{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T11:43:05Z","timestamp":1775043785162,"version":"3.50.1"},"reference-count":88,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The role of the endocannabinoid system (ECS) in the development of depression and anxiety is being actively studied, with evidence suggesting that elevation of ECS signaling can have anxiolytic and antidepressant properties. The current study explored the therapeutic potential of Oleoyl Serine (OS), an endocannabinoid-like lipid, and HU-910, a synthetic selective Cannabinoid type 2 (CB2) receptors agonist, in depression and anxiety, using both sexes of the depressive-like genetic model: Wistar Kyoto (WKY) rats. The aim was to investigate behavioral and molecular mechanisms associated with acute and sub-chronic intraperitoneal administration of these compounds. We showed that, in females, acutely administered OS yielded antidepressant-like and anxiolytic-like effects in the Forced Swim Test (FST) and Open Field Test (OFT), respectively. In males, OS yielded acute and sub-chronic anxiolytic-like effects. HU-910 yielded an acute anxiolytic-like effect in females and an acute antidepressant-like effect in males. Sub-chronic administration of imipramine (IMI), used as a positive control, yielded an antidepressant-like effect in both sexes but an anxiogenic-like effect in females. Sub-chronic administration of all the treatments increased hippocampal Cannabinoid Receptor 1 (CNR1) mRNA expression (but not Fatty Acid Amide Hydrolase (FAAH)) in males. Exploratory in silico absorption, distribution, metabolism, and excretion (ADME) profiling suggests that sex-dependent pharmacokinetic variability may partly underlie the observed behavioral differences, in addition to possible pharmacodynamic factors. Our study provides a lead towards unraveling the putative sex differences in response to both conventional antidepressants (e.g., IMI) and emerging pharmacological agents (e.g., OS, HU-910). Further, our study helps advance the field of neuropharmacology by elucidating the anxiolytic-like and antidepressant-like effects of OS and HU-910.<\/jats:p>","DOI":"10.3390\/ijms27073177","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:23:17Z","timestamp":1774963397000},"page":"3177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Effects of Oleoyl Serine and HU-910 on Anxiety-like and Depression-like Behaviors in Male and Female WKY Rats"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5074-6716","authenticated-orcid":false,"given":"Jenna","family":"Gellman","sequence":"first","affiliation":[{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4037-4341","authenticated-orcid":false,"given":"Natalia","family":"Zemliana","sequence":"additional","affiliation":[{"name":"Institute for Personalized and Translational Medicine, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 4070000, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3351-1706","authenticated-orcid":false,"given":"Yoni","family":"Loterstein","sequence":"additional","affiliation":[{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elin","family":"Kachuki Dory","sequence":"additional","affiliation":[{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devorah","family":"Matas","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, Bar Ilan University, Ramat-Gan 5290002, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gal","family":"Shoval","sequence":"additional","affiliation":[{"name":"Geha Mental Health Center, Petah Tiqva 49100, Israel"},{"name":"Gray Faculty for Medical and Health Science, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eyal","family":"Sharon","sequence":"additional","affiliation":[{"name":"Institute for Personalized and Translational Medicine, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 4070000, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Koman","sequence":"additional","affiliation":[{"name":"Institute for Personalized and Translational Medicine, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 4070000, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gil","family":"Zalsman","sequence":"additional","affiliation":[{"name":"Geha Mental Health Center, Petah Tiqva 49100, Israel"},{"name":"Gray Faculty for Medical and Health Science, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University, New York, NY 10027, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7425-501X","authenticated-orcid":false,"given":"Lee","family":"Koren","sequence":"additional","affiliation":[{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Faculty of Life Sciences, Bar Ilan University, Ramat-Gan 5290002, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-4384","authenticated-orcid":false,"given":"Aron","family":"Weller","sequence":"additional","affiliation":[{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6792-3841","authenticated-orcid":false,"given":"Natalya M.","family":"Kogan","sequence":"additional","affiliation":[{"name":"Institute for Personalized and Translational Medicine, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 4070000, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16065","DOI":"10.1038\/nrdp.2016.65","article-title":"Major Depressive Disorder","volume":"2","author":"Otte","year":"2016","journal-title":"Nat. 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