Background Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. Methods Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast‐mTBI) affects ethanol (EtOH)‐induced behavioral and physiological outcomes using an established mouse model of blast‐mTBI. To investigate potential translational relevance, we also examined self‐report responses to the Alcohol Use Disorders Identification Test‐Consumption questions (AUDIT‐C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast‐mTBI affected drinking behaviors in Iraq/Afghanistan Veterans. Results Both single and repetitive blast‐mTBI in mice increased the sedative properties of EtOH (with no change in tolerance or metabolism), but only repetitive blast potentiated EtOH‐induced locomotor stimulation and shifted EtOH intake patterns. Specifically, mice exposed to repetitive blasts showed increased consumption “front‐loading” (e.g., a higher rate of consumption during an initial 2‐h acute phase of a 24‐h alcohol access period and decreased total daily intake) during an intermittent 2‐bottle choice condition. Examination of AUDIT‐C scores in Iraq/Afghanistan Veterans revealed an optimal 3‐cluster solution: “low” (low intake and low frequency), “frequent” (low intake and high frequency), and “risky” (high intake and high frequency), where Veterans with a history of blast‐mTBI displayed a shift in cluster assignment from “frequent” to “risky,” as compared to Veterans who were deployed to Iraq/Afghanistan but had no lifetime history of TBI. Conclusions Together, these results offer new insight into how blast‐mTBI may give increase AUD risk and highlight the increased potential for adverse health risk behaviors following repetitive blast‐mTBI.

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Background Adverse pathophysiological and behavioral outcomes related to mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain are common following blast exposure and contribute to decreased quality of life, but underlying mechanisms and prophylactic/treatment options remain limited. The dynorphin/kappa opioid receptor (KOR) system helps regulate behavioral and inflammatory responses to stress and injury; however, it has yet to be investigated as a potential mechanism in either humans or animals exposed to blast. We hypothesized that blast-induced KOR activation mediates adverse outcomes related to inflammation and affective behavioral response. Methods C57Bl/6 adult male mice were singly or repeatedly exposed to either sham (anesthesia only) or blast delivered by a pneumatic shock tube. The selective KOR antagonist norBNI or vehicle (saline) was administered 72 h prior to repetitive blast or sham exposure. Serum and brain were collected 10 min or 4 h post-exposure for dynorphin A-like immunoreactivity and cytokine measurements, respectively. At 1-month post-exposure, mice were tested in a series of behavioral assays related to adverse outcomes reported by humans with blast trauma. Results Repetitive but not single blast exposure resulted in increased brain dynorphin A-like immunoreactivity. norBNI pretreatment blocked or significantly reduced blast-induced increase in serum and brain cytokines, including IL-6, at 4 h post exposure and aversive/anxiety-like behavioral dysfunction at 1-month post-exposure. Conclusions Our findings demonstrate a previously unreported role for the dynorphin/KOR system as a mediator of biochemical and behavioral dysfunction following repetitive blast exposure and highlight this system as a potential prophylactic/therapeutic treatment target.