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Title: The role of the endocannabinoid system in the pathogenesis of depression and in the mechanism of action of antidepressants


Depression is the leading cause of disability and the 4th highest contributor to the global disease burden in the twenty-first century. Despite the existence of several preclinical and clinical studies, the pathophysiology of this brain disorder remains still unclear. On the one hand, currently prescribed antidepressants do not meet requirements of patients and clinicians, on the another hand – despite the well-documented the role of stress, infectious agents, and genetic influence in depression - the cause(s) of the disorder have not yet been completely elucidated. Several antidepressants with different mechanisms of action are commonly used in the clinic, which suggests that not the particular drug-target interaction is responsible for the drug therapeutic efficacy; instead, there is likely that a secondary effect of such interaction is important. The endocannabinoid system is involved in modulating emotional responses, memory and learning, and several previous studies have implicated this system in the pathogenesis of depression. Furthermore, it is believed that mechanisms by which the endocannabinoid system may interfere with emotional states associated with depression of action include neuroanatomical localization of CB1 receptors linked to depression, with modulation of monoaminergic transmission, inhibition of the stress axis and/or promotion of neuroplasticity in the brain. Preclinical pharmacological and genetic studies on cannabinoids in depression are just coming to light and they do not provide a complete picture of specificity of interaction endocannabinoid system‒depression‒antidepressants mechanism of action, yet. ; The aim of this doctoral thesis was to examine the role of the endocannabinoid system (ie. endogenous ligands, enzymes involved in the endocannabinoids metabolism and CB receptors) in the pathogenesis of depression with using valid animal models of depression (Wistar Kyoto rats and removal of the olfactory bulbs- bulbectomy). We have also analyzed the biomarkers of the endocannabioid system following repeated vs. acute treatment with several antidepressant drugs (IMI, ESC, TIA) along with compounds in which antidepressant activity has been more recently demonstrated in preclinical research (NAC, URB597) in selected rat brain areas to determine 1) the role in the mechanism of action of antidepressants, 2) the stability of these effects after 10 days washout period of chronically administered drugs and 3) the specific antidepressant drug interaction with the endocannabinoid system using selective CB1 and CB2 receptors antagonists. Another important query was to verify the following hypothesis that drug that increase the signaling of the endocannabinoid system (by blockade of anandamide deactivation) and possess antidepressant-like properties whilst not exhibiting rewarding properties in animal models, mimics functional changes and evoke adaptations within the endocannabinoid system as classical antidepressant drugs do. ; In animal models of depression, which showed a similar phenotype, the differences in the neurochemical state were noted. In Wistar Kyoto rats, it was observed an increase of anandamide levels with increased NAPE-PLD expression, a decrease of 2-AG levels with increased MAGL expression in the prefrontal cortex and a decrease of anandamide levels with increased FAAH expression in the dorsal striatum. The CB1 receptors density was increased in several brain structures, which was also confirmed during study on the expression of CB receptors (CB1- prefrontal cortex, hippocampus, nucleus accumbens, cerebellum and CB2- dorsal striatum, cerebellum). Removal of the olfactory bulbs induced a decrease of anandamide levels in the prefrontal cortex, hippocampus and dorsal striatum, while an increase of anandamide levels was seen in the nucleus accumbens. The 2-AG levels were either increased in the prefrontal cortex or decreased in the nucleus accumbens. Changes in the endocannabinoids levels in the bulbectomized rats resulted from altered expression of metabolizing enzymes. In fact, a decrease of NAPE-PLD expression and an increase of FAAH expression was seen in the prefrontal cortex, as well as a rise of DAGLα expression and a fall of MAGL expression was noted in the prefrontal cortex, an increase of FAAH expression was observed in the hippocampus or an increase of NAPE-PLD and MAGL expression in the nucleus accumbens was reported. Additionally, it was observed a decrease of CB1 receptor expression in the hippocampus, dorsal striatum and nucleus accumbens and a decrease of CB2 receptor expression in the prefrontal cortex and hippocampus, while the CB1 receptor density in the autoradiography was disturbed in the prelimbic cortex and dorsal striatum. The common change for both models was weakness of endocannabinoid signalization (anandamide) in the dorsal striatum, what can induce characteristic symptom of depression, anhedonia. In other brain structures, neurochemical changes were different and it seem to be associated with the particular brain structure, and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation). ; Antidepressant drugs/compounds induced several changes in the endocannabinoids levels, in most cases these changes were related to expression