Both eCBS and chronic stress are independently associated with hedonic capacity4;17. However, the link between chronic stress, anhedonia and the endocannabinoid system is highly complex. Experimental manipulations of CB1 (via knock-out or administration of antagonist) produce phenotypes that mimic human melancholic depression21. For instance, studies find that CB1 is associated with impaired cognition and neurodegeneration21;50 and emotional processing (such as positive affective memory)51;52 which may be recruited in extinction of aversive memories53 and in the inability to process emotions, which are features of melancholic depression. In addition, exposure to chronic stress reduces hippocampal CB1 receptor expression54. Prolonged exposure to elevated glucocorticoid levels, such as those induced by chronic stress conditions, also significantly reduces hippocampal CB1 receptor binding site density55. In fact, a recent study suggests that CB1 receptor deficiency may mimic the effects of chronic stress on emotional behavior20. The most intriguing synergy of chronic stress and CB1 activity is its influence on anhedonia and depression56. Chronic stress also reduces anadamide (an endogenous cannabinoid) signaling in the corticolimbic circuit14.
