Summary Blast-related traumatic brain injury (TBI) incurred in the war theaters of Iraq and Afghanistan is associated with the development of neuropsychiatric injuries (including post-traumatic stress disorder [PTSD] and major depression) among soldiers. Treatment for blast-related TBI is currently limited to counseling and palliative care. We have explored the effects of 74.5-kPa blast exposures that mimic mild TBI (mTBI) in a rat model. Blast- exposed rats exhibit a variety of PTSD-like behavioral traits, including increased anxiety, enhanced acoustic startle, altered responses to a predator scent, and altered cued fear responses. Further experimental evidence indicates that the cerebral vasculature is a main target for blast waves, as acute and chronic vascular degenerative processes develop after blast exposures. In subsequent studies, we found that a mGluR2/3 receptor antagonist (BCI-838) is able to reverse most of the PTSD-related traits seen in rats. This led to the observation that mGluR2/3 expression is increased following blast injury in the rat. Subsequent studies showed that this increased mGluR2/3 expression results in decreased expression of TRPV1, its modulating target. Capsaicin is an alkaloid known to activate TRPV1 and to have antidepressant and anxiolytic properties. In addition, it has strong angiogenic protective properties. The overall goal of the proposed research is to test whether systemic administration of capsaicin can reverse the established cerebrovascular and cognitive degenerative processes present in our rat model of blast-induced mTBI. We propose to administer capsaicin to blast-exposed rats (3 × 74.5 kPa) once they have developed the chronic PTSD phenotype (6 months post-blast exposure) to test whether this treatment improves the cognitive deficits and vascular alterations associated with the condition. We will test for depression (forced swimming and novelty-suppressed feeding tests), memory (Morris Water Maze), contextual and cued fear conditioning, and novel object recognition. Using micro X-ray computed tomography, immunohistochemical, and stereological methods, we will analyze alterations in the brain vasculature, including the presence of abnormal vasculature and changes in vascular density, length, surface, and volume. Biochemical analyses will identify any molecular structural changes in the vasculature that occur with capsaicin treatment. Collectively, the proposed studies will explore the potential therapeutic benefits of capsaicin and agents targeting TRPV1 for the treatment of blast-induced PTSD. These studies may uncover new therapeutic options for the treatment of active duty military personnel and veterans affected by this devastating condition.