Abstract Methamphetamine use disorder is a major public health problem afflicting millions of people. Currently, there are no FDA approved medications and clinical trials aiming to repurpose existing medications for other therapeutic indications have yielded limited efficacy for the treatment of methamphetamine addiction. Given the recent rising trend of methamphetamine abuse, largely as a result of restrictions of opioid prescriptions, there is an urgent need to discover novel targets to facilitate the discovery of new medications for this condition. Literature evidence suggests that the Neuropeptide FF (NPFF) system, a well-established opioid modulatory system, plays a role in alteration of methamphetamine's pharmacological effects including locomotor sensitization and expression of conditioned place preference. These findings corroborate with extensive interactions between central dopaminergic and opioidergic systems. However, studies on roles of the NPFF system in modulating methamphetamine's effects have been limited due to unavailability of suitable tool compounds, particularly ligands with good NPFFR receptor subtype selectivity. Recently, our group and others have discovered new NPFFR ligands, including selective and nonselective agonists and antagonists, which can serve as important tool compounds to study the roles of the NPFF system in methamphetamine's signaling pathways. In this application, we propose to employ these newly developed tool compounds to validate the NPFFRs as potential targets for therapeutic development for methamphetamine use disorder.

Narrative To date, there are no FDA approved medications for methamphetamine use disorder. As methamphetamine abuse has been rising recently due to limitations of opioid prescriptions, there is an urgent need to discover novel targets to treat methamphetamine addiction. The Neuropeptide FF (NPFF) system has been shown to modulate methamphetamine's effects in rats. However, this NPFF system has not been investigated extensively due to a lack of suitable tool compounds. In this application, we seek to validate the NPFF receptor 1 and NPFF receptor 2 as potential targets for therapeutic development for methamphetamine use disorder using newly developed selective and nonselective NPFF receptor subtype agonists and antagonists.