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This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (\u03949-THC), as well as (iii) the serotonin (5-HT)1A receptor\u2019s role in CBD\u2019s mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2\/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 \u00b5M CBD alone and combined with \u03949-THC was evaluated. To examine CBD\u2019s mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD\u2019s effect was evaluated. An amount of \u226530 \u00b5M CBD alone exerted significant anticonvulsant effects while 10 \u00b5M CBD did not. However, 10 \u00b5M CBD combined with low-dose \u03949-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD\u2019s effects. Thus, our results demonstrate the efficacy of low-dose CBD and \u03949-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD\u2019s mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.<\/jats:p>","DOI":"10.3390\/cells13060466","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T08:59:37Z","timestamp":1709801977000},"page":"466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cannabidiol Exerts Anticonvulsant Effects Alone and in Combination with \u03949-THC through the 5-HT1A Receptor in the Neocortex of Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6255-9672","authenticated-orcid":false,"given":"Yasaman","family":"Javadzadeh","sequence":"first","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, ON M5S 0T8, Canada"},{"name":"Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7381-043X","authenticated-orcid":false,"given":"Alexandra","family":"Santos","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, ON M5S 0T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Aquilino","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, ON M5S 0T8, Canada"},{"name":"Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanthini","family":"Mylvaganam","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, ON M5S 0T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Urban","sequence":"additional","affiliation":[{"name":"Avicanna Inc., Toronto, ON M5G 1V2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3339-8102","authenticated-orcid":false,"given":"Peter L.","family":"Carlen","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, ON M5S 0T8, Canada"},{"name":"Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Department of Medicine (Neurology), University Health Network, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1056\/NEJM200002033420503","article-title":"Early Identification of Refractory Epilepsy","volume":"342","author":"Kwan","year":"2000","journal-title":"N. 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