Effects of Mild Blast Traumatic Brain Injury on Cognitive- and Addiction-Related Behaviors

Abstract

Traumatic brain injury (TBI) commonly results in cognitive and psychiatric problems. Cognitive impairments occur in approximately 30% of patients suffering from mild TBI (mTBI), and correlational evidence from clinical studies indicates that substance abuse may be increased following mTBI. However, understanding the lasting cognitive and psychiatric problems stemming from mTBI is difficult in clinical settings where pre-injury assessment may not be possible or accurate. Therefore, we used a previously characterized blast model of mTBI (bTBI) to examine cognitive- and addiction-related outcomes. We previously demonstrated that this model leads to bilateral damage of the medial prefrontal cortex (mPFC), a region critical for cognitive function and addiction. Rats were exposed to bTBI and tested in operant learning tasks several weeks after injury. bTBI rats made more errors during acquisition of a cue discrimination task compared to sham treated rats. Surprisingly, we observed no differences between groups in set shifting and delayed matching to sample, tasks known to require the mPFC. Separate rats performed cocaine self-administration. No group differences were found in intake or extinction, and only subtle differences were observed in drug-primed reinstatement 3–4 months after injury. These findings indicate that bTBI impairs acquisition of a visual discrimination task and that bTBI does not significantly increase the ability of cocaine exposure to trigger drug seeking.

Repeated blast model of mild traumatic brain injury alters oxycodone self‐administration and drug seeking

“…These increases were also observed in both single and repeated blast exposure models of mTBI (i.e., single in (Lim et al, 2015), repeated in the present study), consistent with other preclinical studies finding elevated intake of drugs of abuse using different models of TBI (Mayeux et al, 2015;Weil et al, 2016;Merkel et al, 2017b;Vonder Haar et al, 2018). It should be noted that in our studies using cocaine and oxycodone ((Muelbl et al, 2018) and the present study), food self-administration was conducted prior to drug self-administration. This was done to determine if injury affected operant conditioning and to ensure that rats had a similar ability to perform the task prior to drug exposure.…”

“…These tests were conducted without food restriction and with a limit of 64 reinforcers earned per day to minimize overtraining effects. We saw no differences between injured and non-injured rats in drug seeking during extinction sessions following cocaine self-administration (Muelbl et al, 2018) or oxycodone self-administration under an FR-1 schedule of reinforcement in the present study. Thus, the contribution of prior association between the Rats underwent repeated blast injury (n = 11) or sham exposure (n = 12) once a day for 3 days, after which they were implanted with a jugular catheter, and then trained for food self-administration under an FR-1 schedule of reinforcement.…”

“…These tests were conducted without food restriction and with a limit of 64 reinforcers earned per day to minimize overtraining effects. We saw no differences between injured and non‐injured rats in drug seeking during extinction sessions following cocaine self‐administration (Muelbl et al ., ) or oxycodone self‐administration under an FR‐1 schedule of reinforcement in the present study. Thus, the contribution of prior association between the environment and cues with food self‐administration is not thought to be a contributing factor to the differences in extinction responding observed following FR‐4 oxycodone self‐administration.…”

“…We previously demonstrated that a subset of rats exposed to bTBI had increased alcohol intake using short access to bottle choice tests (Lim et al ., ). However, we found that the same single exposure to bTBI did not alter cocaine self‐administration, extinction, or drug‐primed reinstatement (Muelbl et al ., ). Thus, for alcohol and opioids, we found that increases in measures of substance abuse liability were consistent across studies.…”

Executive (dys)function after traumatic brain injury: special considerations for behavioral pharmacology

“…To date, few studies have examined voluntary drug self-administration after TBI. However, these studies largely converge on the conclusion that animals with injury self-administer more drug, or escalate their intake more quickly, across both alcohol and cocaine ( Lim et al , 2015 ; Mayeux et al , 2015 ; Weil et al , 2016 ; Vonder Haar et al , 2018 ), although such self-administration may depend upon injury type, severity, and substance, as one group found no changes in cocaine intake after blast injury ( Muelbl et al , 2018 ), while others have seen increased alcohol intake after blast ( Lim et al , 2015 ), and increased cocaine after mild or severe focal injury ( Vonder Haar et al , 2018 ). Moreover, studies have found interesting subgroup differences within TBI animals with regard to acquisition of drug self-administration ( Lim et al , 2015 ; Vonder Haar et al , 2018 ), in which some TBI rats show faster acquisition of drug self-administration than others, suggesting potential biological or behavioral mediators of resilience that warrant investigation.…”