The endocannabinoid system modulates the stress coping strategies in the dorsolateral periaqueductal grey (dlPAG). The most relevant endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG) exert inhibitory control over defensive reactions mediated by the dlPAG. However, the protective role of anandamide is limited by its lack of effect in higher concentrations. Thus, the 2-AG emerges as a complementary target for developing new anxiolytic compounds. Nevertheless, the role of 2-AG on stress responsivity may vary according to the nature of the stimulus. In this study, we verified whether the dlPAG injection of 2-AG or inhibitors of its hydrolysis induce anxiolytic-like effects in male Wistar rats exposed to behavioral models in which physical stress (mild electric shock) is a critical component, namely the contextual fear conditioning test (CFC) and the Vogel conflict test (VCT). We also investigated the contribution of cannabinoid receptor type 1 (CB1) and type 2 (CB2) in such effects. The facilitation of 2-AG signaling in the dlPAG reduced contextual fear expression and exhibited an anxiolytic-like effect in the VCT in a mechanism dependent on activation of CB1 and CB2. However, the VCT required a higher dose than CFC. Further, the monoacylglycerol inhibitors, which inhibit the hydrolysis of 2-AG, were effective only in the CFC. In conclusion, we confirmed the anti-aversive properties of 2-AG in the dlPAG through CB1 and CB2 mechanisms. However, these effects could vary according to the type of stressor and the anxiety model employed.
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