Project summary/abstract: Cocaine use disorder affects nearly one million Americans, yet there are no current approved therapeutics for effective treatment or to prevent relapse. Major contributors to relapse are drug paired cues that can elicit feelings of craving in humans and lead to drug seeking. The ability of cues to maintain drug seeking behavior after sufficient number of cue and cocaine pairings is termed the conditioned reinforcing effects of cocaine. Previous work suggests that dopaminergic and glutamatergic systems in reward circuitry are involved, and other studies have implicated the endogenous opioid system, particularly in the nucleus accumbens, in mediating behavior elicited by cocaine-paired cues. Specifically, blocking opioid receptor activation attenuates drug seeking behavior. Similarly, increases in levels of enkephalin, an endogenous opioid peptide, in the nucleus accumbens have been shown with some primary reinforcers and can lead to reinstatement of drug seeking. Little is known about the role of endogenous opioids in conditioned reinforcement nor the opioidergic mechanisms contributing to this complex behavior. To gain insights into the contribution of the endogenous opioid system in addiction and specifically in cocaine-paired cues, I will explore the enkephalinergic response to cues and opioid receptor activation modulating these effects. The current proposal is supported by our preliminary studies that activation of the delta opioid receptor (DOR) potentiates operant responding for drug-paired cues, indicating an increase in conditioned reinforcement. Here I will test the central hypothesis that presentation of cues that have acquired conditioned reinforcing properties lead to an increase of enkephalin in the nucleus accumbens shell that acts on DORs to drive operant responding for cocaine-paired cues. This work will 1) measure and potentiate enkephalin levels and 2) manipulate opioid receptor activation pharmacologically in the nucleus accumbens during a stringent test of cocaine conditioned reinforcement. This work will lead to better understanding of and insight into the underlying mechanisms behind the conditioned reinforcing properties of cocaine cues. This proposal will provide me essential training in 1) in vivo neuropeptide collection, 2) pharmacological manipulation of the endogenous opioid system, and 3) rigorous behavioral experiments in addiction research. The skills and training opportunities described in this proposal will enable me to be a successful professional scientist working in drug development to identify novel therapeutics for neurological disorders.