Involvement of the medial prefrontal cortex (mPFC) in the rapid and sustained effect of Cannabidiol: possible involvement of endocannabinoid modulation on the cortical GABAergic system

Abstract

More than 350 million people worldwide are affected by major depressive disorder (DM), which makes it one of the most prevalent mental illnesses. According to the WHO (World Health Organization, 2017). Brazil is a country with the highest incidence of anxiety and depression in the world and MD will be the second leading cause of disability worldwide. Despite many advances in understanding the neurobiology and treatment of depression, the treatments currently available still face many important limitations: 1.about 30% of patients do not respond to currently approved antidepressants; 2 the majority of patients responds only partially to treatment, thus remaining with many residual symptoms; 3.the therapeutic response is observed only after weeks of continuous treatment. Cannabidiol (CBD), a nonpsychotomimetic phytocannabinoid, has shown rapid and sustained antidepressant-like effects. It promotes its effects by structural and molecular plasticity in the mPFC and also by possibly regulating gabaergic cell function. However, this hypothesis has not been directly tested and, regarding the antidepressant effect of CBD, it is not known: a) CBD effects on the activation of GABAergic interneurons in the mPFC of animals exposed to a stress model of depression; b) if CBD effects are direct or due an indirect regulation of endocannabinoids in the PFC; c) what are the primary molecular targets in the mPFC involved in CBD antidepressant effects. Therefore, our aim is to investigate the involvement of the mPFC neurocircuitry in the antidepressant effects of CBD and characterize its molecular targets. This will be investigated through 2 subprojects: 1. Test CBD effects in the Social Defeat Stress (SDS) model, in comparison to ketamine and fluoxetine, and how it affects the activation of gabaergic and glutamatergic neurons in the mPFC; 2. Investigate if the chemogenetic modulation of mPFC interneurons interfere with CBD effects, both behavioral and molecular (WB, qPCR) and neurochemical techniques (immunohistochemistry, HPLC). The results can contribute to a better understanding of the mechanisms involved in CBD antidepressant properties, as well as mPFC dysfunction in depression neurobiology. (AU)