PROJECT SUMMARY The national opioid crisis continues to progress in the United States. Few effective treatments for opioid use disorder (OUD) exist and there is a need for new medications to treat OUD. Treatment for OUD is complicated by the co-use of alcohol. Chronic opioid and alcohol use, separately, are known to disrupt dopamine and glutamate homeostasis in the nucleus accumbens; a brain region that mediates the seeking of addictive drugs. In considering treatments for opioid-alcohol polysubstance use, a therapeutic with the ability to act upon these common mechanisms, through restoration of nucleus accumbens dopamine and glutamate, may be advantageous. Oxytocin effectively reduces alcohol and opioid intake and relapse in pre-clinical models employing the use of only one drug (monosubstance use) and is known to act on dopamine and glutamate systems. Clinical trials show efficacy for intranasal oxytocin as a treatment for alcohol use disorder (AUD). Based on the clinical and pre-clinical evidence, we posit that oxytocin may be a viable therapeutic in the treatment of opioid-alcohol polysubstance use. The experiments outlined in this proposal will investigate oxytocin’s therapeutic potential in opioid-alcohol polysubstance use. Based on our previous findings that 1) alcohol alters demand for oxycodone and 2) that oxytocin reduces demand for oxycodone in a monosubstance model, here we will test the dose-dependent effects of oxytocin on oxycodone demand in male and female oxycodone-only and oxycodone+alcoholpolysubstance rats using our established oxycodone+alcoholpolysubstance use model. Based on our prior work showing that oxytocin increases nucleus accumbens dopamine and glutamate efflux in the nucleus accumbens of cocaine-experienced rats, here we will investigate the effects of oxytocin administration on dopamine and glutamate efflux in oxycodone and oxycodone+alcohol-experienced rats. The proposed work will provide important data regarding oxytocin’s therapeutic potential to reduce oxycodone monosubstance use and oxycodone+alcohol polysubstance use, illuminate potential sex differences in these effects, and elucidate the role of nucleus accumbens dopamine and glutamate efflux in the effects of oxytocin.