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Principal Investigator: Xuan Anna Li
Organization: UNIV OF MARYLAND, COLLEGE PARK
Fiscal Year: 2024
Award: $185,452
Funding agency: National Institute on Drug Abuse
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.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATP-Dependent Proteolysis Factor 1><Abstinence><Anatomic Sites><Anatomic structures><Anatomy><Behavior><Biochemical><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Chemical Dependence><Clinical><Common Rat Strains><Cues><Data><Dephosphin><Dihydrohydroxycodeinone><Drug Addiction><Drug Dependence><Drug Dependency><Drug usage><Drugs><Dynamin><E3 Ligase><E3 Ubiquitin Ligase><Exploratory/Developmental Grant><Exposure to><Extinction><Frequencies><HMG-20><High Mobility Protein 20><Incubated><Infumorph><Intervention><Intervention Strategies><Kadian><Label><Lead><Length><Link><Literature><MS Contin><MSir><Macropain><Macroxyproteinase><Mediating><Mediator><Medication><Metabolic Protein Degradation><Mice><Mice Mammals><Mitochondria><Modeling><Molecular><Molecular Target><Morphia><Morphine><Morphology><Multicatalytic Proteinase><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nucleus Accumbens><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Oramorph><Oramorph SR><Oxycodeinon><Oxycodone><Oxycodone SR><Oxycontin><Pb element><Pharmaceutical Preparations><Play><Prosome><Proteasome><Proteasome Endopeptidase Complex><Protein Turnover><Proteins><Proteosome><Publishing><R21 Mechanism><R21 Program><Rat><Rats Mammals><Rattus><Regulation><Regulatory Protein Degradation><Relapse><Research><Rewards><Role><Roxanol><Roxicodone><Saline><Saline Solution><Self Administered><Self Administration><Statex SR><Subcellular Process><System><Testing><Time><Ubiquitilation><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Viral><Viral Vector><Work><activity marker><addiction><addictive disorder><cocaine relapse><cocaine seeking><craving><drug abstinence><drug craving><drug use><drug/agent><exploratory developmental study><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><heavy metal Pb><heavy metal lead><innovate><innovation><innovative><interventional strategy><mRNA Expression><male><mitochondrial><mitochondrial dysfunction><multicatalytic endopeptidase complex><neural mechanism><neuromechanism><neuronal><opiate crisis><opioid addiction><opioid crisis><opioid dependence><opioid dependent><opioid epidemic><opioid medication abuse><opioid prescription drug abuse><oxycodone seeking><oxycodone self-administration><pharmacologic><prescription opiate abuse><prescription opioid abuse><prevent relapse><prolonged abstinence><protein degradation><protein expression><psychostimulant><relapse against cocaine><relapse prevention><self-administer oxycodone><social role><sustained abstinence><therapeutic target><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase>