One possible mechanism to account for this would be a disruption of glucocorticoid mediated rapid inhibition of the HPA axis. Specifically, once glucocorticoids are secreted in response to stress, they exert a rapid feedback inhibition of the HPA axis, possibly by engaging endocannabinoid signaling to suppress excitatory transmission which activates CRH neurosecretory cells in the PVN. By blocking the induction of endocannabinoid signaling elicited by glucocorticoids, it is possible that this prevents the early phase of HPA axis shutdown by glucocorticoids and results in an exaggerated activation of the HPA axis. In support of this hypothesis, recent data has demonstrated that local inhibition of CB1 receptors within the PVN can impair glucocorticoid-mediated rapid inhibition of the HPA axis (Evanson et al., 2007). Thus, one functional role of an induction of 2-AG signaling in the hypothalamus in response to stress may be to limit HPA axis activation and contribute to termination of the stress response. These data indicate that the endocannabinoid system is involved in the “thermostat” regulation of the HPA axis, but it does not preclude that endocannabinoid signaling also
