Effects of the 5-HT2A Receptor Inverse-Agonist Pimavanserin on a Rodent Model of Post-Traumatic Stress Disorder

Post-Traumatic Stress Disorder (PTSD) is a chronic and debilitating psychological disorder that manifests in individuals that are witness to or directly exposed to intense life-threatening situations. Exposure to such events can result in a cluster of symptoms that include intrusive memories, avoidance, persistent anxiety, and hyper-reactivity. While PTSD in returning veterans bought this disorder to public attention, it is widespread in the civilian population, with a majority of cases reported in females. The most common pharmacological treatments for PTSD and related anxiety disorders are the class of drugs known as Selective Serotonin Reuptake Inhibitors (SSRIs). However, many individuals diagnosed with PTSD are resistant to such treatments, and some patients experience aversive side effects. To remedy this problem more selective therapeutic approaches are required.
The neurobiological correlates related to PTSD appear to be quite complex. However, the up-regulation and activation of the Serotonin 2A Receptor sub-type (5-HT2AR) is implicated in the formation, maintenance and symptoms of PTSD. Our research group developed a rodent model of PTSD in female Lewis rats, utilizing chronic isolation in conjunction with acute episodes of restraint stress and predator threat as the stressors. The current experiment set out to test the hypotheses that our rodent model of PTSD would increase the expression of several PTSD-like behaviors, as assessed on the Elevated Plus Maze (EPM), Conditioned Place Aversion Test (CPA), Acoustic Startle Response Test (ACSR) and Open Field Test. In addition, we wanted to determine whether a 1mg/kg injection of Pimavanserin, a selective 5-HT2A serotonin receptor inverse agonist, could attenuate the behavioral symptoms resulting from our PTSD model.
Findings from our experiments suggested that our model was able to produce several robust phenotypes resembling PTSD. Additionally, Pimavanserin-treated animals demonstrated greatly reduced PTSD-like behaviors, further suggesting that 5-HT2AR plays a role in the expression of several characteristics of PTSD.