Developing Treatments for Hyperarousal in a Model System

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DESCRIPTION (provided by applicant): PTSD is a major health problem for military and civilian populations and treatment has proven to be less than effective. There are many people exposed to trauma who suffer flashbacks, bad dreams, numbing, fear, anxiety, sleeplessness, hyper-vigilance, hyperarousal, and an inability to cope. Current behavioral and drug treatment strategies are based on fear conditioning and are capable of treating only some of the symptoms of PTSD because the extinction of fear does not deal with the various forms of hyperarousal experienced by people with PTSD. The inability to treat more of the symptoms of PTSD is a major problem for the field. To help address this problem, researchers have developed animal models of PTSD but many of these models suffer from several limitations. First, they focus on extinguishing the fear associated with trauma without assessing or treating the hyperarousal caused by trauma. Second, they rely on group data, and it is clear that not everyone exposed to trauma develops PTSD. We have developed an animal model of PTSD in which conditioning and hyperarousal can be extinguished. The model is based on observations that the nictitating membrane response becomes exaggerated as a function of pairing a tone and shock. This exaggerated response occurs when the shock is tested by itself (without the tone) and is a form of hyperarousal termed conditioning-specific reflex modification (CRM). CRM is detected by comparing responses to a range of US intensities by themselves before and after classical conditioning. We now have strong evidence we can "treat" CRM as well as extinguish CRs which uniquely positions us to address two core features of PTSD and examine the relationship between them. Importantly, high levels of CRM only occur in 15-25 percent of rabbits exposed to tone-shock pairings - levels consistent with the incidence of PTSD. The current renewal will use our model of PTSD to test three specific aims that will move between the bench and the bedside to: (1) Determine the characteristics of CRM treatment that predict PTSD symptom treatment by uncovering better ways to extinguish CRM; (2) Understand the mechanisms underlying CRM treatment by inactivating areas key to executing responses and using drugs that treat PTSD to better understand CRM; and (3) Locate and characterize neural substrates of CRM treatment to develop targets for PTSD symptom treatment. These aims are designed to meet our goal of providing clinical approaches to treating PTSD.