March5 and Associated Mitochondrial Dynamics in Incubation of Oxycodone Craving

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Project summary/abstract Reducing rates of relapse after abstinence is a key challenge for curbing the ongoing opioid epidemic. One of the common factors for triggering relapse is re-exposure to drug-associated cues. In rats, cue-induced oxycodone seeking progressively intensifies (incubates) over the first weeks of abstinence from extended access oxycodone self-administration, and remains high for at least a month of abstinence. Our recently published work demonstrated a critical role of orbitofrontal cortex (OFC) in this incubation. However, molecular mechanisms in OFC underlying this incubation are largely unknown. Specifically, our observation of a progressive increase of neuronal activation in OFC associated with oxycodone seeking could be the result of time-dependent molecular adaptations in OFC during abstinence. Emerging evidence has implicated both the ubiquitin proteasome system (UPS) and mitochondrial regulation in addiction-related plasticity. Linking these two lines of work, we found that mRNA expression of March5, a mitochondrial E3 ubiquitin ligase, was significantly decreased in OFC on abstinence day 15 compared with saline control. A key role of March5 is to suppress mitochondrial fission, by degrading mitochondrial fission mediators such as dynamin-related protein 1(Drp1). Based on this preliminary work, here we propose to examine the role of March5 and associated mitochondria dynamics in incubation of oxycodone craving. In Aim 1, we will use biochemical approaches to examine protein expression of March5 and its downstream target Drp1 in the OFC, and use viral-mediated gene manipulation to determine if March5 in the OFC plays a causal role in the incubation of oxycodone craving. In Aim 2, we will use viral vectors to label mitochondria in OFC neurons and examine the morphology of mitochondria in OFC neurons during incubation of oxycodone craving. Overall, this proposal will initiate a new line of research focusing on the mitochondrial E3 ubiquitin ligase in OFC in relapse to drug seeking. From a clinical perspective, this work will provide targets for developing pharmacological interventions to decrease drug craving and promote abstinence.