Dexamethasone Attenuates the Enhanced Rewarding Effects of Cocaine Following Experimental Traumatic Brain Injury

Abstract

Clinical studies have identified traumatic brain injury (TBI) as a risk factor for the development of cocaine dependence. This claim is supported by our recent pre-clinical studies showing enhancement of the rewarding effects of cocaine in mice sustaining moderate controlled cortical impact (CCI) injury during adolescence. Here, we test the efficacy of dexamethasone, an anti-inflammatory corticosteroid, to attenuate augmentation of the behavioral response to cocaine observed in CCI-TBI animals using the conditioned place preference (CPP) assay. These studies were performed in order to determine whether pro-inflammatory activity in the nucleus accumbens (NAc), a key brain nucleus in the reward pathway, mediates enhanced cocaine induced CPP in adolescent animals sustaining moderate CCI-TBI. Our data reveal robust glial activation in the NAc following CCI-TBI and a significant increase in the cocaine induced CPP of untreated CCI-TBI mice. Furthermore, our results show that dexamethasone treatment following CCI-TBI can attenuate the cocaine place preference of injured animals without producing aversion in the CPP assay. Our studies also found that dexamethasone treatment significantly reduced the expression of select immune response genes including CCL2 and ICAM-1, returning their expression to control levels, which prompted an investigation of peripheral blood monocytes in dexamethasone-treated animals. Experimental findings showed that no craniectomy/dexamethasone mice had a significant increase, while CCI-TBI/dexamethasone animals had a significant decrease in the percentage of circulating non-classical patrolling monocytes. These results suggest that a portion of these monocytes may migrate to the brain in response to CCI-TBI, potentially sparing the development of chronic neuroinflammation in regions associated with the reward circuitry such as the NAc. Overall, our findings indicate that anti-inflammatory agents, such as dexamethasone, may be effective in normalizing the rewarding effects of cocaine following CCI-TBI.

Factors affecting increased risk for substance use disorders following traumatic brain injury: What we can learn from animal models

“…As reports by Shah et al and Alhilali et al also observed white matter injury in the NAc of TBI patients 39, 40 , similar immune cell activation and accumulation may occur in all white matter tracts including the anterior commissure, which runs directly through the NAc. In fact, as mentioned, our recent studies show that reactive microglia and chronic neuroinflammation occur not only at the cortical site of injury, but also in distal brain regions like the PFC and NAc (Figure 2) 21, 41 .…”

“…As previous studies have shown that immunosuppressive agents can modulate the severity of substance abuse behavior 72 , we wanted to determine whether neuroinflammation plays an important role in enhancing the rewarding effects of cocaine following adolescent brain injury. Our results show that administration of a synthetic, anti-inflammatory glucocorticoid receptor agonist (dexamethasone) significantly attenuates the enhanced rewarding effects of cocaine and returns drug-seeking behavior to control levels 41 . Furthermore, we show that dexamethasone therapy significantly reduced the expression of select immune response genes (i.e.…”

“…Using a passive clarity technique and multi-photon microscopy, we observed a significant increase in GFAP intensity and the appearance of hypertrophic astrocytic processes (reactive astrocytes) in the NAc of animals sustaining moderate CCI 41 . Likewise, we saw significant increases in IBA-1 immunostaining and microglial volume and the appearance of amoeboid-shaped microglia in the NAc following moderate CCI, again consistent with glial reactivity 41 . Furthermore, using a large immune response panel, we found that 66 of 92 target genes were significantly upregulated in the NAc 2 weeks after moderate CCI, suggesting that a number of cytokines, chemokines, adhesion molecules, stress response genes, etc.…”

“…Notably, although neurocircuits and neurotransmitter systems may comprise the machinery that enables substance abuse behaviors, recent reports suggest that the expression of innate immune factors (i.e. toll-like receptors 62–64 , adapter proteins 65 , chemokines 41, 66, 67 , interleukins 68 , etc.) may actually be the driving force that fuels the neurobiology of addiction 69, 70 .…”

“…Additionally, we recently reported on the effect of neuroimmune activation as a mediator of substance abuse behavior by administering a potent anti-inflammatory therapy to animals beginning 24 hours after open-head CCI 41 . As previous studies have shown that immunosuppressive agents can modulate the severity of substance abuse behavior 72 , we wanted to determine whether neuroinflammation plays an important role in enhancing the rewarding effects of cocaine following adolescent brain injury.…”