Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression
Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model o...
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004900 |
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| author | Nicole R. Silva Shokouh Arjmand Luana B. Domingos Adriano M. Chaves-Filho Melina Mottin Caroline C. Real Anna L. Waszkiewicz Pedro H. Gobira Alessio Nicola Ferraro Anne M. Landau Carolina H. Andrade Heidi K. Müller Gregers Wegener Sâmia R.L. Joca |
| author_facet | Nicole R. Silva Shokouh Arjmand Luana B. Domingos Adriano M. Chaves-Filho Melina Mottin Caroline C. Real Anna L. Waszkiewicz Pedro H. Gobira Alessio Nicola Ferraro Anne M. Landau Carolina H. Andrade Heidi K. Müller Gregers Wegener Sâmia R.L. Joca |
| author_sort | Nicole R. Silva |
| collection | DOAJ |
| description | Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15 mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology. Changes in eCB receptors and enzymes were assessed at mRNA and protein levels (qPCR and western blot), CB1 binding ([3H]SR141716A autoradiography) and endocannabinoid content (lipidomics). The results demonstrated that the depressive behavior in FSL was negatively correlated with 2-AG levels, which were restored upon acute S-KET treatment. Although S-KET decreased CB1 and FAAH gene expression in FSL, there were no significant changes at protein levels. [3H]SR141716A binding to CB1 receptors was increased by S-KET and in silico analysis suggested that it binds to CB1, CB2, GPR55 and FAAH. Overall, S-KET effects correlated with an increased endocannabinoid signaling in the PFC, but systemic treatment with rimonabant failed to block its behavioral effects. Altogether, our results indicate that S-KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways. |
| format | Article |
| id | doaj-art-583938a886564617bb579dea8865da0b |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-583938a886564617bb579dea8865da0b2025-01-09T06:13:03ZengElsevierPharmacological Research1096-11862025-01-01211107545Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depressionNicole R. Silva0Shokouh Arjmand1Luana B. Domingos2Adriano M. Chaves-Filho3Melina Mottin4Caroline C. Real5Anna L. Waszkiewicz6Pedro H. Gobira7Alessio Nicola Ferraro8Anne M. Landau9Carolina H. Andrade10Heidi K. Müller11Gregers Wegener12Sâmia R.L. Joca13Department of Biomedicine, Aarhus University, Denmark; Translational Neuropsychiatry Unit, Aarhus University, DenmarkTranslational Neuropsychiatry Unit, Aarhus University, DenmarkDepartment of Biomedicine, Aarhus University, Denmark; Translational Neuropsychiatry Unit, Aarhus University, DenmarkDivision of Medical Sciences, University of Victoria, Canada; Neuropharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, BrazilLaboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmácia, Universidade Federal de Goiás, BrazilTranslational Neuropsychiatry Unit, Aarhus University, Denmark; Department of Nuclear Medicine and PET Center, Aarhus University and Hospital, DenmarkTranslational Neuropsychiatry Unit, Aarhus University, DenmarkTranslational Neuropsychiatry Unit, Aarhus University, DenmarkDepartment of Biomedicine, Aarhus University, DenmarkTranslational Neuropsychiatry Unit, Aarhus University, Denmark; Department of Nuclear Medicine and PET Center, Aarhus University and Hospital, DenmarkLaboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmácia, Universidade Federal de Goiás, BrazilTranslational Neuropsychiatry Unit, Aarhus University, DenmarkTranslational Neuropsychiatry Unit, Aarhus University, DenmarkDepartment of Biomedicine, Aarhus University, Denmark; Translational Neuropsychiatry Unit, Aarhus University, Denmark; Correspondence to: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15 mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology. Changes in eCB receptors and enzymes were assessed at mRNA and protein levels (qPCR and western blot), CB1 binding ([3H]SR141716A autoradiography) and endocannabinoid content (lipidomics). The results demonstrated that the depressive behavior in FSL was negatively correlated with 2-AG levels, which were restored upon acute S-KET treatment. Although S-KET decreased CB1 and FAAH gene expression in FSL, there were no significant changes at protein levels. [3H]SR141716A binding to CB1 receptors was increased by S-KET and in silico analysis suggested that it binds to CB1, CB2, GPR55 and FAAH. Overall, S-KET effects correlated with an increased endocannabinoid signaling in the PFC, but systemic treatment with rimonabant failed to block its behavioral effects. Altogether, our results indicate that S-KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways.http://www.sciencedirect.com/science/article/pii/S1043661824004900S-KetamineFlinders sensitive lineEndocannabinoidsLipidome |
| spellingShingle | Nicole R. Silva Shokouh Arjmand Luana B. Domingos Adriano M. Chaves-Filho Melina Mottin Caroline C. Real Anna L. Waszkiewicz Pedro H. Gobira Alessio Nicola Ferraro Anne M. Landau Carolina H. Andrade Heidi K. Müller Gregers Wegener Sâmia R.L. Joca Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression Pharmacological Research S-Ketamine Flinders sensitive line Endocannabinoids Lipidome |
| title | Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression |
| title_full | Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression |
| title_fullStr | Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression |
| title_full_unstemmed | Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression |
| title_short | Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression |
| title_sort | modulation of the endocannabinoid system by s ketamine in an animal model of depression |
| topic | S-Ketamine Flinders sensitive line Endocannabinoids Lipidome |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004900 |
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