As mentioned, glucocorticoid administration appears to exert similar, but distinct, regulation of endocannabinoid ligands as stress does. Thus while stress decreases AEA and increases 2-AG in most limbic brain structures, acute glucocorticoid administration rapidly increases AEA in most limbic regions while only exerting a rapid induction of 2-AG within the hypothalamus (Hill et al., 2009b). Our current working theory on these differences is that glucocorticoids, through actions at a membrane bound Gs coupled receptor, rapidly induce AEA synthesis. With respect to the relative absence of effects of systemically administered glucocorticoids on 2-AG content, it is possible that this non-genomic glucocorticoid receptor activation needs to be coupled to changes in neuronal activation and increased calcium conductance (as would be seen following stress) to induce noticeable changes in tissue levels of 2-AG. Thus, glucocorticoids may be necessary for the effects of acute stress on 2-AG induction, but for AEA they may be more important for reinstating AEA levels following the rapid decline that is evoked by stress. It should be noted, however, that this model is hypothetical and requires experimental validation.
