Twenty-one days of chronic restraint stress (CRS) impairs DSI in the hippocampus of adult male animals (Hu et al., 2011); providing evidence that chronic stress is capable of affecting GABAergic CB1 function. CRS is a validated method to increase HPA activity to achieve hypersecretion of glucocorticoids; however this homotypic stress usually produces habituation of the HPA response (Vyas et al., 2002; Hill et al., 2010). In contrast, CMS paradigms that use heterotypic stressors tend to produce non-habituating HPA responses. CMS is considered a valid animal model of depression partly due to the fact that incorporating multiple stressors minimizes HPA habituation (Willner, 2005). Furthermore, Vyas et al. (2002) observed that chronic restraint stress produces more severe dendritic atrophy than CMS in the hippocampus. They also reported that CRS, but not CMS, causes dendritic hypertrophy in the amygdala. These differences in the two most common chronic stress protocols suggest that CMS may result in different effects on the endocannabinoid system. This highlights the necessity to investigate stress-modulation of eCBs with both methods.