of their metabolizing enzymes. After acute administration of drugs/compounds (IMI or NAC) it was observed an increase of anandamide in the hippocampus and dorsal striatum, and altered levels of 2-AG were seen in the prefrontal cortex after NAC treatment, frontal cortex after ESC and IMI treatment (with increased DAGLα expression), dorsal striatum after URB597 treatment or cerebellum after IMI or NAC treatment. The chronic administration of all investigated drugs/compounds increased anandamide levels in the hippocampus and dorsal striatum, as well as an increase of anandamide levels in the frontal cortex after NAC treatment and cerebellum after URB597 treatment was noted. Raised levels of anandamide were associated with increased NAPE-PLD expression in the frontal cortex, hippocampus and dorsal striatum (after NAC or ESC treatment), or reduced FAAH expression in the hippocampus and dorsal striatum ( after URB597 or IMI, ESC, NAC administration, respectively). The 2-AG levels were increased in the frontal cortex (IMI, TIA, NAC), hippocampus (ESC) and dorsal striatum (all drugs/compounds) or decreased in the prefrontal cortex (ESC, NAC), frontal cortex (ESC), nucleus accumbens (NAC) and cerebellum (IMI, ESC, NAC). These changes were resulted from altered expression of 2-AG metabolizing enzymes- expression of 2-AG synthesizing enzyme (DAGLα) or expression of degrading enzyme (MAGL). Antidepressant drugs/compounds altered density and expression of CB receptors. An increase of CB1 receptors density was seen in the cortical structures after chronic administration of ESC, TIA or URB597 and in the hippocampal areas after IMI, ESC, TIA and NAC administration, while a decrease of CB1 receptors density in the dorsal striatum after IMI and ESC administration and in the nucleus accumbens after chronic IMI treatment was reported. These changes were confirmed in the study on expression of CB1 receptors. Additionally, for the first time changes in expression of CB2 receptors after antidepressant drugs/compounds were reported, an increase of expression of CB2 receptors was observed in the cortical structures and hippocampus after administration of ESC, TIA or NAC, as well as a decrease of this expression was noted in the dorsal striatum, nucleus accumbens and cerebellum after IMI administration. The effects of antidepressant drugs/compounds on the endocannabinoid system seem to be short-lived, endocannabinoids levels returned to control (vehicle) levels after a 10-day washout period of IMI, TIA, NAC and URB597. Raised levels of these neurotransmitters were maintained in the hippocampus and dorsal striatum even after a 10-day washout period of ESC.Specificity of effects occurring after antidepressant drugs/compounds were related to activity of CB1 and CB2 receptors. Only the mechanism of changes in the levels of 2-AG in the dorsal striatum after ESC treatment was not related to CB1 receptors, while changes in the levels of this neurotransmitter in the frontal cortex and hippocampus (after administration of IMI, TIA or ESC, respectively), and changes in the levels of anandamide in the dorsal striatum and frontal cortex (after administration of IMI, ESC, TIA or NAC, respectively) were not dependent on the receptor CB2. ; In summary, in the neurochemical state ‒ animal models of depression showed multidirectional changes within the endocannabinoid system (i.e. receptors and endocannabinoids levels evoked by altered expression of metabolizing enzymes), and these changes seem to be associated with the particular brain structure and factor inducing this disease. A common feature for both models was a reduction of the anandamide levels in the dorsal striatum, which may be associated with anhedonia, a symptom of depression, while all chronically administered antidepressant drugs/compounds caused an increase in the levels of anandamide in this brain structure. Antidepressant drugs/compounds evoked an increase of anandamide levels in the hippocampus and also an increase of 2-AG levels in the dorsal striatum. 10-day washout period kept changes following repeated treatment with ESC, while changes after other drugs/compounds seem to be short-lived. The changes in the endocannabinoids levels were in most cases dependent on both types of CB receptors. Neurochemical studies on CB receptors showed different changes in the density/expression of CB receptors in rat brain, which seem to be related to brain structure and/or properties of a drug/compound.Study in this doctoral thesis contributed to explore the mechanisms related to depression and the mechanisms of action of antidepressant drugs/compounds with particular focus on components of endocannabinoid system. We hope, that the obtained findings will show new directions in studies on depression as a more comprehensive understanding of the enodocannabinoid system with its cellular signaling targets that subserve this brain disorder.

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2 - studia doktoranckie

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Wydział Farmaceutyczny. Uniwersytet Jagielloński. Collegium Medicum.


Małgorzata Filip

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Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

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Jun 26, 2019

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ZB-126290 Jun 26, 2019


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