While the HPA (hypothalamic-pituitary-adrenal) axis is central to stress adaption, in rodents, the endocannabinoid signaling system (eCBS) has been implicated in this process as well, both independently and in concert with the HPA-axis14. Specifically, the eCBS, which consists of the endocannabinoid receptors (CB1 and CB2) and the endogenous cannabinoids (e.g. anandamide), is instrumental in moderating the effects of chronic unpredictable stress on anhedonia. Compared with wild-type, CB1 knock-out mice subjected to chronic unpredictable stress demonstrate decreased intake of sucrose-sweetened water15, an experimental paradigm for anhedonia in rodents. Administration of CB1 inverse agonist Rimonabant coupled with stress also produces similar effects16. These experiments, along with other studies that show the impact of eCBS on hedonic tone17;18 as well as modulations in eCBS attributable to stress19, have led preclinical researchers to posit that eCBS may be a vital contributor to the plasticity of the link between stress and depression-like phenotypes20–21.
