Involvement of endocannabinoid signaling and neuroplasticity within the prefrontal cortex in the behavioral effects of the combination cannabidiol and escitalpram in stressed mice

Abstract

The time required for the induction of neuroplastic responses in corticolimbic areas, such as the medial Prefrontal Cortex (mPFC), is thought to be one of the mechanisms that contribute to the late onset of action of Selective Serotonin Reuptake Inhibitors (SSRIs), which is one of the main limitations of these drugs in the clinical practice. In animal models based on the exposure to repeated stress, SSRIs is able to trigger anti-stress effects only after 2 weeks or more of repeated treatment. Plastic processes in the mPFC occur in different cell populations, including neurons and polydendrocytes. When investigating the possibility of optimizing the action of the SSRI escitalopram by combining it with the phytocannabinoid cannabidiol (CBD), previous data revealed that after only 7 days of treatment the combination induced an anxiolytic-like effect in mice submitted to repeated stress. Therefore, the combination with CBD seems to be able to accelerate the anti-stress effects of the SSRI escitalopram. Hence, the main goal of our project is to investigate the role of plastic processes of cell populations of the mPFC on the anti-stress effects of the combined treatment with escitalopram and CBD. To study that, C57Bl6 mice will be submitted to 10 days of Chronic Unpredictable Stress (CUS). The effects of the 7-day combination of escitalopram and CBD on the morphology of neurons and morphology, distribution and proliferation of NG2 glia (polydendrocytes), as well as NG2- and PDGFR-beta-positive cells in the mPFC of stressed mice will be investigated. The role of the cell populations of the mPFC on the anti-stress effects of the combination of escitalopram and CBD will be assessed through chemogenetic inhibition of synaptic terminals and pharmacological depletion of NG2-positive cells in the mPFC. (AU)