Anandamide Hydrolysis Inhibition Modulates Stress Markers via Beta-Catenin in the PFC in A Rat Model Of PTSD

Post-traumatic stress disorder (PTSD) involves dysregulation of stress modulators, particularly corticotrophin-releasing factor (CRF) and glucocorticoid receptor. Endocannabinoid )ECB( signaling usually serves to inhibit the stress response and has been suggested as a potential target for PTSD treatment. The Wnt/β-catenin pathway was found to play a significant role in anxiety and depression. We examined the expression of stress markers in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in a rat model for PTSD, and whether the stress-buffering effects of enhancing ECB signaling are mediated via β-catenin in the mPFC. Rats were exposed to the shock and reminders model for PTSD and injected with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.4 mg/kg.). URB597 was found to normalize the dysregulation in stress markers in the mPFC and BLA as well as the anxiogenic phenotype. Importantly, downregulation by viral-mediated gene transfer of β-catenin in the mPFC blocked the stress-buffering effects of URB597 on CRF, a key modulator of the stress response, as well as on CB1r and β-catenin protein levels. We suggest a novel mechanism for the stress-buffering effects of FAAH inhibition on CRF that is dependent on β-catenin activation in the mPFC in a PTSD rat model.