Possible involvement of the endocannabinoid and epigenetic mechanisms in the treatment-resistant behaviors induced in Flinders sensitive line rats by exposure to a traumatic stressor

Abstract

Stress exposure has been closely associated with the development of several psychiatric conditions, such as depression and post-traumatic stress disorder (PTSD). Stress causes several neuroimmunoendocrine axis dysfunctions, leading to biomolecular and behavioral changes. Some changes that occur in PTSD include decreased endocannabinoid signaling in brain regions such as the hippocampus, medial prefrontal cortex, and amygdala. There is a strong relationship between PTSD and depression. Both conditions are treated with antidepressants and psychological counseling, although the majority will not achieve remission. Moreover, recent studies have shown that comorbidity increases the chance of treatment-resistant depression development, making treatment even more difficult. Based on this, we hypothesized that the association between depression and PTSD may also generate resistance to the treatment of PTSD-related behaviors, such as the deficit of fear memory extinction. We suggest that decreased endocannabinoid signaling and epigenetic mechanisms may be involved in this process. Therefore, we intend to combine a genetic rat model of depression to a PTSD paradigm to evaluate if there is resistance to the facilitation of fear extinction by conventional antidepressant treatment, and if this is correlated with alteration in endocannabinoid molecules expression that may be caused by epigenetic mechanisms in the brain. Moreover, we will investigate whether a drug that increases endocannabinoid signaling via cannabinoid CB1 receptors but blocks vanilloid TRPV1 receptors, could facilitate fear extinction.