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There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components of Semen Ziziphi Spinosae that exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the A2AR remains to be elucidated. Methods: In the study, the involvement of A2ARs in spinosin\u2019s hypnotic effect was investigated using caffeine and further elucidated in A2AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the A2AR. Results: The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with A2AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in A2AR-KO mice. Spinosin significantly increased the activity of \u03b3-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in A2AR-KO mice. Finally, the results of molecular docking showed that spinosin had a good binding potential with the A2AR. MD simulations further demonstrated that spinosin had strong binding stability with the A2AR. Conclusions: Our findings strongly suggest that spinosin exerts the hypnotic effects through the A2AR, and thus may have therapeutic potential for insomnia. Our identification of spinosin\u2019s direct molecular target supports its translational potential as a novel natural-origin candidate for clinical insomnia drug development.<\/jats:p>","DOI":"10.3390\/nu18111785","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:19:42Z","timestamp":1780316382000},"page":"1785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Hypnotic Effect of Spinosin Is Mediated by Adenosine A2A Receptors in Male Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Jianping","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haimin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenrui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5149-5881","authenticated-orcid":false,"given":"Lisheng","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15026","DOI":"10.1038\/nrdp.2015.26","article-title":"Insomnia disorder","volume":"1","author":"Morin","year":"2015","journal-title":"Nat. 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