Changes in Gene Expression in the Locus Coeruleus-Amygdala Circuitry in Inhibitory Avoidance PTSD Model.

The locus coeruleus (LC)-amygdala circuit is implicated in playing a key role in responses to emotionally arousing stimuli and in the manifestation of post-traumatic stress disorder (PTSD). Here, we examined changes in gene expression of a number of important mediators of the LC-amygdala circuitry in the inhibition avoidance model of PTSD. After testing for basal acoustic startle response (ASR), rats were exposed to a severe footshock (1.5 mA for 10 s) in the inhibitory avoidance apparatus. They were given contextual situational reminders every 5 day for 25 days. Controls were treated identically but with the footshock inactivated. Animals were re-tested on second ASR and decapitated 1 h later. The shock group had enhanced hyperarousal and several changes in gene expression compared to controls. In the LC, mRNA levels of norepinephrine (NE) biosynthetic enzymes (TH, DBH), NE transporter (NET), NPY receptors (Y1R, Y2R), and CB1 receptor of endocannabinoid system were elevated. In the basolateral amygdala (BLA), there were marked reductions in gene expression for CB1, and especially Y1R, with rise for corticotropin-releasing hormone (CRH) system (CRH, CRH receptor 1), and no significant changes in the central amygdala. Our results suggest a fast forward mechanism in the LC-amygdala circuitry in the shock group.

The effects of enhancing endocannabinoid signaling and blocking corticotrophin releasing factor receptor in the amygdala and hippocampus on the consolidation of a stressful event.

Current clinical and pre-clinical data suggest that both cannabinoid agents and blockage of CRF through corticotrophin releasing factor receptor type 1 (CRFr1) may offer therapeutic benefits for post-traumatic stress disorder (PTSD). Here we aim to determine whether they are more effective when combined when microinjected into the basolateral amygdala (BLA) or CA1 area of the hippocampus after exposure to a stressful event in the shock/reminders rat model for PTSD. Injection of the fatty acid amide hydrolase (FAAH) inhibitor URB597 after the shock into either the BLA or CA1 facilitated extinction, and attenuated startle response and anxiety-like behavior. These preventive effects of URB597 were found to be mediated by the CB1 receptor. Intra-BLA and intra-CA1 microinjection of the CRFr1 antagonist, CP-154,526 attenuated startle response. When microinjected into the BLA, CP-154,526 also attenuated freezing behavior during exposure to the first reminder and decreased anxiety-like behavior. The combined treatment of URB597 and CP-154,526 was not more effective than the separate treatments. Finally, mRNA levels of CRF, CRFr1 and CB1r were significantly higher in the BLA of rats exposed to shock and reminders compared to non-shocked rats almost one month after the shock. Taken together, the results show that enhancing endocannabinoid signaling in the amygdala and hippocampus produced a more favorable spectrum of effects than those caused by the CRFr1 antagonist. The findings suggest that FAAH inhibitors may be used as a novel treatment for stress-related anxiety disorders.