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anxious behavior, basolateral amygdala, endocannabinoid signaling, HPA Axis, stress
Abstract:
Corticotropin-releasing hormone (CRH) is a central integrator in the
brain of endocrine and behavioral stress responses, whereas activation
of the endocannabinoid CB1 receptor suppresses these responses. Although
these systems regulate overlapping functions, few studies have
investigated whether these systems interact. Here we demonstrate a novel
mechanism of CRH-induced anxiety that relies on modulation of
endocannabinoids. Specifically, we found that CRH, through activation of
the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme
fatty acid amide hydrolase (FAAH), which causes a reduction in the
endocannabinoid anandamide (AEA), within the amygdala. Similarly, the
ability of acute stress to modulate amygdala FAAH and AEA in both rats
and mice is also mediated through CRHR1 activation. This interaction
occurs specifically in amygdala pyramidal neurons and represents a novel
mechanism of endocannabinoid-CRH interactions in regulating amygdala
output. Functionally, we found that CRH signaling in the amygdala
promotes an anxious phenotype that is prevented by FAAH inhibition.
Together, this work suggests that rapid reductions in amygdala AEA
signaling following stress may prime the amygdala and facilitate the
generation of downstream stress-linked behaviors. Given that
endocannabinoid signaling is thought to exert "tonic" regulation on
stress and anxiety responses, these data suggest that CRH signaling
coordinates a disruption of tonic AEA activity to promote a state of
anxiety, which in turn may represent an endogenous mechanism by which
stress enhances anxiety. These data suggest that FAAH inhibitors may
represent a novel class of anxiolytics that specifically target
stress-induced anxiety.
