PROJECT SUMMARY/ABSTRACT Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments and associated with neurobiological alterations impacting multiple cognitive functions. Challenges to treating CUD include an imbalance in neurofunctional systems that ‘re-wire’ the brain such that appetitive and habitual processes direct maladaptive decision-making and behavior. The proposed research aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamate and functional brain networks. The metabotropic glutamate 5 receptor (mGluR5) is a postsynaptic receptor involved in neuroplastic mechanisms, and associated with modulating the acquisition and persistence of addictive behavior in CUD. Studies of mGluR5 in CUD demonstrate a widespread reduction in availability during early abstinence; however, less is known regarding mGluR5 availability in current users, and relationships to reorganized brain circuitry underlying cognitive functioning. Resting-state and task-based (e.g., response inhibition) performance involve coordinated activity in known functional brain networks and alterations in connectivity patterns in CUD lend insight in a reorganization of circuitry (e.g., fronto-parietal systems) central to addictive behaviors. This application proposes to investigate the distribution of mGluR5 through PET imaging using the highly-selective radioligand [18F]FPEB (Aim 1), and functional network activity at resting-state and related to response inhibition using a Go/NoGo task during fMRI (Aim 2) in currently-using individuals with CUD and matched healthy comparison participants. Additional sophisticated analytics (e.g., independent component analysis) will be used to integrate these multi-modal data (Aim 3), providing novel insight into the relationship between these neurofunctional systems in CUD. This program of research and training will integrate state-of-the-art biomedical imaging facilities at the Yale School of Medicine. The mentorship team consists of internationally renowned experts in addiction psychiatry, computational statistics and molecular neuroscience. The program will provide the candidate with the requisite skills and experience to become an independent investigator in the field of addictions neuroscience. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas: (i) the conduct of human PET research protocols and image analysis methods; (ii) sophisticated statistics toward the integration of multi-modal neuroimaging data; and (iii) the molecular neuroscience of addictions psychiatry. The opportunities afforded by this award would enable the candidate to embark on a comprehensive, structured 5-year program of training and research designed to develop an expertise in innovative neurobiological research methods toward a career as an independent addictions investigator.