{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:35:51Z","timestamp":1790994951242,"version":"4.1.0"},"reference-count":92,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"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 pathophysiology of major depressive disorder (MDD) is diverse and multi-factorial, yet treatment strategies remain limited. While women are twice as likely to develop the disorder as men, many animal model studies of antidepressant response rely solely on male subjects. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. Cannabidiolic Acid-Methyl Ester (CBDA-ME, EPM-301) demonstrated anti-depressive-like effects in male rats. Here, we explored acute effects of CBDA-ME and some possible mediating mechanisms, using a depressive-like genetic animal model, the Wistar\u2013Kyoto (WKY) rat. In Experiment 1, Female WKY rats underwent the Forced swim test (FST) following acute CBDA-ME oral ingestion (1\/5\/10 mg\/kg). In Experiment 2, Male and female WKY rats underwent the FST after injection of CB1 (AM-251) and CB2 (AM-630) receptor antagonists 30 min before acute CBDA-ME ingestion (1 mg\/kg, males; 5 mg\/kg, females). Serum levels of Brain-Derived Neurotrophic Factor (BDNF), numerous endocannabinoids and hippocampal Fatty Acid Amide Hydrolase (FAAH) levels were assessed. Results indicate that females required higher doses of CBDA-ME (5 and 10 mg\/kg) to induce an anti-depressive-like effect in the FST. AM-630 blocked the antidepressant-like effect in females, but not in males. The effect of CBDA-ME in females was accompanied by elevated serum BDNF and some endocannabinoids and low hippocampal expression of FAAH. This study shows a sexually diverse behavioral anti-depressive response to CBDA-ME and possible underlying mechanisms in females, supporting its potential use for treating MDD and related disorders.<\/jats:p>","DOI":"10.3390\/ijms24043828","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T02:31:23Z","timestamp":1676428283000},"page":"3828","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6552-2227","authenticated-orcid":false,"given":"Danielle","family":"Hen-Shoval","sequence":"first","affiliation":[{"name":"Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lital","family":"Moshe","sequence":"additional","affiliation":[{"name":"Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Indig-Naimer","sequence":"additional","affiliation":[{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Mechoulam","sequence":"additional","affiliation":[{"name":"Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem 9112002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Shoval","sequence":"additional","affiliation":[{"name":"Geha Mental Health Center, Petah Tiqva 4910002, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Zalsman","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08540, USA"},{"name":"Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya M.","family":"Kogan","sequence":"additional","affiliation":[{"name":"Institute of Personalized and Translational Medicine, Molecular Biology, Ariel University, Ariel 4070000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-4384","authenticated-orcid":false,"given":"Aron","family":"Weller","sequence":"additional","affiliation":[{"name":"Psychology Department, Bar-Ilan University, Ramat Gan 5290002, Israel"},{"name":"Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1111\/j.1476-5381.2009.00585.x","article-title":"Open Questions in Current Models of Antidepressant Action","volume":"159","author":"Tanti","year":"2010","journal-title":"Br. 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