Abstract In seminal preclinical studies nearly 20 years ago, Robinson & Kolb [1, 2] demonstrated enduring changes in synaptic (dendritic spine) density in medial prefrontal cortex (mPFC) of rodents following behaviorally sensitizing regimens of cocaine. Their findings suggested a potentially important pathophysiological mechanism – aberrant structural synaptic plasticity – whereby cocaine might produce the chronic, recalcitrant behaviors (e.g., craving, compulsive use, and relapse) so seemingly ‘hard-wired’ in those suffering from the disorder. Our group has developed a novel radiotracer, 11C-UCB-J, for imaging synaptic density (i.e., synaptic vesicle glycoprotein type 2A or SV2A availability) in the living human brain using positron emission tomography (PET) [3, 4]. . Pilot data collected under the Cutting Edge Basic Research Award (CEBRA)/R21 mechanism are compelling, we believe, and provide the first translation support for: 1) altered (i.e., lower) synaptic density in the mPFC of individuals with CUD that is both 2) positively correlated with the frequency (days per month) of recent cocaine use, and 3) negatively correlated with duration of cocaine abstinence (days since last use). Together, these data suggest a dynamic model of synaptic plasticity in which SV2A availability is “normalized” by recurrent cocaine use, only to return to abnormal (i.e., low) levels during periods of sustained drug abstinence. The current R01 application proposes to replicate and extend these promising preliminary findings and more definitively test the former model through two experimental aims: Aim 1) a larger cohort of 40 CUD and 40 matched HC subjects using a single-scan, between group design, and Aim 2) the same 40 CUD subjects using a longitudinal, two-scan (baseline/pre-abstinence vs. 3 weeks of in-hospital abstinence) within-subject design. If confirmed, the current study would have a potentially major impact, providing powerful clinical- translational support for the aberrant synaptic plasticity hypothesis of CUD, advancing our neurobiological understanding of the role of drug-induced changes in synaptic function in CUD, and ultimately, encouraging the development of more effective treatments for CUD (e.g., those based on synaptotrophic mechanisms).