Evaluating DR2 agonism as a potential therapeutic approach to substance abuse and traumatic brain injury

Title: Evaluating DR2 agonism as a potential therapeutic approach to substance abuse and traumatic brain injury Abstract Substance use disorder (SUD) and traumatic brain injury (TBI) are inextricably and bidirectionally linked. SUD is one of the strongest predictors of TBI, and a substantial proportion of TBIs occur in addicted individuals. An inverse relationship is also emerging, such that TBI can serve as a risk factor for, or modulate the course of, SUD. Critically, substance use after TBI is a key predictor of rehabilitation outcomes, prognosis, and additional head injuries. Currently, there are no FDA-approved treatment options for either TBI or SUDs associated with psychostimulants. DR2 agonism has potentially reemerged as a potential therapeutic approach under both conditions because of their relatively low abuse liability profile. Using a translational approach, the objective of this application is to explore the therapeutic potential of DR2 agonism in TBI and substance use. This application will seek to answer these research questions: 1) Does DR2 mitigate the neuroinflammatory state associated with TBI and substance use and 2) Does D2 agonism influence the proteogenomic relationship in either TBI and/or SUDs. The objective of this application will be accomplished by addressing the following: Aim 1: Determine the neuroprotective potential of dopaminergic agonists in an in vitro ischemic/substance use model of the neurovascular unit and Aim 2: Define the proteogenomic profiles of D2 agonism on TBI/SUD protein expression by cutting- edge RNA-seq and proteomics. This study is innovative because it employs a novel, dynamic blood-brain barrier platform capable of recapitulating human in vivo physiological parameters. This study is significant because it will highlight specific signaling and gene expression profiles associated with TBI, and substance use to develop specific treatment endpoints The long-term goal of this is to develop data for further proposal preparation and to identify new molecular targets for further therapeutic development.