Adolescent Traumatic Brain Injury Induces Chronic Mesolimbic Neuroinflammation with Concurrent Enhancement in the Rewarding Effects of Cocaine in Mice during Adulthood

Abstract

Clinical psychiatric disorders of depression, anxiety, and substance abuse are most prevalent after traumatic brain injury (TBI). Pre-clinical research has focused on depression and anxiety post-injury; however, virtually no data exist examining whether the preference for illicit drugs is affected by traumatic injury in the developing adolescent brain. Using the controlled cortical impact (CCI) model of TBI and the conditioned place preference (CPP) assay, we tested the underlying hypothesis that brain injury during adolescence exacerbates the rewarding properties of cocaine in adulthood possibly through an active inflammatory status in the mesolimbic pathway. Six-week old, C57BL/6 mice sustained a single CCI-TBI to the right somatosensory cortex. CPP experiments with cocaine began 2 weeks post-TBI. Animals receiving cocaine displayed significant place preference shifts compared to saline controls. Further, within the cocaine-experienced cohort, moderate CCI-TBI during adolescence significantly increased the preference shift in adulthood when compared to naïve controls. Additionally, persistent neuroinflammatory responses were observed in the cortex, nucleus accumbens (NAc), and ventral tegmental area post-CCI-TBI. Significant increases in both astrocytic, glial fibrillary acidic protein, and microglial, ionization basic acid 1, markers were observed in the NAc at the end of CPP testing. Moreover, analysis using focused array gene expression panels identified the upregulation of numerous inflammatory genes in moderate CCI-TBI animals, compared to naïve controls, both in the cortex and NAc at 2 weeks post-TBI, before onset of cocaine administration. These results suggest that sustaining moderate TBI during adolescence may augment the rewarding effects of psychostimulants in adulthood, possibly by induction of chronic mesolimbic neuroinflammation.

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

“…Therefore, the groups used in the study were as follows: no craniectomy/untreated, CCI-TBI/untreated, no craniectomy/dexamethasone, CCI-TBI/dexamethasone. Of note, we did not observe any significant differences between naïve and sham animals for either glial activation in the nucleus accumbens or cocaine CPP 4 . Therefore, since our previous data show similar control end-results for both naïve and sham animals, we selected naïve (no craniectomy) mice to control for data presented in this study.…”

“…Notably, current studies in substance abuse research suggest that the expression of innate immune factors in the NAc may mediate drug and alcohol abuse behavior 7–12 . Our recent data demonstrated overexpression of numerous immune response genes in the NAc following CCI-TBI 4 . Therefore, in the current study, we hypothesize that neuroinflammation in the NAc mediates the augmentation of cocaine place preference following moderate, adolescent CCI-TBI.…”

“…Animals were prepared for surgery as previously described 4 . Briefly, animals were weighed and anesthetized using 100/10mg/kg ketamine/xylazine (Henry Schein Animal Health; Dublin, OH) administered via intraperitoneal (i.p.)…”

“…Specifically, in the context of cocaine addiction, clinical studies have shown that 84% of cocaine-dependent research volunteers sustained their first TBI (mean age 16) prior to initiating cocaine use (mean age: 23) 3 . Furthermore, using preclinical animal models, our recent report, Merkel et al (2016), shows that adolescent mice with a history of moderate controlled cortical impact (CCI) injury exhibit greater susceptibility to the rewarding effects of cocaine in a conditioned place preference (CPP) assay compared to controls 4 .…”

Impact of traumatic brain injury on dopaminergic transmission

“…TBI-induced chronic mesolimbic neuroinflammation may thus contribute to the long-term changes in rewarding effects in adulthood. 80 After TBI, amyloid precursor protein (APP) accumulates in white matter tracts, and this leads to deficits in striatal DARPP-32 phosphorylation. These downstream signaling mediators of striatal DAergic neurotransmission increased sensitivity to ethanol-induced sedation while altering ethanol consumption.…”