Cellular and Molecular Changes Associated to Fast-antidepressant Effects of Cannabidiol in Rodent Models

One outstanding clinic concern nowadays is the delay of the therapeutic effects of current antidepressant drugs available respect to their administration. Recent pre-clinical studies show that cannabidiol exerts rapid onset antidepressant-like effects in animal models. Moreover, this action seems to be highly related with the prefrontal cortex activity. However, its exact mechanism of action remains elusive. In this study, we have evaluated the behavioral effects as well as the associated expression levels of biomarkers related with the neurophysiopathology of depression. In addition, we are also interested in the activity of several brain areas associated with emotional responses, in particular, depression, such as the pre-limbic and infra-limbic prefrontal cortices, the amygdala and the dorsal raphe nucleus. Upon systemic administration of 30 mg/kg of cannabidiol in mice, we observed a decrease in the immobility-spent time on the tail suspension test (antidepressant-like effect). On the other hand, intracortical (infra-limbic) administration in rats of 60 nmol of cannabidiol significantly reduced the immobility-spent time in the forced swimming test with a concomitant increase of the swimming-spent time (serotoninergic-related behavior) 30 minutes after drug administration. In order to verify the activity of brain areas related with depressive behaviors, we performed an immunohistochemistry assay of c-Fos (an early expression gene) in mice brain. Our results demonstrate a clear neuronal activity increase in the infra-limbic cortex when the animals are subdued to stress. Moreover, this increase in neuronal activity seems to be enhanced by cannabidiol. We also demonstrate that a reduced GABAergic activity is produced as a consequence of behavior-related stress. This unbalance is partially restored when animals are treated with CBD. Using Western blot assays, we observed an increase in the expression levels in the rat prefrontal cortex of mTOR, its phosphorylated form and BDNF in animals treated with cannabidiol compared to the vehicle ones. Interestingly, the ratio P-mTOR/mTOR (which represents the activation of the mTOR pathway) is also increased in the cannabidiol-treated group, whereas the phosphorylation levels of GSK3-β decreases. This lead us to think that cannabidiol may trigger neuroplasticity phenomena, as all this signaling promotes the translation of genes related with synaptic plasticity. Our results clearly reinforce the role of cannabidiol as a putative antidepressant drug exhibiting fast-acting behavioral changes and demonstrate the presence of associated molecular changes related with neuroplasticity. In addition, we identify one neuronal pathway that may be responsible for the behavioral changes observed in animals.Máster en Biología Molecular y Biomedicin