Cocaine self‐administration is increased after frontal traumatic brain injury and associated with neuroinflammation

Abstract

Traumatic brain injury (TBI) has been linked to the development of numerous psychiatric diseases, including substance use disorder. However, it can be difficult to ascertain from clinical data whether the TBI is cause or consequence of increased addiction vulnerability. Surprisingly few studies have taken advantage of animal models to investigate the causal nature of this relationship. In terms of a plausible neurobiological mechanism through which TBI could magnify the risk of substance dependence, numerous studies indicate that TBI can cause widespread disruption to monoaminergic signaling in striatal regions, and also increases neuroinflammation. In the current study, male Long-Evans rats received either a mild or severe TBI centered over the frontal cortex via controlled cortical impact, and were subsequently trained to self-administer cocaine over 10 6-hour sessions. At the end of the study, markers of striatal dopaminergic function, and levels of inflammatory cytokine levels in the frontal lobes, were assessed via western blot and multiplex ELISA, respectively. There was significantly higher cocaine intake in a subset of animals with either mild or severe TBI. However, many animals within both TBI groups failed to acquire self-administration. Principal components analysis suggested that both dopaminergic and neuroinflammatory proteins were associated with overall cocaine intake, yet only an inflammatory component was associated with acquisition of self-administration, suggesting neuroinflammation may make a more substantial contribution to the likelihood of drug-taking. Should neuroinflammation play a causal role in mediating TBI-induced addiction risk, anti-inflammatory therapy may reduce the likelihood of substance abuse in TBI populations.

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

“…These drugs have dramatically different mechanisms of action; alcohol is a positive modulator of GABA A receptors, an antagonist of NMDA glutamate receptors, and has actions at several ion channels, while oxycodone primarily functions as a mu opioid receptor agonist (Cui & Koob, ; Yaksh & Wallace, ). These increases were also observed in both single and repeated blast exposure models of mTBI (i.e., single in (Lim et al ., ), 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 ., ; Weil et al ., ; Merkel et al ., ; Vonder Haar et al ., ). It should be noted that in our studies using cocaine and oxycodone ((Muelbl et al ., ) and the present study), food self‐administration was conducted prior to drug self‐administration.…”

“…() using the lateral fluid percussion model found increased levels of glial fibrillary acidic protein (GFAP), CD68, and ionized calcium‐binding adapter molecule 1 (Iba‐1) to indicate increased levels of neuroinflammation, in addition to increased neuronal degradation measured by Fluoro‐Jade. Other studies using different models of TBI have also reported increased levels of neuroinflammatory markers (Lowing et al ., ; Merkel et al ., ; Merkel et al ., ; Vonder Haar et al ., ). Of note, adolescent mice exposed to a controlled cortical impact TBI had higher preference during cocaine‐induced conditioned place preference compared to non‐TBI mice, however administration of dexamethasone, an anti‐inflammatory steroidal compound, normalized the degree of place preference (Merkel et al ., ).…”

“…There was also no difference in cue‐induced drug seeking. In light of the epidemiological evidence for a link between mTBI and substance abuse, and evidence that TBI models that damage the frontal cortex increase drug intake (Mayeux et al ., ; Weil et al ., ; Vonder Haar et al ., ) and impair extinction processes (Schneider et al ., ), these findings went against our hypothesis. In Experiment 2, rbTBI‐exposed rats exhibited significantly lower drug intake compared to sham‐exposed rats during the FR‐2 schedule of oxycodone self‐administration; however, this difference did not persist under an FR‐4 schedule.…”

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

“…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 ., ). These studies have clear clinical implications given the well‐established increase in risk of substance abuse in those with a history of early life TBI (Cannella et al ., ).…”

Profiles of women in science: Prof. Catharine Winstanley of the University of British Columbia

“…Her latest publication in EJN is titled “Cocaine self‐administration is increased after frontal traumatic brain injury and associated with neuroinflammation”, (Vonder Haar et al., ), https://doi.org/10.1111/ejn.14123.…”