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The purpose of this study was to investigate the molecular mechanisms underlying the antidepressant effects of CSS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Behavioral experiments and ELISA were employed to assess depressive-like behaviors and measure serum ACTH and CORT levels in chronic unpredictable mild stress (CUMS) rats. Western blotting, immunofluorescence, and Co-Immunoprecipitation were used to analyze \u03b12\u03b4-1 and NMDAR subunit NR1 expression and interactions in the hypothalamus. Cacna2d1 gene knockout and a disruptive peptide (\u03b12\u03b4-1 Tat) were applied in vitro to investigate the \u03b12\u03b4-1-NR1 complex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>CSS ameliorated depressive-like behaviors in CUMS rats and decreased serum levels of ACTH and CORT. CSS reversed the upregulated expression of \u03b12\u03b4-1 and NR1 in the hypothalamus of CUMS rats, weakening the \u03b12\u03b4-1-NR1 complex binding. When the Cacna2d1 gene was knocked out or the \u03b12\u03b4-1-NR1 complex was disrupted with \u03b12\u03b4-1 Tat peptide, CSS-containing serum failed to significantly enhance NR1 expression in PC12 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CSS ameliorates depressive-like behaviors in CUMS rats by interfering with the \u03b12\u03b4-1-NR1 complex, reducing the expression levels of \u03b12\u03b4-1 and NR1 in the hypothalamus, and consequently inhibiting the excessive excitability of the hypothalamic\u2013pituitary\u2013adrenal axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jpp\/rgag058","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T11:48:42Z","timestamp":1778845722000},"source":"Crossref","is-referenced-by-count":0,"title":["Chaihu Shugan San alleviates depression-like behavior in rats exposed to chronic unpredictable mild stress by targeting \u03b12\u03b4-1-NR1 complex in hypothalamus"],"prefix":"10.1093","volume":"78","author":[{"given":"Xin","family":"Wei","sequence":"first","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]},{"name":"Diabetes Heart Department, Xingtai Hospital of Traditional Chinese Medicine , 238 Jianshe Avenue, Xingtai 054000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingchen","family":"Hou","sequence":"additional","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyun","family":"Ban","sequence":"additional","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxian","family":"Zang","sequence":"additional","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyan","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyu","family":"An","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1478-3854","authenticated-orcid":false,"given":"De-Pei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri , Columbia, MO 65203 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4684-3359","authenticated-orcid":false,"given":"Yuanyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]},{"name":"International Cooperation Center for Ion Channel Function and Innovative Traditional Chinese Medicine , 326 Xinshi South Road, Shijiazhuang 050091 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7337-0901","authenticated-orcid":false,"given":"Yonggang","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine , 3 Xingyuan Road, Shijiazhuang 050200 ,","place":["China"]},{"name":"International Cooperation Center for Ion Channel Function and Innovative Traditional Chinese Medicine 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