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The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N\u2010methyl\u2010D\u2010aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU\u2010580), an analogue of CBDA known to act as an agonist of the serotonin\u20101A receptor (5\u2010HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL\/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK\u2010801, .3\u00a0mg\/kg) once daily for 17\u2009days. After 7\u00a0days, they were concurrently given HU\u2010580 (.01 or .05\u2009\u03bcg\/kg) for 10\u00a0days. Behavioural deficits were assessed at two time points. We conducted enzyme\u2010linked immunosorbent assays to measure the concentration of PFC 5\u2010HT1AR and CB1R. We found that MK\u2010801 effectively induced schizophrenia\u2010related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low\u2010dose HU\u2010580 (.01\u2009\u03bcg\/kg), but not the high dose (.05\u2009\u03bcg\/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK\u2010801 downregulated both CB1R and 5\u2010HT1AR, an effect that was blocked by both low\u2010 and high\u2010dose HU\u2010580. This study sheds light on the potential antipsychotic properties of HU\u2010580, particularly in the context of NMDAR\u2010induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU\u2010580 and related compounds\u00a0in alleviating symptoms.<\/jats:p>","DOI":"10.1111\/ejn.16278","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T10:12:07Z","timestamp":1708596727000},"page":"2403-2415","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Therapeutic\u2010like activity of cannabidiolic acid methyl ester in the MK\u2010801 mouse model of schizophrenia: Role for cannabinoid CB1 and serotonin\u20101A receptors"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0325-9216","authenticated-orcid":false,"given":"Brandon","family":"Richardson","sequence":"first","affiliation":[{"name":"Memorial University of Newfoundland and Labrador  St. John's Newfoundland 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