Molecular Neurobiology of Human Opioid Use Disorder

Project Summary Opioid addiction is a national epidemic contributing to the deadliest drug overdose crisis in US history and accompanied by excessive healthcare burdens due to the misuse of heroin and opioid prescription medications. There continues to be a lack of neurobiological knowledge about opioid use disorder to drive novel therapies critically needed to provide options to the current medications that are predominantly opioid-based and thus of abuse liability themselves. A fundamental core of our reverse translational research efforts has been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Through such strategies we recently discovered a previously unrecognized neurobiological impact of opioids suggesting opioid-induced epigenetic alteration linked to the FYN which mediates glutamatergic signaling and phosphorylates tau (pTau); we also detected significant glutamatergic alterations and hyper-pTau pathology in heroin abusers. FYN is a Src family tyrosine kinase within the postsynaptic density that phosphorylates tau, involved in microtubule stability and dynamics, and thus a regulator of cytoskeletal remodeling which is a key feature of addiction. We verified elevation of FYN-targeted Tau phosphorylation in rats that self-administered heroin and in our chronic opioid in vitro cell culture model. Moreover, we were able to inhibit heroin self-administration (SA) and seeking behaviors in animals treated with a Fyn inhibitor and Fyn knockdown. These multidisciplinary and integrative data provides a strong foundation on which to interrogate FYN in opioid abuse with the goal of therapeutic development. We hypothesize that upregulation of Fyn and its resulting downstream target impairments in mesocorticolimbic brain areas contribute to heroin addiction behavior and can be targeted for treatment interventions. We propose to (1) determine the molecular signature of FYN-related networks in mesocorticolimbic regions associated with heroin abuse by RNA-sequencing in a cell-specific manner in human and the rat heroin SA model and to (2) characterize cell-specific downstream alterations mediated by Fyn underlying heroin SA and seeking behaviors. The downstream mechanisms leverage viral mediated cell-specific effects of Fyn on intracellular signaling cascades and pTau as well as cytoskeletal organization. Results gained from our integrative multidisciplinary study will advance knowledge of Fyn-related abnormalities underlying opioid abuse and provide science-based pharmacotherapeutic targets to expand treatment options for opioid addiction.