Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression

D Hen-Shoval; T Indig-Naimer; L Moshe; N M Kogan; H Zaidan; I Gaisler-Salomon; E Okun; R Mechoulam; G Shoval; G Zalsman; A Weller

doi:10.1016/j.jpsychires.2024.04.033

Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression

J Psychiatr Res. 2024 Apr 24:175:50-59. doi: 10.1016/j.jpsychires.2024.04.033. Online ahead of print.

Authors

D Hen-Shoval¹, T Indig-Naimer², L Moshe³, N M Kogan⁴, H Zaidan⁵, I Gaisler-Salomon⁵, E Okun⁶, R Mechoulam⁷, G Shoval⁸, G Zalsman⁹, A Weller³

Affiliations

¹ Psychology Department, Bar-Ilan University, Ramat Gan, Israel; Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel. Electronic address: daniellehenshoval@gmail.com.
² Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.
³ Psychology Department, Bar-Ilan University, Ramat Gan, Israel; Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.
⁴ Institute of Personalized and Translational Medicine, Molecular Biology, Ariel University, Ariel, 4070000, Israel.
⁵ School of Psychological Sciences and the Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel.
⁶ Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel; The Mina and Everard Goodman Faculty of Life Sciences, Israel; The Paul Feder laboratory for Alzheimer disease research, Bar-Ilan University, Ramat Gan, Israel; Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States.
⁷ Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, Israel.
⁸ Geha Mental Health Center, Petah Tiqva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States.
⁹ Geha Mental Health Center, Petah Tiqva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University, New York, NY, United States.

PMID: 38704981
DOI: 10.1016/j.jpsychires.2024.04.033

Abstract

Major depressive disorder (MDD) stands as a significant cause of disability globally. Cannabidiolic Acid-Methyl Ester (CBDA-ME) (EPM-301, HU-580), a derivative of Cannabidiol, demonstrates immediate antidepressant-like effects, yet it has undergone only minimal evaluation in psychopharmacology. Our goal was to investigate the behavioral and potential molecular mechanisms associated with the chronic oral administration of this compound in the Wistar Kyoto (WKY) genetic model of treatment-resistant depression. Male WKY rats were subjected to behavioral assessments before and after receiving chronic (14-day) oral doses of CBDA-ME (0.5 mg/kg), 15 mg/kg of imipramine or vehicle. At the end of the study, plasma corticosterone levels and mRNA expression of various genes in the medial Prefrontal Cortex and Hippocampus were measured. Behavioral outcomes from CBDA-ME treatment indicated an antidepressant-like effect similar to imipramine, as oral ingestion reduced immobility and increased swimming duration in the Forced Swim Test. Neither treatment influenced locomotion in the Open Field Test nor preference in the Saccharin Preference Test. The behavioral impact in WKY rats coincided with reduced corticosterone serum levels, upregulated mRNA expression of Cannabinoid receptor 1, Fatty Acid Amide Hydrolase, and Corticotropin-Releasing Hormone Receptor 1, alongside downregulation of the Serotonin Transporter in the hippocampus. Additionally, there was an upregulation of CB1 mRNA expression and downregulation of Brain-Derived Neurotrophic Factor in the mPFC. These findings contribute to our limited understanding of the antidepressant effects of CBDA-ME and shed light on its potential psychopharmacological mechanisms. This discovery opens up possibilities for utilizing cannabinoids in the treatment of major depressive disorder and related conditions.

Keywords: Cannabidiolic acid methyl ester; Endocannabinoid system; Genetic animal models of depression; Major depression disorder; Molecular mechanisms; Wistar–Kyoto (WKY).