These data support the “gatekeeper” hypothesis of AEA regulation of the HPA axis, but add to this model by indicating that a reduction of AEA tone within the basolateral amygdala contributes to activation of the HPA axis (Hill et al., 2009c). The working theory of these findings is that under basal conditions AEA levels within the basolateral amygdala are high and provide a steady state constrainment of excitatory transmission onto the projection neurons of the basolateral amygdala. In response to stress, FAAH activity increases and AEA levels decrease, which results in a disinhibition of excitation and increased firing activity of the projection neurons from the basolateral amygdala, which ultimately increases neuronal activity within the PVN and thus the HPA axis (Hill et al., 2009c). Thus, one functional consequence of the stress-induced decline in AEA signaling appears to removal of an inhibitory tone over the HPA axis. Taken with the hypothesis that stress-induced 2-AG signaling in the PVN may function to promote feedback inhibition on the HPA axis, these data create a ying-yang model of endocannabinoids and stress-induced HPA axis activation whereby endocannabinoid signaling is involved in both the activation and inhibition of the HPA axis in response to stress.
