Pharmacological Characterization of Aptinyx Compounds

In this program under the direction of Dr. Jelena Radulovic at Northwestern University, we plan to determine, using mice, the effects of NYX-783 on (1) fear extinction in extinction-resistant models of post-traumatic stress disorders (PTSD); and (2) the development of persistent molecular changes associated with PTSD-like behavior in mice. Overview (1) We propose to use two animal models involving exposure of mice to uncontrollable stress that typically results in extinction-resistant anxiety-like phenotypes, which are of high relevance for PTSD. These are the partial reinforcement model (PRF), described and validated in the Radulovic lab (Huh et al., 2009; Leaderbrand et al., 2014), and the unpredictable social defeat stress model (SD) adapted from Hammamieh et al. ( 2012). Given that the SD model is well validated for the occurrence of severe social avoidance, we expect that this behavior will also show resistance to extinction. A cohort of mice trained on a continuous reinforcement (CRF) schedule will also be utilized as a comparison to the PRF model and to evaluate the effects of NYX-783 on the persistence of fear extinction at remote time points. (2) We will also process brain and blood tissue for molecular analyses (mRNA, miRNA, and protein. Samples will be given to Aptinyx for further processing. (3) We will analyze the behavioral data and contribute to manuscript preparation.