title: 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.
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.|2 The Center for Substance Abuse Research, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Merkel
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Roshanak
authors.initials: R
authors.lastname: Razmpour
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Lutton
authors.affiliation: 2 The Center for Substance Abuse Research, Temple University School of Medicine , Philadelphia, Pennsylvania.|4 Department of Pharmacology, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Tallarida
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Heldt
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Lee Anne
authors.initials: LA
authors.lastname: Cannella
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.|2 The Center for Substance Abuse Research, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Persidsky
authors.affiliation: 2 The Center for Substance Abuse Research, Temple University School of Medicine , Philadelphia, Pennsylvania.|4 Department of Pharmacology, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.|2 The Center for Substance Abuse Research, Temple University School of Medicine , Philadelphia, Pennsylvania.|3 The Shriners Hospitals Pediatric Research Center, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Servio H
authors.initials: SH
authors.lastname: Ramirez
mesh_terms: D000367:Age Factors; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003042:Cocaine / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012201:Reward; D012646:Self Administration
chemical_list: D018836:Inflammation Mediators; D003042:Cocaine
keywords: TBI; addiction; adolescent; neuroinflammation; psychostimulants