At a systems level, genetic or pharmacological disruption of endocannabinoid signaling increases CRH transcription within the PVN, enhances both basal and stress-induced corticosterone secretion and impairs glucocorticoid-mediated negative feedback regulation of the HPA axis (Patel et al., 2004; Cota et al., 2007; Steiner et al., 2008a). On the other hand, pharmacological augmentation of endocannabinoid neurotransmission attenuates the neuroendocrine response to psychological stressors (Patel et al., 2004). The neural circuitry subserving the inhibitory effects of endocannabinoids on the HPA axis is not well characterized; in particular, the influence of endocannabinoid signaling within limbic structures on activation of the HPA axis by psychological stress is not known. In this regard, the aim of the current study was to employ biochemical analyses of endocannabinoid signaling and local microinjections of cannabinoid ligands to determine the contributions of stress-induced modulation of endocannabinoid signaling within discrete nuclei of the amygdala to the activation of the HPA axis. Our findings reveal that endocannabinoid/CB1 receptor signaling in the amygdala is disrupted by acute exposure to psychological stress, which in turn contributes to stress-induced activation of the HPA axis.
