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2-Arachidonoylglycerol(2-AG), Glucocorticoid, fatty acid amide hydrolase(FAAH), restraint, corticotropin-releasing Hormone receptor 1 (CRHR1), HPA axis
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 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, after which we 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 were 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. (C) 2016 Elsevier Ltd. All
rights reserved.
