Sustained glucocorticoid exposure recruits cortico-limbic CRH signaling to modulate endocannabinoid function

Abstract

Sustained exposure to stress or corticosteroids is known to cause changes in brain endocannabinoid (eCB) signaling, such that tissue contents of the eCBs N-arachidonylethanolamine (AEA) are generally reduced while 2-arachidonoylglycerol (2-AG) levels increase. These changes in eCB signaling are to be important for many of the aspects of chronic stress, such as anxiety, reward sensitivity and stress adaptation, yet the mechanisms mediating these changes are not fully understood. We have recently found that the stress-related neuropeptide corticotropin-releasing hormone (CRH), acting through the CRH type 1 receptor (CRHR1), can reduce AEA content by increasing its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) as well as increase 2-AG contents. As extra-hypothalamic CRH is upregulated by chronic corticosteroid or stress exposure, we hypothesized that increased CRH signaling through CRHR1 contributes to the effects of chronic corticosteroid exposure on the eCB system within the amygdala and prefrontal cortex. Male rats were exposed to 7 days of systemic corticosterone capsules, with or without concurrent exposure to a CRHR1 antagonist and examined eCB content. Consistent with previous studies in the amygdala, sustained corticosterone exposure increases CRH mRNA in the prefrontal cortex. As was shown previously, FAAH activity was increased and AEA contents reduced within the amygdala and prefrontal cortex following chronic corticosterone exposure. Chronic corticosterone exposure also elevated 2-AG content in the prefrontal cortex but not the amygdala. These corticosteroid-driven changes were all blocked by systemic CRHR1 antagonism. Consistent with these data indicating sustained increases in CRH signaling can mediate the effects of chronic elevations in corticosteroids, CRH overexpressing mice also exhibited increased FAAH-mediated AEA hydrolysis in the amygdala and prefrontal cortex compared to wild type. CRH overexpression increased 2-AG content in the amygdala, but not the prefrontal cortex. These data indicate that chronic elevations in CRH signaling, as is seen following exposure to chronic elevations in corticosterone or stress, drive persistent changes in eCB function. As reductions in AEA signaling mediate the effects of CRH and chronic stress on anxiety, these data provide a mechanism linking these processes together.

Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype

“…Thus, we expand on the acute nature of the CRF 1 -FAAH interaction to provide a direct link between dysregulation in these mechanisms and persistent anxiety-like effects. Our findings are consistent with studies showing a similar pattern of AEA signaling dysfunction induced by sustained glucocorticoid exposure that increases amygdalar CRF signaling, as well as in mutant mice exhibiting forebrain overexpression of the CRF gene (49). Finally, whereas prior studies characterized CRF-FAAH interactions in the BLA, we have extended these observations to the CeA that serves as an integrative hub for processing and converting stress-related information into behavioral and physiologic responses (6).…”

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

“…For now, our finding on FAAH status in cannabis withdrawal is still preliminary and no data are available on FAAH changes during the course of cannabis withdrawal and its relationship to endocrine (e.g., glucocorticoids, corticotropin-releasing factor (74, 75)) and neuroinflammation. If decreased FAAH binding represents a compensatory rescuing effort of the brain to maintain endocannabinoid activity, further inhibition with drugs such as the Pfizer compound might help boost the effect.…”

Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis

“…Recent data indicate that acute increases in CRH that occur during stress act through CRH-R1 receptors to increase FAAH activity and thereby decrease AEA concentrations in the amygdala, but not in the PFC (41). However, further studies demonstrate that sustained CORT exposure recruits CRH signaling in the PFC, resulting in sustained increase in FAAH activity and lowering of AEA concentrations (42). Thus, stress affects AEA concentrations via at least two mechanisms.…”

“…Similar changes are seen in the amygdala of the male rat (55). Recent studies demonstrate that chronic CORT treatment also increases 2-AG content in the mPFC, but not amygdala of male rats (42). Interestingly, this effect of CORT was abolished by coadministration of the CRH-R1 antagonist, antalarmin, suggesting a role for elevated CRH in the ability of repeated elevation of CORT to potentiate 2-AG content in the mPFC.…”