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.

Keywords: brain injury; cytokine; dopamine; psychostimulant; rat.

Figure 1.

Behavioral outcomes in cocaine self-administration. A) Both Mild and Severe animals took more infusions overall (p < 0.001, p = 0.003, respectively). B) Increased active lever presses were also observed in Mild and Severe animals relative to Sham (p’s < 0.001). C) Severe TBI animals pressed the inactive lever more than Shams (p < 0.001). D) Severe TBI animals also showed weaker discrimination of the active lever relative to Sham (p < 0.001). E) Severe TBI animals were also worse at discriminating the cue that signaled cocaine availability (p < 0.001). *** = p < 0.001; ** = p < 0.01.

Figure 2.

Behavioral outcomes in saline self-administration. A) There were no group differences in number of infusions. B) There were no group differences in active lever presses. C) Both Mild and Severe TBI animals pressed the inactive lever less than Shams (p < 0.001, p = 0.013, respectively). *** = p < 0.001; * = p < 0.05.

Figure 3.

Levels of inflammatory cytokines. A) The Severe group had lower IL-6 levels than the Mild group (p = 0.008). B) Severely-injured animals also had lower IL-10 relative to Mild (p = 0.038). C) Mild animals had significantly higher levels of IL-12 relative to Sham (p < 0.001), and Severe TBI animals had higher levels than both Sham and Mild TBI groups (p < 0.001, p = 0.009, respectively). Open circles represent individual data points; *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

Figure 4.

Principal components analysis of cytokine data. A) Scree plot of extracted components. The first three were selected for further analysis. B) Relative loading of different cytokines in PC1 vs. PC2, illustrating the degree to which each cytokine contributes to its component. PC2 displayed relatively common profiles, with the exception of IL-12. C) Relative loading of different cytokines in PC2 vs. PC3. PC2 revealed orthogonally opposed cytokine loadings, with IL-12 again showing the largest, and most independent effect. D) Relative PC2 loading (group mean +/− SEM; open circles represent individual data points), stratified by group. The Severe TBI group had significantly higher levels than both Sham and Mild TBI (p < 0.001, p = 0.001, respectively), which is likely driven by the strong group differences in IL-12. The Sham and Mild TBI were not significantly different (p = 0.133). *** = p < 0.001.

Figure 5.

Levels of markers of dopaminergic signaling. A) Both Mild and Severe TBI groups had lower levels of D1 receptors in the striatum (p = 0.020, p = 0.019, respectively). B) However, the Mild TBI had higher D1 receptor levels in the nucleus accumbens compared to Sham or Severe TBI (p = 0.042, p = 0.017, respectively). C) Cocaine animals had increased D2 receptor levels in the striatum (p = 0.014). D) Cocaine animals demonstrated lower D1 receptor levels in the accumbens (p = 0.035). E) Cocaine animals displayed higher levels of DAT in the accumbens (p = 0.026). Open circles represent individual data points; * = p < 0.05.

Figure 6.

Principal components analysis of markers of dopaminergic function. A) Scree plot of extracted components. The first four were selected for further analysis. B) Relative loading of different dopamine markers in PC1 vs. PC4 illustrating the degree to which each protein contributes to its component. C) Relative loading of different dopamine markers in PC2 vs. PC4. D) Relative loading of different dopamine markers in PC3 vs. PC4. E) Relative PC4 loading, stratified by injury group (group mean +/− SEM; open circles represent individual data points). The Severe TBI group had significantly lower levels than the Sham group (p = 0.028). Comparison of PC4 across these cases shows relatively opposing loadings for the accumbens versus striatum, and D1 versus D2, highlighting the importance of these relationships in TBI. * = p < 0.05.

Figure 7.

Regression predictions of behavior as a function of extracted principal components. A) Number of infusions as predicted by a regression including injury, session, inflammation PC3, dopamine PC1, and dopamine PC4. Specifically shown is the relationship of high levels of PC3 to higher cocaine intake. B) The same function shown at the end of cocaine self-administration, demonstrating that PC3 interacts with session, but that higher levels are still associated with relatively low cocaine intake. C) Logistic regression function, in which inflammation PC3 was the only significant predictor. This data demonstrates the ability of PC3 to account for acquisition of cocaine self-administration, suggesting that inflammation precedes high levels of cocaine intake, rather than being caused by it.