Evidence for altered brain reactivity to norepinephrine in Veterans with a history of traumatic stress

Abstract

BackgroundIncreases in the quantity or impact of noradrenergic signaling have been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). This increased signaling may result from increased norepinephrine (NE) release, from altered brain responses to NE, or from a combination of both factors. Here, we tested the hypothesis that Veterans reporting a history of trauma exposure would show an increased association between brain NE and mental health symptoms commonly observed after trauma, as compared to Veterans who did not report a history of trauma exposure, consistent with the possibility of increased brain reactivity to NE after traumatic stress. MethodsUsing a convenience sample of 69 male Veterans with a history of combat-theater deployment, we examined the relationship between trauma-related mental health symptoms and the concentration of NE in cerebrospinal fluid (CSF). CSF NE levels were measured by HPLC in CSF from morning lumbar puncture. Behavioral symptoms associated with diagnoses of PTSD, depression, insomnia, or post-concussive syndrome (PCS), which together cover a wide variety of symptoms associated with alterations in arousal systems, such as sleep, mood, concentration, and anxiety, were assessed via self-report (PTSD Checklist [PCL] for PTSD, Patient Health Questionnaire 9 [PHQ9] for depression, Pittsburgh Sleep Quality Index [PSQI] for sleep problems including insomnia, and Neurobehavioral Symptom Inventory [NSI] for PCS) and structured clinical interview (Clinician-Administered PSTD Scale [CAPS]). Individuals meeting criterion A of the DSM-IV diagnostic criteria for PTSD were considered trauma-exposed. Linear regression models were used to quantify the association between CSF NE and symptom intensity in participants with and without a history of trauma exposure, as well as in participants with a history of trauma exposure who were currently taking the noradrenergic receptor antagonist prazosin. ResultsFifty-two Veterans met criteria for a history of trauma exposure; of these, 36 met criteria for PTSD. CSF NE levels were not significantly different in Veterans with a history of trauma compared to those without, nor in Veterans with PTSD as compared to those without. Veterans with a history of trauma and who were not using the medication prazosin demonstrated a significantly more positive correlation between CSF NE and behavioral symptom expression than Veterans who had not experienced traumatic stress. No relationship between CSF NE and behavioral symptom expression was found in Veterans who had experienced traumatic stress and were taking prazosin at the time of the assessments. ConclusionsThese results are consistent with increased central nervous system responsiveness to noradrenergic signaling in individuals with a history of traumatic exposure, raising the possibility that there may be long-lasting physiologic effects of trauma-exposure that exist independently of whether an individual meets criteria for PTSD at any given point in time. Exploration of the mechanism by which brain responsiveness to NE is modulated following trauma holds the possibility of finding new strategies for both preventing and treating PTSD.