{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:37:07Z","timestamp":1779921427470,"version":"3.53.1"},"reference-count":60,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T00:00:00Z","timestamp":1724112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009337","name":"Saitama Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009337","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013420","name":"Tsumura and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013420","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined the effects of RKT on food intake and neuronal c\u2010Fos expression in restraint stress\u2010 and cholecystokinin octapeptide\u2010induced anorexia in male rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>RKT treatment significantly restored stress\u2010 and cholecystokinin octapeptide\u2010induced decreased food intake. RKT increased c\u2010Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase\u2010immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D\u2010Lys<jats:sup>3<\/jats:sup>]\u2010GHRP\u20106. RKT increased the number of c\u2010Fos\/orexin\u2010double\u2010positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT\u2010induced increase in food intake and c\u2010Fos expression in the LH, VTA, and NAc. RKT increased c\u2010Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D\u2010Lys<jats:sup>3<\/jats:sup>]\u2010GHRP\u20106.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>RKT may restore appetite in subjects with anorexia through ghrelin\u2010 and orexin\u2010dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.14900","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T02:11:32Z","timestamp":1724292692000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rikkunshito improves anorexia through ghrelin\u2010 and orexin\u2010dependent activation of the brain hypothalamus and mesolimbic dopaminergic pathway in rats"],"prefix":"10.1111","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9917-5542","authenticated-orcid":false,"given":"Koji","family":"Yakabi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshige","family":"Takayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Hosomi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaro","family":"Hori","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoki","family":"Ro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuko","family":"Ochiai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Maezawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichi","family":"Yakabi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"},{"name":"Department of Gastroenterology University of Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Harada","sequence":"additional","affiliation":[{"name":"TSUMURA Kampo Research Laboratories, TSUMURA \uff06 CO.  Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Fujitsuka","sequence":"additional","affiliation":[{"name":"TSUMURA Kampo Research Laboratories, TSUMURA \uff06 CO.  Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumiko","family":"Nagoshi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Saitama Medical Center Saitama Medical University  Kawagoe City Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.2147\/CEG.S26297"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-011-0488-5"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.5754\/hge11246"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.49.3803"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.02.078"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecam\/nep173"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12348"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000355608"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1479-8301.2010.00347.x"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13319"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-021-01843-7"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.curtheres.2017.07.003"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05026"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0306-4522(98)00583-1"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1369-1600.2010.00216.x"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-21-09130.1998"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.02.016"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00695.2010"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0061"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1037\/h0034870"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111809"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(81)80115-1"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1994.tb44077.x"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2008.02041.x"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.03.039"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.03.035"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.psy.0000075977.90337.e7"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-020-03079-y"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.04.214"},{"key":"e_1_2_12_31_1","volume-title":"Paxino's and Watson's the Rat Brain in Stereotaxic Coordinates","author":"Paxinos G","year":"2014"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(89)90150-7"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2010.06249.x"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/35007534"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0896-6273(02)00969-8"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.8.1714"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/35038090"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.12.8111"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/45230"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.35954"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20823"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0133159"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2011.25"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13177"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-0633"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnsys.2017.00050"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80949-6"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.017"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04071"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0896-6273(03)00063-1"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1656"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2002-220788"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-3940(02)00241-0"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-381272-8.00021-0"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(94)90111-2"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90635-m"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0006-8993(97)00865-2"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.07.084"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2023.12.046"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15219"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-0340"}],"container-title":["Neurogastroenterology &amp; Motility"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/nmo.14900","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T11:46:35Z","timestamp":1730893595000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/nmo.14900"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,20]]},"references-count":60,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1111\/nmo.14900"],"URL":"https:\/\/doi.org\/10.1111\/nmo.14900","archive":["Portico"],"relation":{},"ISSN":["1350-1925","1365-2982"],"issn-type":[{"value":"1350-1925","type":"print"},{"value":"1365-2982","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,20]]},"assertion":[{"value":"2023-11-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14900"}}