Mechanisms involved in the behavioral and pro-neurogenic effects of repeated administration of cannabidiol in mice submitted to chronic unpredictable stress

Abstract

Chronic stress (CS) can induce neuroplastic and behavioral changes that can lead to the development of several psychiatric disorders, including anxiety disorders. Studies indicate that exposure to CS decreases hippocampal neurogenesis, a process important for the generation of new neurons in adult brains from neural progenitors. Thus, the EC appears to interfere in pathways important for cell survival, proliferation and differentiation, as the Akt/GSK-3beta/beta-catenina and mTOR pathways, and alters the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF). In a previous study, chronic administration of cannabidiol (CBD), a non-psychoactive cannabinoid compound present in the plant Cannabis sativa, increased neurogenesis in non-stressed animals and prevented its decrease in animals exposed to chronic unpredictable stress regime (CUS). In addition, inhibition of neurogenesis prevented the effects of CBD. In this same study, in vitro experiments suggested that the pro-neurogenic effect of CBD depends on the facilitation of action of endocannabinoids on CB1 and CB2 receptors. However, several questions still remain, including: 1. Do the pro-neurogenic effect of CBD and its anxiolytic action in animals submitted to CUS depend, in vivo, on the action of CB1 and CB2 receptors? 2. Are the intracellular pathways of mTOR and Akt/GSK-3beta/beta-catenina involved in these CBD effects? To help answer these questions C57 male mice will be submitted to the regime of CUS for 14 days, receiving two daily injections of vehicle or antagonist of CB1 receptor, CB2 receptor or rapamycin (mTOR pathway inhibitor) + vehicle or CBD. On day 15, animals will be exposed to the test of novelty suppression feeding, in order to assess anxiety-like behavior. Then their brains will be taken to evaluate the expression of proteins Akt, GSK-3beta, beta-catenin, mTOR and BDNF.