Social isolation as a promising animal model of PTSD comorbid suicide: neurosteroids and cannabinoids as possible treatment options

Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by drastic alterations in mood, emotions, social abilities and cognition. Notably, one aspect of PTSD, particularly in veterans, is its comorbidity with suicide. Elevated aggressiveness predicts high-risk to suicide in humans and despite the difficulty in reproducing a complex human suicidal behavior in rodents, aggressive behavior is a well reproducible behavioral trait of suicide. PTSD animal models are based on a peculiar phenotype, including exaggerated fear memory and impaired fear extinction associated with neurochemical dysregulations in the brain circuitry regulating emotion. The endocannabinoid and the neurosteroid systems regulate emotions and stress responses, and recent evidence shows these two systems are interrelated and critically compromised in neuropsychiatric disorders. For instance, levels of the neurosteroid, allopregnanolone, as well as those of the endocannabinoids, anandamide and its congener, palmitoylethanolamide are decreased in PTSD. Similarly, the endocannabinoid system and neurosteroid biosynthesis are altered in suicidal individuals. Selective serotonin reuptake inhibitors (SSRIs), the only FDA-approved treatments for PTSD, fail to help half of the treatment-seeking patients. This highlights the need for developing biomarker-based efficient therapies. One promising alternative to SSRIs points to stimulation of allopregnanolone biosynthesis as a treatment and a valid end-point to predict treatment response in PTSD patients. This review highlights running findings on the role of the endocannabinoid and neurosteroid systems in PTSD and suicidal behavior both in a preclinical and clinical perspective. A specific focus is given to predictive PTSD/suicide animal models. Ultimately, we discuss the idea that disruption of neurosteroid and endocannabinoid biosynthesis may offer a novel promising biomarker axis to develop new treatments for PTSD and, perhaps, suicidal behavior.