Models of depression and anxiety involving stress have shown that the function of the ECS is reduced. For example, CB1R has been shown to be decreased in several brain structures implicated in depression in rats exposed to chronic unpredictable stress (CUS) [98,99,100]. When tested, the levels of eCBs, notably AEA, were reduced in different brain structures in studies of the CUS model of depression [97,98,99,100,101,102], demonstrating that chronic stress paradigms result invariably in a loss of AEA signaling. In addition, chronic stress exposure dramatically decreased the aptitude of CB1R to inhibit neurotransmitter release in regions involved in depression, such as the striatum and hypothalamus [103,104,105]. Additional evidence for the role of the ECS, and precisely the CB1R, in depression in preclinical studies came from knock-out mouse models in which CB1R (CB1R-KO) was eliminated. To simplify, studies from this model showed that decrease or elimination of CB1R or its signaling resembles the effects of antagonists, in that it is pro-depressive and pro-anxiogenic overall.
