Determination of factors that influence addiction-related outcomes following brain injury

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Each year, an estimated 1.7 million Americans suffer from traumatic brain injury (TBI). The incidence of TBI among veterans of the military may be as high as 30%, with blast injury from explosive devices causing the overwhelming majority of TBIs in combat settings. An association between non-severe (i.e., mild or moderate) mTBI and substance abuse has been demonstrated in numerous epidemiological studies. Therefore, veterans of the military that have experienced TBI during deployment or during non-deployed and civilian life may be at higher risk for drug abuse disorders than people that have not experienced TBI. However, despite extensive evidence of increased substance abuse disorder following non-severe TBI, little is known about how traumatic brain injury changes brain structure and function to make somebody more susceptible to drug abuse. Thus, there is a great deal of inconsistency in clinical treatments prescribed to non-severe TBI sufferers that can include no drug treatment, non-steroidal anti-inflammatory drugs, or even opioids. The long-term consequences for millions of veterans remains unknown. Advanced magnetic resonance imaging (MRI) techniques (e.g., diffusion tensor imaging) in humans have revealed subtle damage to brain tissues following mTBI, in which specific brain regions seem to be particularly vulnerable to injury. In our published data, an experimental model of blast mTBI in rodents led to an enduring inflammatory response that was evident in the medial prefrontal cortex (mPFC) of the brain, which was evident using advanced MRI techniques and pathological investigation. There is emerging evidence of a link between these types of inflammatory responses in the brain and drug abuse behavior. In fact, recent research has indicated that the use of opioids, which are commonly prescribed for TBI, initiate similar inflammatory responses. Therefore, our hypothesis is that drug intake and/or drug abuse relapse would be more likely following mTBI. Given that opioids are commonly administered to mTBI patients in emergency departments, combined with the fact that over 13 million Americans misused prescription pain killers or used heroin in 2016, this could lead to a significant public health issue with mTBI patients that are treated with opioids suffering from possible life-long issues with drug dependency. This study will explore the relationship between mTBI and substance abuse disorder using a laboratory model, wherein rodents will be exposed to blast mTBI and post-injury opioid self-administration to model individual drug treatment following injury. After removal of opioids, rodents will later be exposed again to opioid self- administration to identify relapse behaviors and addiction liability. The effects of pharmacological treatment on addiction liability will also be defined. The mechanisms for these changes in the brain following mTBI and opioid exposure will be determined using advanced MRI techniques and analysis of brain structure and chemistry. Results of this study may help to define a correlation between mTBI and substance abuse disorders that can be used by VA clinicians to better understand and treat veterans with drug addiction issues and history of TBI.