Summary Substance use disorders have a devastating impact on individuals, families, and society. Present pharmacological treatments do not fully ameliorate patients’ symptoms and in many cases are unable to treat the full spectrum of symptoms. Therefore, it is paramount to identify new targets for pharmacological intervention. To do this we must better understand the neural mechanisms underpinning drug-mediated reward, persistent drug-taking and relapse behavior. The Neuropeptide S (NPS) receptor when activated in rats facilitates reward-related behaviors (e.g. cocaine seeking). Paradoxically, NPS receptor activation is also anxiolytic-like. As part of our drug discovery efforts, a NPS receptor targeted molecule was found that retains the anxiolytic-like properties but reduces cocaine seeking behaviors. In regard to opioids, the levels of NPS receptor changes in rats that have been made dependent on morphine, and levels of the receptor further change after withdrawal. Therefore, the data suggest that the NPS-system may be a prime target for addressing the unmet therapeutic need of substance use disorders. To understand the mechanism by which NPS receptor targeted molecules produce their effects, the fundamental circuit pathway and behavioral analyses need to be completed. The goals of this project are proof of concept that NPS receptor targeted molecules can mitigate opioid seeking. And, whether these same molecules can 1) reduce oxycodone taking and 2) reduce the motivation to obtain oxycodone. Ultimately, knowledge gained through these experiments will allow for the determination of the therapeutic potential of the NPS receptor as a target for mitigating substance use disorders.

Narrative Addiction to drugs of abuse, such as oxycodone, produces a myriad of negative effects and societal consequences. In understanding this disease, one long-standing question has been how to reduce opioid seeking and relapse behavior? Our goal is to demonstrate the utility of a novel class of molecules that when administered to rats mitigates drug seeking.