Animal models of post-traumatic stress disorder and novel treatment targets

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABA(A) receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.