Investigation of the involvement of endocannabinoid system on behavioral and plastic effects of antidepressant drugs

Abstract

Despite their therapeutic efficacy, antidepressant drugs (AD) treatment is associated with a delayedresponse of, at least, 4 weeks, considerable side effects and low rates of response due treatment resistance. Several theories, related or not to the monoamiergic theory of Depression, tried to explain the delayed response of AD, but the common sense is that AD repeated treatment induces long-term plastic changes in the SNC mainly by modulating serotonergic neurotransmission (e.g. desensitization of presynaptic 1A serotonergic receptors, increase in hippocampal proliferative processes, dendritic remodeling etc). Morever, Serotonergic and C annabinoid neurotransmission may also interacts to promote their behavioral and plastic effects. C hronic treatment with AD modulates the expression of C B1 receptors and increases levels of Endocannabinoids- EC Bs (Anandamide-AEA and 2-arachidonoylglycerol 2-AG) in the hippocampus and in medial prefrontal cortex (mPFC ), brain areas involved in the control of depressive states and anxiety disorders. In addition, studies with Knock Out (K.O) animals lacking the enzyme responsible for the degradation of AEA (FAAH- Fatty acid amide hydrolase) exhibit a significant increase in the firing of serotonergic neurons in the mPFC . Moreover, both serotonergic and EC Bs system are involved in plastic processes of SNC such as dendritic remodeling, production of neurotrophins and neurogenesis, processes that are up regulated after chronic AD treatment. However, all these evidences are based on correlational studies and thus, behavioral and plastic consequences of the modulations (up or down regulation) of EC B signaling on long-term effects of AD are still poorly understood. In the present work, we plan to use pharmacological (CB1 antagonist/ FAAH inhibitors) and genetic approaches(RNAi/optogenetics) to test the hypothesis that AD chronic treatment interacts to (endo)cannabinoidsystem to produces increase on SNC plastic events (adult hippocampal neurogenesis, dendriticremodeling) and as consequence antidepressant/anxiolytic effects. Specifically, by using chronic stress paradigm (chronic unpredictable) to induces behavioral and SNC plastic changes, we intend to evaluate:1) if repeated treatment with AD might promote up-regulation of the expression of enzymes of synthesis and degradation of EC Bs and C B1 or C B2 receptors in areas such as mPFC ,hippocampus; 2) if chronic pharmacological inhibition of C B1 and / or C B2 receptors influences the behavioral effects and plastic (in vivo and ex vivo: neurogenesis, dendritic remodeling, Brain Derived Nerotrophic factor-BDNF levels)promoted by AD repeated treatment; 3) whether pharmacological inhibition of enzymes responsible for AEA and 2-AG degradation may facilitate the behavioral effects of antidepressants in chronically stressed animals; 4) whether the inhibition of expression (through the technique of interference RNA) of enzyme responsible for the synthesis or degradation of the EC Bs, 2-AG and AEA, specifically in the hippocampal formation of adult animals, may influence the behavioral effects of antidepressants in animals chronically stressed by two different paradigms; 5) if the inhibition of the expression (by RNA interference) of theenzymes responsible for the synthesis or the degradation of 2-AG and AEA, specifically in the hippocampalformation, influences SNC plastic events associated to AD long-term treatment (in vivo and ex vivo:neurogenesis, dendritic remodeling, BDNF levels). (AU)