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

Abstract

Each year, traumatic brain injuries (TBI) affect millions worldwide. Mild TBIs (mTBI) are the most prevalent and can lead to a range of neurobehavioral problems, including substance abuse. A single blast exposure, inducing mTBI alters the medial prefrontal cortex, an area implicated in addiction, for at least 30 days post injury in rats. Repeated blast exposures result in greater physiological and behavioral dysfunction than single exposure; however, the impact of repeated mTBI on addiction is unknown. In this study, the effect of mTBI on various stages of oxycodone use was examined. Male Sprague Dawley rats were exposed to a blast model of mTBI once per day for 3 days. Rats were trained to self‐administer oxycodone during short (2 h) and long (6 h) access sessions. Following abstinence, rats underwent extinction and two cued reinstatement sessions. Sham and rbTBI rats had similar oxycodone intake, extinction responding and cued reinstatement of drug seeking. A second group of rats were trained to self‐administer oxycodone with varying reinforcement schedules (fixed ratio (FR)‐2 and FR‐4). Under an FR‐2 schedule, rbTBI‐exposed rats earned fewer reinforcers than sham‐exposed rats. During 10 extinction sessions, the rbTBI‐exposed rats exhibited significantly more seeking for oxycodone than the sham‐injured rats. There was a positive correlation between total oxycodone intake and day 1 extinction drug seeking in sham, but not in rbTBI‐exposed rats. Together, this suggests that rbTBI‐exposed rats are more sensitive to oxycodone‐associated cues during reinstatement than sham‐exposed rats and that rbTBI may disrupt the relationship between oxycodone intake and seeking.

Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

“…The acquisition in the males was consistent with that observed using similar procedures in a group of experimentally naïve adult males (Nguyen et al, 2019). Unfortunately the majority of rat oxycodone IVSA studies published so far have been in male rats (Austin Zamarripa et al, 2018;Blackwood et al, 2019;Bossert et al, 2018;Jordan et al, 2019;Leri and Burns, 2005;Mavrikaki et al, 2019;Nawarawong et al, 2018;Neelakantan et al, 2017;Nguyen et al, 2019;Nguyen, J. D. et al, 2018b;Pravetoni et al, 2014;Townsend et al, 2017;Wade et al, 2015;You et al, 2018;You et al, 2017); one exception was a study in pregnant rats (Vassoler et al, 2018). Interestingly, when female animals were evaluated on a fentanyl dose substitution under an FR procedure, the THC exposed rats self-administered more drug at the lowest dose (Figure 9).…”

Repeated blast mild traumatic brain injury and oxycodone self-administration produce interactive effects on neuroimaging outcomes

“…We have previously demonstrated that our blast model of mild TBI leads to enduring microstructural changes in the medial prefrontal cortex 13 , a brain region critically involved in drug seeking in humans and rodent models (reviewed in [14][15][16] ). We have also found that repeated blast mild TBI (rbTBI) persistently elevated levels of oxycodone seeking, despite similar levels of prior drug self-administration 17 . In the current study, we hypothesized that rbTBI and oxycodone self-administration would lead to persistent changes in structure and/or function of the medial prefrontal cortex which may also extend to other aspects of mesocorticolimbic circuitry that would be associated with elevated drug seeking.…”

“…Rats were exposed to repeated blast overpressure or repeated sham conditions as described in 13,[17][18][19] . During blast or sham treatment, rats were maintained under anesthesia with a continuous delivery of 1.5% isoflurane and administered Rimadyl (carprofen, 5 mg/kg, s.c., Zoetis Inc, Kalamazoo, MI, USA).…”

“…Food training and oxycodone self-administration were performed as described in 17 At the beginning of each session, the fan was turned on, both levers were extended, and a sucrose pellet was delivered. Rats were first trained on a fixed ratio (FR)-1 schedule of reinforcement, with a single press on the active lever resulting in sucrose pellet delivery.…”

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…Another promising translational approach targets issues relevant to predisposition and comorbidity. For example, compared with sham‐exposed rats, repeated blast traumatic brain injury (TBI)‐exposed rats were more sensitive to oxycodone‐associated cues during reinstatement, suggesting that repeated blast TBI may disrupt the relationship between oxycodone intake and seeking (Nawarawong et al ., ). Inflammation in the frontal cortex may be one underlying mechanism, as suggested by a study using TBI to expose to cocaine self‐administration (Vonder Haar et al ., ).…”