SUMMARY Alcohol use disorder (AUD) represents a significant public health concern and confers a large cost to society due to violence, lost productivity, and healthcare expenditures. Despite decades of intense research efforts, there are just a few FDA-approved medications for AUD, each of which are only modestly efficacious. GET73 is a promising new medication that has shown promise in its initial development phase for improving AUD symptoms, as evidenced by anti-alcohol-drinking and anxiolytic properties in preclinical/animal studies. Preclinical research also indicates that GET73’s mechanism of action relates to its negative allosteric modulation of the metabotropic glutamate subtype 5 receptor (mGluR5), a novel potential therapeutic target of growing interest. Phase 1 clinical studies show GET73 to be safe and well-tolerated in both individuals with AUD and healthy volunteers. Thus, considerable preliminary evidence supports GET73 as a new, safe, well-tolerated, and potentially therapeutic treatment for AUD. Extending this preclinical and clinical research, the proposed research project represents the first investigation of the effects of GET73 on alcohol drinking, both in a tightly controlled laboratory setting and in the natural environment, in individuals with AUD. Neuroimaging indicators of purported GET73 mechanisms of action, including fronto-cortical glutamate and GABA levels via proton magnetic resonance spectroscopy (1H-MRS) and brain reactivity to alcohol cues via functional magnetic resonance imaging (fMRI), will be investigated as potential mediators of the effect of GET73 on drinking. Non-treatment- seeking participants with AUD (N=90) will be randomized to GET73 (300 mg, 3x/day) or placebo for the proposed 8-day study. Prior to randomization (Day-1), a pre-treatment MRI will be completed, during which anatomical, 1H-MRS, and alcohol-cue reactivity fMRI scans will be acquired. On Day-7, participants’ drinking over the previous five days will be assessed, and all MRI procedures will be repeated. On Day-8, participants will consume a standard priming drink and undergo a limited-access alcohol self-administration (bar-lab) paradigm, in a similar fashion to previous Charleston ARC clinical studies. It is hypothesized that GET73-treated participants, relative to placebo-treated participants, will drink less in the 5-day free-access period as well as during bar-lab limited- access procedure. GET73-treated participants are also hypothesized to have increased fronto-cortical levels of glutamate and GABA, reflecting normalization of the pathologically low glutamate and GABA levels typically found in individuals with AUD who are not experiencing acute alcohol withdrawal, paired with decreased reactivity to alcohol cues in key cognitive-control and cue-reactivity-related brain regions (e.g., medial prefrontal cortex and ventral striatum, respectively). These effects are anticipated to mediate the relationship between GET73 and alcohol drink...