Modulation of anxiety by the endocannabinoid anandamide signaling in the prefrontal cortex is dependent on the emotional arousal state

Cannabinoids can cause distinct and opposite effects on anxiety behaviour depending on the stress level and the aversiveness of the environmental conditions. Aim: We evaluated whether the endocannabinoid anandamide and 2-arachidonoylglycerol, in the prefrontal cortex (PFC), differentially regulate anxiety depending on the level of environment-associated emotional arousal. Methods: Rats were divided in two groups and tested for anxiety in the Elevated Plus Maze (EPM). To increase the level of environment-associated emotional arousal, one group was not handled or habituated to the experimental room and tested under high light condition (High-Arousal group; HA); the second group was handled and habituated to the experimental room and tested under red light condition (Low-Arousal group; LA). We measured anandamide and 2-arachidonoylglycerol levels immediately after the EPM, in the PFC, and tested the effects of intra-PFC administration of the anandamide hydrolysis inhibitor URB597 and the 2-arachidonoylglycerol hydrolysis inhibitor KML29 on anxiety, in HA and LA rats. Results: As expected, the HA group exhibited significant higher anxiety as compared to the LA group. In addition, HA rats showed decreased anandamide levels in the PFC as compared to their home cage control group. Moreover, URB597 increased the anxiety response shown by LA rats without affecting emotional behavior in the HA group. KML29 injections did not alter anxiety response in the LA or the HA group. Conclusions: These findings show that the endocannabinoid system in the PFC is differentially activated to regulate anxiety, depending on the level of the environment-associated emotional arousal.