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

Many people who suffer from anxiety disorders self-medicate with cannabis which seems to reduce anxiety. However, cannabis usage has also been shown to have the opposite effect and some people have reported feeling increased anxiety and depressive mood when using cannabis. Animal studies have indicated that cannabinoid drugs can cause these distinct opposite effects on anxiety behaviour depending on both the animal stress levels and the aversiveness of the environmental conditions. Furthermore, animal studies have shown the critical involvement of the prefrontal cortex (PFC) endocannabinoid system in the regulation of stress and anxiety behaviours. The goal of this study was to evaluate whether the endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in the PFC, differentially regulate anxiety behaviour depending on the level of environment-associated emotional arousal. Sprague-Dawley 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 extensively handled and habituated to the experimental room prior to the EPM and tested under red light condition (Low-Arousal group; LA). We evaluated the effects of intra-PFC administration of the AEA hydrolysis inhibitor URB597 or the 2-AG hydrolysis inhibitor KML29 on anxiety behavior. HA and LA rats were given bilateral intra-PFC administration of URB597 (10 ng/side), KML29 (0.2ug/side) or their vehicle 30 min prior to the EPM test. Rats were, then, sacrificed for brain dissection and histological analysis to assure proper cannula placement. As was expected, the LA group exhibited a significant lower anxiety behavioral profile as compared to the HA group in the EPM. We also found that URB597 decreased the anxiety response shown by LA rats as compared to the correspondent vehicle group, without affecting emotional behavior in the HA group. KML29 injections did not alter anxiety response in the LA or the HA group. Taken together, these findings show how the endocannabinoid system is differentially activated to regulate anxiety response, depending on the level of the environment-associated emotional arousal and help to shed light on the neurobiological mechanism involved in the differential impact of stress on emotionality.