Participação do endocanabinoide 2-araquidonoilglicerol (2-AG) nas respostas defensivas mediadas pela substância cinzenta periaquedutal dorsolateral e pelo córtex pré-frontal ventromedial

Abstract

The cannabinoid system modulates defensive behaviors mediated by the dorsolateral periaqueductal gray (dlPAG) and the ventromedial prefrontal cortex (vmPFC). Among the various cannabinoids described, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which exert their effects through activation cannabinoid receptor type 1 (CB1r) and type 2 (CB2r). Although AEA participation in responses related to anxiety disorders is very well described, little is known concerning the role of of 2-AG in these responses. Thus, the first aim of this study was verify if the augmentation of 2AG signaling in brain regions responsible for defensive reactions, such as the dlPAG and vmPFC, would induce anxiolytic-like effects. For this, we verified if intra-dlPAG or intra-vmPFC injection of 2-AG or URB602 (monoacilglicerol lipase inhibitor, enzyme responsible for 2-AG hydrolisis) would induce anxiolytic-like effect in the EPM test or anti-aversive effect after chemical stimulation of dlPAG. We also verified the type o cannabinoid receptor involved in such effects. In addition, some studies have suggested that activation of metabotropic glutamate receptor type 5 (mGluR5) would be necessary for the synthesis of 2-AG and consequently, to the effects triggered by this endocannabinoid. Thus, our study also verified if the pretreatment with mGluR5 antagonist would inhibit the anxiolytic-like response promoted by URB602 (into-dlPAG or into-vmPFC) in the EPM. We also performed immunofluorescence assay that showed co-expression of diacylglicerol lipase (the enzyme involved in the synthesis of 2-AG) and the mGluR5 in dlPAG and vmPFC. Altogether, our results showed a role for 2-AG in defensive reactions similar to AEA. Their actions are mediated by both CB1 and CB2 receptors. Additionally, our pharmacological and immufluorescence data of dlPAG and vmPFC reinforce the hypothesis of 2-AG synthesis is dependent mGluR5-DGL pathway.