| Summary: | Rationale : Endocannabinoids have been shown to be important for the regulation of multiple aspects of the stress response, although the neural circuits underlying this phenomenon are not well characterized. The amygdala is rich in cannabinoid receptors and endocannabinoid content and is well seated to integrate the role of endocannabinoid signaling to the regulation of the stress response. This series of studies sought to determine the roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the amygdala with respect to both activation and adaptation of the stress response. Methods : For the first two experiments, male Sprague-Dawley rats were employed. For acute activation of the stress response, a 30 min exposure to restraint stress was employed, while 9 days of 30 min restraint was employed to examine adaptation of the stress response. In the third study, C57Bl/6 mice (both wild type and those deficient in the AEA degrading enzyme fatty acid amide hydrolase, FAAH) were employed. Results : Exposure to acute restraint stress increased the hydrolytic activity of FAAH and decreased AEA content within the amygdala. Local administration of a FAAH inhibitor (10 ng) into the basolateral amygdala (BLA) reduced stress-induced corticosterone secretion, indicating that a FAAH-mediated loss of AEA signaling in the BLA contributes to activation of the stress response. Following 9 days of repeated restraint, the corticosterone response to stress habituated, and this adaptive response was reversed by local administration of AM251 (1 µg), a CB1 receptor antagonist, into the BLA. Consistent with this, repeated restraint stress caused an increase in 2-AG content within the amygdala, indicating that a recruitment of amygdalar 2-AG signaling is required for stress adaptation. Chronic stress exposure caused an increase in FAAH activity and a reduction in AEA content within the amygdala. FAAH deficient mice did not exhibit this reduction in AEA content and were similarly protected against the ability of chronic stress to cause dendritic expansion and spine growth within the BLA, as well as heightened indices of anxiety. Conclusion : These findings indicate that AEA and 2-AG signaling at the CB1 receptor within the amygdala both serve to inhibit activation of the stress response. AEA appears to serve more of a tonic, gatekeeper role, the loss of which promotes activation of the stress response. Prevention of this loss of AEA signaling, through a blockade of FAAH activity, is capable of dampening the effects of acute and chronic stress. On the other hand, 2-AG signaling is recruited by repeated restraint stress to promote habituation and adaptation of the stress response. As such, a ying-yang model exists within the amygdala with the two endocannabinoid ligands serving different roles to regulate the stress response.
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