While the latter studies reveal that facilitation of endocannabinoid signaling in response to stress plays a functional role in some neurobehavioral responses to stress, they do not explain the functional consequences of the decline in limbic AEA levels that occurs following stress exposure. To examine the role of this change, studies have employed the use of pharmacological agents which inhibit the uptake and/or metabolism of AEA to prevent the stress-induced reduction in AEA content. Consistent with the effects of CB1 receptor antagonism on stress-induced activation of the HPA axis, inhibition of AEA uptake and/or metabolism has been found to dampen stress-induced corticosterone secretion (Patel et al., 2004). Unlike the hypothesis that stress induces endocannabinoid signaling to promote feedback inhibition of the HPA axis, these data instead suggest that AEA signaling may exert a steady state regulation of the HPA axis, and that removal of this AEA tone in response to stress may permit activation of the HPA axis. In this sense, AEA signaling may function more as a “gatekeeper” (Patel et al., 2004). Interestingly, while the locus of action for
