Involvement of Adenozine A2a Receptors in Anxiety-like Behaviors in Tetrahydrocannabinol Treated Mice

Previous studies have suggested that adenosinergic system in the central nervous system, may play a role in both behavioral changes and the physiopathology induced by Δ9-tetrahydrocannabinol (THC), and this is thought to be mediated by adenosine A₂A receptors (A₂AR). However, the contribution of the adenosinergic system to the anxiety-like behaviors in response to THC in mice is not well understood. In this study, we aimed to investigate the possible role of the adenosinergic system in THC-treated mice. For that purpose, we combined behavioral tests and molecular analyses to investigate the effects of THC, in relation with the agonist and antagonist of the adenosinergic system, CGS-21680 (CGS) and Istradefylline, respectively, on both anxiety-like behaviors and hippocampal gene expression. The results demonstrated that THC induced anxiety-like behavior, and gene expression patterns indicated a significant interaction between the adenosinergic and cannabinoidergic systems. Notably, the data suggests that THC plays a predominant role in this molecular interplay, with its effects being partially modulated by changes in the expression of both cannabinoidergic and adenosinergic receptors, CB₁R and Adora2a (A₂AR), respectively. These findings contribute to the understanding of THC's complex pharmacological actions, highlighting the importance of receptor cross-talk in modulating anxiety and other behavioral outcomes.