ML184 influences coping strategies via GPR55-dependent mechanisms following its delivery in the periaqueductal gray (PAG) region.

GPR55 is a cannabinoid and lysophospholipid-related receptor involved in multiple functions in the mammalian central nervous system (CNS). In the periaqueductal gray (PAG), GPR55 participates in pain integration, anxiety-related behaviors, and alcohol intake. In this study, ML184 (a synthetic GPR55 agonist) was injected into the PAG region in the absence and presence of CID16020046 (a selective GPR55 antagonist) to analyze the role of GPR55 in anxiety, exploration, and coping responses. Admittedly, the exact areas affected by the drug delivery were not confirmed. Hence, the drugs might have spread to adjacent PAG regions. In the open field (OF) test, ML184 and CID16020046 showed no significant effects (p > 0.05 vs. vehicle) in all parameters tested, but the combination ML184 + CID16020046 increased rearing (p < 0.05). In the elevated plus maze (EPM) test, ML184 and CID16020046 lack an effect (p > 0.05 vs. vehicle) in all parameters tested. In contrast, the combination ML184 + CID16020046 increased time and distance in open arms (p < 0.05). In the defensive burying behavior (DBB) test, CID16020046 produced no effects in all parameters tested (p > 0.05 vs. vehicle). However, ML184 increased freezing and decreased pile height, time in motion, and bury ratio (p < 0.05). All those actions were prevented with CID16020046-pretreatment. Our results suggest that GPR55 in PAG and/or its surrounding regions promote passive coping responses. Moreover, ML184 may induce anxiolytic effects and higher-rearing behaviors by GPR55-independent mechanisms (which remain to be identified).