This R21 application aims to identify the neural, behavioral, and pharmacological mechanisms promoting diminished expression of drug-related memories in human cocaine addiction. Drug addiction is a chronic disorder where cues previously associated with drug reinforcement (e.g., pipe) evoke salient and pervasive memories of the drug experience. These memories contribute to craving, precipitating relapse even after long periods of abstinence. Traditional cue-exposure therapies aimed at extinguishing these provoking effects of drug cues have therefore been widely used. However, these therapies do not usually prevent relapse, highlighting the need for alternative strategies. The goal of this exploratory project is to identify a pharmacologically-enhanced learning- based behavioral approach and its underlying neural mechanisms that could ultimately be targeted for decreasing craving and relapse in human addiction. Our behavioral approach, designed to interfere with the return of drug memories in individuals with cocaine use disorders (iCUD), builds on animal and human behavioral studies showing that retrieval of drug-cue memories 10 min before their extinction results in long-lasting attenuation of cue-induced drug-seeking and craving. This approach thus takes advantage of cutting-edge research on the mechanisms underlying memory reconsolidation, a time-dependent process in which specific consolidated memories become transiently unstable shortly after their retrieval, making them amenable to either disruption or strengthening. Since iCUD exhibit deficits in learning and memory and underlying neural substrates, we will enhance this behavioral approach pharmacologically, using methylphenidate (MPH, a dopamine agonist) as a cognitive enhancer to promote learning-induced neural plasticity in iCUD. Choice of MPH is based on a series of neuroimaging studies in iCUD where we reported normalization of function (behavioral and neural) on other relevant cognitive-behavioral tasks. Specifically, in this functional magnetic resonance imaging (fMRI) study, in a within-subjects placebo-controlled double-blind cross-over design, oral MPH (20 mg) will be administered to iCUD to peak during the retrieval of a drug-cue memory before extinction; in addition to fMRI activations, skin conductance responses (SCR, acquired simultaneously) will serve as the psychophysiological indicators of memory modification. Assessments of interference with the return of drug-cue memories via SCR and craving will be conducted the day following MRI. This project will delineate the neural correlates of a pharmacologically-enhanced behavioral approach to decrease drug memories and craving in iCUD, which could be ultimately used to develop effective cue-exposure therapies. If, compared to standard therapies, these novel approaches are later shown to improve clinical outcome in iCUD, this exploratory study may pave the way towards enhancing the efficacy of cue-exposure therapy in reducing cue-...