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I. MORGANSTERN, Q. CHANG, A. CHOO, L. THIEDE, K. HOMA, E. SABATH, W. ALVINS, J. SUTPHEN, M. LANG, S. DAVIS, T. HANANIA

Behavioral Pharmacol., Psychogenics, Tarrytown, NY

Posttraumatic stress disorder (PTSD) is a common anxiety disorder characterized by hyper-arousal, disturbing flashbacks and numbing or avoidance of memories of a traumatic event or experience (DSM V, 2013). In order to fill the current gap in PTSD treatment research and increase our understanding of the underlying neurobiological and pathophysiological mechanisms, the development and validation of robust preclinical models with high face and construct validity is absolutely necessary.

The current series of studies present findings from two animal models of PTSD, namely the mouse chronic social defeat (CSDS) model (Berton et al., 2006; Golden et al., 2011) recently developed in collaboration with Dr. Eric Nestler and also the fear-conditioned, Wistar- Kyoto (WKY) rat model (DaSilva et al., 2011; 2013). Specifically, our data with the CSDS model suggests that animals most susceptible to social stress after going through the 10-day social defeat paradigm exhibit increased social avoidance behavior, anhedonia and potentiated fear responding to sound cues. Most interesting are the findings with our proprietary algorithm-based behavioral SmartCube® system, which measures whole animal behavior. These analyses demonstrated very unique and specific behaviors related to anxiety and fear of the susceptible versus control mice that progressed over time and were evident as long as 6 weeks after the social defeat stress. In a separate series of experiments, we characterized the extinction profile of fear-conditioned WKY rats (0.6mA shock, 6 shocks over 8 min). The findings suggest that compared to their outbred counterparts (Wistar), this stress-sensitive rat strain (WKY) exhibits deficits in fear extinction that are pronounced and long lasting. Pharmacological data with acute or intermittent ketamine treatment as well as compounds targeting more traditional mechanisms related to 5-HT or adrenergic signaling will also be presented for these models.

Collectively, the data gathered from these two preclinical models offers a dynamic portfolio of PTSD-relevant behavioral profiles (anxiety, social avoidance, abnormal fear regulation) that can potentially be utilized as a tool to screen novel drug compounds. Our pharmacological evidence demonstrates the predictive validity of these models and further supports the use of CSDS mouse model and WKY rat model in future PTSD drug testing.