Antidepresant-like effect of infralimbic cannabidiol administration in rat: involvement of the mtor pathway and brain cellular activation

Abstract

Nowadays major depression (MD) presents a high prevalence and one of the main problems is that current pharmacological drugs produce a delayed response and many patients are resistant to them. Thus, the finding of new antidepressants is considered of paramount importance. We have focused our study in cannabidiol (CBD), which has a potential therapeutic effect for non-psychiatric and psychiatric diseases, although its mechanism of action is still unrevealed. Therefore, the aim of this work is to determine the molecular mechanism by which CBD exerts its antidepressant properties and the brain areas involved. We have infused 60 nmols of CBD in two relevant brain areas for the antidepressant effect, which are the infra-limbic (IL) cortex and the dorsal raphe nucleus (DRN) of male Sprague Dawley rats. The behavioral effect was evaluated in an open field (OF) test and a forced swimming test (FST) 30 minutes after the infusion. Then, protein expression of different signaling pathways associated to neuronal plasticity (i.e.: mTOR, BDNF) was evaluated in prefrontal cortex (PFC) samples. Furthermore, we studied the effect of IL-CBD on the activation of different brain areas in the presence or absence of acute stress. The bilateral IL-CBD infusion induced an antidepressant-like effect shown by a reduction in immobility (p<0.05), and an increase in swimming (p<0.05) in the FST. Intra-DRN CBD administration presented no changes in the FST immobility, although an increase in swimming (p<0.05) and a decrease in climbing (p<0.05) behaviors were detected. No changes were observed in locomotion and anxious behavior assessed in the OF test after either IL or DRN CBD administration. Interestingly, the IL-CBD infusion produced an increase of synaptic plasticity markers such as BDNF (p<0.01) and p-mTOR (p<0.05) in the PFC. The CBD infusion in DRN also induced an increase in BDNF (p<0.05) in PFC, with no changes in p-mTOR. Moreover, IL-CBD administration increased c-Fos expression in DRN but not in IL and prelimbic (PL) cortices. Finally, IL-CBD infusion prevented the stress-induced increase of c-Fos in DRN and IL cortex but not in PL cortex. In summary, our data indicates that the local administration of CBD in the infralimbic prefrontal cortex induces an antidepressant-like response that may be mediated by the activation of synaptic plasticity pathways as mTOR in prefrontal cortex and the regulation of dorsal raphe nucleus and infralimbic cortex cellular activation. Additional experiments are required to completely understand the CBD behavioral and molecular effects.