stress disorders, gastrointestinal disorders, and cancer. Pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC), serotonin (5-HT) and its 2C receptor (5-HT2CR) are implicated in anorexia. Rikkunshito, a traditional Japanese medicine, has been used to treat anorexia and gastrointestinal disorders. The present study aimed to clarify whether rikkunshito influences the 5-HT action on ARC POMC neurons. We isolated single neurons from the ARC of adult rats and measured cytosolic Ca²⁺ concentration ([Ca²⁺](i)) by fura-2 microfluorometry combined with immunocytochemical identification of POMC neurons. Administration of 5-HT increased [Ca²⁺](i) in ARC neurons, and 80% of the 5-HT-responsive neurons were immunoreactive to POMC. Rikkunshito concentration-dependently and 5-HT2CR antagonist SB242084 significantly suppressed 5-HT-induced [Ca²⁺](i) increases. The rikkunshito-suppressed neurons highly overlapped SB242084-suppressed neurons. Isoliquiritigenin, an ingredient of rikkunshito, suppressed 5-HT-induced [Ca²⁺](i) increases to a lesser extent than rikkunshito. These results demonstrate that rikkunshito counteracts 5-HT-induced 5-HT2CR-mediated Ca²⁺ signaling in ARC POMC neurons, and that isoliquiritigenin may serve as an active component of rikkunshito. The ability of rikkunshito to antagonize 5-HT action in ARC POMC neurons could underlie the rikkunshito's action to attenuate anorexia induced by excessive 5-HT release and/or action associated with psychiatric diseases, gastrointestinal disorders, cancer, and anti-cancer medicines.
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 3290498, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Arai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maejima
authors.forename: Shinji
authors.initials: S
authors.lastname: Muroya
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*
chemical_list: D047188:Chalcones; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D044405:Receptor, Serotonin, 5-HT2C; C084136:liu-jun-zi-tang; D012701:Serotonin; D011333:Pro-Opiomelanocortin; C040920:isoliquiritigenin; D002118:Calcium