Repetitive but not single blast mild traumatic brain injury increases ethanol responsivity in mice and risky drinking behavior in combat Veterans

Abstract

ABSTRACTMild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military Servicemembers and in contact sports athletes. mTBI, especially within military populations, is often comorbid with posttraumatic stress disorder (PTSD), and can increase health-risk behaviors (e.g., sensation/novelty seeking, impulsivity, risk taking, irritability/aggression) and substance misuse/abuse, but underlying mechanisms remain poorly understood. Using an established mouse model of blast mTBI, here we examined the effects of single (1x) and repetitive (3x) blast exposure on ethanol responsivity using a battery of tests, each associated with distinct aspects of alcohol abuse vulnerability. While both single and repetitive blast exposure increased the sedative properties of high-dose ethanol (with no change in tolerance or metabolism), only repetitive blast exposure potentiated ethanol-induced locomotor stimulation and shifted ethanol intake patterns (i.e., increased consumption ‘front-loading’) during intermittent two bottle choice. To establish translational relevance, we next examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption Questions (AUDIT-C) and used a novel unsupervised machine learning approach to investigate whether a history of blast with acute symptoms and mTBI affected drinking behaviors in Iraq and Afghanistan Veterans. AUDIT-C scores were increased in Veterans with a history of blast exposure and subsequent cluster analysis identified a three-cluster solution: ‘low’ (low intake and low frequency), ‘frequent’ (low intake but 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 and/or Afghanistan who had no lifetime history of TBI. Together, these results offer new insight regarding how blast mTBI may give rise to increased substance use/misuse and highlight the increased potential for adverse health-risk behaviors following repetitive blast mTBI exposure.