Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression
N. Silva1, S. Arjmand2, L. Domingos1, A. Chaves-Filho3, M. Mottin4, C. Real5, A. Waszkiewicz2, P. Gobira2, A. Ferraro1, A. Landau2, C. Andrade4, H. Müller2, G. Wegener2, S. Joca1
1Aarhus University, Biomedicine, Aarhus, Denmark, 2Aarhus University, Translational Neuropsychiatry Unit, Aarhus, Denmark, 3Universidade Federal do Ceara, Drug Research and Development Center, Ceará, Brazil, 4Universidade Federal de Goias, Laboratory for Molecular Modeling and Drug Design, Goias, Brazil, 5Aarhus University, Department of Nuclear Medicine and PET Center, Aarhus, Denmark
Background: Major depressive disorder (MDD) is a prevalent and debilitating condition worldwide. Ketamine (KET) has been shown to rapidly and effectively treat patients resistant to classical antidepressants. Emerging evidence implicates the endocannabinoid system (ECS) in MDD's neurobiology, potentially linking it to KET's effects.
Aims & Objectives: Here, we aimed to determine whether the rapid regulation of the ECS could be associated with KET’s rapid antidepressant effects. We used an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL).
Method: We developed a novel integrative approach combining behavioral evaluations, molecular biology, and lipidomic analyses in the prefrontal cortex (PFC) with computational predictions of the binding affinity and binding mode of KET and its enantiomers to ECS targets.
Results: 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.
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.
Discussion & Conclusions: In conclusion, our study demonstrated that S-KET regulates the tone of the ECS in the PFC of FSL animals. This effect potentially occurs through the regulation of gene expression of some ECS catabolizing enzymes, such as FAAH, as well as through its (and its metabolites') direct interactions with ECS targets. 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.
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