Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF 1 receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine (anandamide; AEA) via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic stress induces maladaptive changes in amygdalar eCB signaling to promote anxiety. Here, we used genetically-selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF 1 receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects.
We applied behavioral, pharmacological, and biochemical methods to broadly characterize anxiety-like behaviors and amygdalar eCB clearance enzymes in msP versus non-selected Wistar rats. Subsequent studies examined the influence of dysregulated CRF and FAAH systems in altering excitatory transmission in the central amygdala (CeA).
MsPs display an anxious phenotype accompanied by elevations in amygdalar FAAH activity and reduced dialysate AEA levels in the CeA. Elevations in CRF-CRF 1 signaling dysregulate FAAH activity, and this genotypic difference is normalized with pharmacological blockade of CRF 1 receptors. MsPs also exhibit elevated baseline glutamatergic transmission in the CeA, and dysregulated CRF-FAAH facilitates stress-induced increases in glutamatergic activity. Treatment with a FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype.