PROJECT SUMMARY Substance use disorders present one of the greatest pervasive health concerns in the United States, with opioid use disorder (OUD) being declared a public health emergency. Relapse, in particular, is a dynamic process and an essential barrier to abstinence in OUD with a culmination of precipitating factors, such as exposure to cues previously associated with the drug-taking experience working alongside a complex neurobiology. Behavioral interventions coupled with FDA-approved OUD pharmacotherapeutics, such as the partial µ-opioid receptor agonist buprenorphine, mitigate withdrawal, reduce mortality, opioid intake and opioid-seeking relapse-like behaviors as well as improve psychosocial functioning. However, while current medication-assisted treatment is an effective tool in the proper management of OUD patients, additional prospects exist to develop non-opioid therapeutics to facilitate extended recovery from OUD. Opioid use and abstinence produce long-term effects on neurocircuitry and synaptic plasticity which can lead to unique patterns of gene expression, possibly contributing to long-term neuroadaptations. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) regulation is synonymous with synaptic plasticity and linked to many neuropsychiatric disorders, including OUD. AMPAR antagonism dose-dependently evokes cognitive dysfunction, which is reversed following the co- administration of aniracetam, an AMPAR positive allosteric modulators (PAM). AMPAR PAMs, i.e., AMPAkines, are clinically relevant compounds that allosterically activate the AMPAR and simultaneously decrease the likelihood of receptor desensitization and increase AMPAR-mediated synaptic currents without inducing excitotoxicity. AMPAkines are also listed as one of the “top ten most wanted” mechanisms for medication development/validation in response to the United States opioid epidemic. In this light, we identified the patent- protected AMPAkine HJC0122 using a combined bioinformatics and chemoinformatics approach. HJC0122 promotes neuroprotective effects and prevents neuroapoptosis, both in vivo and in vitro, and blunts morphine tolerance and dependence in mice. In initial proof-of-concept studies, we discovered that HJC0122 attenuated fentanyl cue-evoked drug-seeking in male rats. These preclinical data, coupled with published studies, strongly support the scientific premise that an AMPAkine regulates functional processes underlying OUD-related behaviors. This U18 will employ a suite of rodent OUD models to validate the efficacy of HJC0122 to suppress opioid intake and opioid-seeking primed by opioid or opioid-associated cues in male and female rats. The outcomes of the U18 will have an impact in our field with the prospect to validate a novel medication target to buffer relapse triggers, providing additional coverage to extend recovery and address treatment-related challenges in OUD.