With respect to the neuroendocrine response that occurs in response to stress, genetic or pharmacological blockade of the CB1 receptor has consistently demonstrated that disruption of this system exaggerates the neuroendocrine response to stress, suggesting that endocannabinoid signaling in the hypothalamus limits responsivity of the HPA axis to stress. Specifically, mice lacking the CB1 receptor have been found to exhibit potentiated secretion of both ACTH and corticosterone following exposure to an array of psychological stressors such as restraint (Uriguen et al., 2004), tail suspension (Aso et al., 2008), forced swim (Steiner et al., 2008) and novelty stress (Barna et al., 2004; Haller et al., 2004). Similarly, pharmacological antagonism of the CB1 receptor potentiates stress-induced glucocorticoid secretion and neuronal activation within the PVN (Patel et al., 2004; Steiner et al., 2008). These data suggest that endocannabinoid signaling is engaged by stress to constrain activation of the HPA axis; if this signaling is disrupted an exaggerated response occurs.
