Research Project
7882191
DESCRIPTION (provided by applicant): The overall goal of this grant is to understand the neurobiological mechanisms that underlie posttraumatic stress disorder (PTSD)-like conditions as well as the treatment of these conditions in an established rodent model. The specific aims are: 1) to delineate the immediate and long term effects of a traumatic experience on sleep architecture, freezing behavior and heart rate changes in Wistar-Kyoto (WKY) and Wistar (WIS) rats and correlate these changes with noradrenergic activity in the prefrontal cortex, amygdala and hippocampus;2) to evaluate whether treatments with prazosin or propranolol will differentially ameliorate the behavioral and neuroanatomical outcomes measured in Aim 1 in the vulnerable WKY vs. resistant WIS rats. The basic approach will be to use fear conditioning, accomplished by pairing tones (conditioned stimulus [CS]) with foot shocks (unconditioned stimulus [US]), to assess conditioned fear. Freezing, ultrasonic vocalization, heart rate and sleep behavior will be compared between the two strains. Treatment with prazosin (11 adrenoceptor antagonist) or propranolol (21 adrenoceptor antagonist) will take place at appropriate timings relative to the initial triggering and subsequent exacerbating events. Following sleep recording, animals will be decapitated, and trunk blood and brains removed for analysis of stress hormones and noradrenergic pre and post-synaptic receptors. It is expected that PTSD-like symptoms will be more pronounced in the stress-reactive WKY rats compared to the more stress-resistant WIS rats. Furthermore, these strain differences will be related to altered expression and function of 11 and 21-adrenoceptors in the prefrontal cortex, amygdala and hippocampus, the three brain regions strongly implicated in the pathophysiology of PTSD. By defining the noradrenergic pathways by which these drugs alleviate PTSD-like conditions, our studies will provide relevant information which would otherwise be difficult to obtain from clinical studies, and will enhance our ability to develop effective treatment strategies to improve the quality of life for PTSD patients. PUBLIC HEALTH RELEVANCE: Our proposed studies are designed to provide information regarding the noradrenergic mechanisms that underlie posttraumatic stress disorder (PTSD)-like conditions in the Wistar-Kyoto rat, an established animal model for studying stress-related psychiatric disorders. The basic approach will be to use a fear conditioning procedure, followed by measurements of freezing, ultrasonic vocalization, heart rate and sleep behaviors. Following sleep recordings, noradrenergic pre and post-synaptic receptors will be measured in the brains of these animals. Treatment with prazosin (11 adrenoceptor antagonist) or propranolol (21 adrenoceptor antagonist) will take place at appropriate timings relative to the initial triggering and subsequent exacerbating events. By defining the noradrenergic pathways by which these drugs alleviate PTSD-like conditions, our studies will provide relevant information which would otherwise be difficult to obtain from clinical studies, and will enhance our ability to develop effective treatment strategies to improve the quality of life for PTSD patients.
