PROJECT SUMMARY Cocaine use disorder (CUD) is a chronic relapsing disease that leads to neuroadaptations in energy homeostasis after repeated drug exposure. There is currently no FDA-approved treatment that lowers the risk of relapse in CUD. Reported annual deaths involving cocaine have nearly quintupled in the United States from 4,939 in 2013 to 24,538 in 2021, making this a major public health concern. Despite recent scientific advances elucidating critical neuronal circuitry and biological conditions that drive cocaine-seeking behaviors, the development of interventions to disrupt the repeating cycle of addiction has proved more difficult. The operant behavioral model of drug self-administration, extinction, and cue-induced reinstatement emulates cue priming and drug craving in patients in recovery experiencing settings, cues, or memories associated with past drug use. Craving and relapse of cocaine seeking is driven by glutamatergic (Glu) neurotransmission in the NAcC, observed in both humans and animal models. Clinically, susceptibility to cocaine relapse is notably higher in female patients with reports of stronger craving to cocaine-paired cues. This significant sex difference, also reflected in animal models of CUD, represents an obstacle in treatment development that yields therapeutic benefit across sexes. Our lab has demonstrated that metformin (MET), an FDA-approved Type II Diabetes (T2D) treatment, has pre-clinical promise in reducing cue-induced cocaine reinstatement after a period of withdrawal when administered intracranially in both female and male rats. My own preliminary data shows that systemic metformin reduces the conditioned rewarding effects of cocaine in male rats. In T2D, MET improves glucose management in part through activation of adenosine monophosphate activated protein kinase (AMPK), which when phosphorylated, restores the intracellular ratio of AMP to ATP in response to environmental stressors. AMPK is decreased in the nucleus accumbens core (NAcC) after chronic exposure to cocaine, with MET-induced increases in AMPK activity thus providing a promising putative mechanism of action. Still, it remains unknown how oral MET is biodistributed to the NAcC and how it may impact critical Glu circuitry underlying cocaine relapse events. This study will explore the therapeutic potential of MET by defining central pharmacodynamics and pharmacokinetics of oral MET in the NAcC. This proposal tests the hypotheses that oral administration of MET will: 1) have a more robust effect in reducing cue-induced cocaine-seeking behavior after self-administration in male rats as compared to female rats, 2) reduce cue-induced reinstatement via activation of AMPK, and 3) augment Glu neurotransmission in the NAcC reducing the signal to noise of cue-associated glutamate transmission as measured by in vivo fiber photometry. The goal of the proposed work is to provide significant evidence that supports the potential repurposing of MET as a treat...