N‐methyl‐D‐aspartate Receptor Antagonist Agmatine Prevents Oxycodone Self‐Administration

Abstract

Opioid use disorder (OUD) can be defined as the continued use of opioids despite the negative physical, psychological, and social consequences that result from its use. Since the 1970s, several strategies have been approved by the Food and Drug Administration (FDA) to treat OUD and reverse opioid overdose. Despite their implementation and other exhaustive efforts and resources expended by the scientific and public health communities, the increase in opioid use disorder (OUD) in the United States continues to have staggering economic and quality of life impacts. Decades of research has established that chronic activation of the N‐methyl‐D‐aspartate (NMDA) receptor is a major driving force of the neuroplastic pathology that underlies opioid use disorder. The therapeutic potential of antagonism of the NMDA receptor has been explored, however due to the ubiquity of the receptor, several off‐site side‐effects have hindered development. In recent years, the endogenous NMDA receptor antagonist agmatine has come under consideration for its therapeutic potential in combatting CNS disorders such as neuropathic chronic pain as well as OUD, without producing unwanted side‐effects.Female ICR mice (21‐30g) were separated into dosing groups and oriented to self‐administration operant chambers in which they were able to press either for oral oxycodone reward (30 mg/L, 200 mg/L, or 1,000 mg/L) or inactive control (H2O + quinine) over 12 hours. Animals were sacrificed and perfused with tissue fixative for later molecular analysis of reward pathways. Animals with the 30 mg/L and 200 mg/L dose option showed consistently higher responding compared to animals pressing for 1,000 mg/L and control. Notably, animals in the 200 mg/L group showed an almost immediate increase in lever presses while the animals in the 30 mg/L group showed a slow increase in responding over time when compared to inactive control. We next sought to characterize agmatine’s ability to prevent oxycodone self‐administration, with 200 mg/L of oral oxycodone selected as the reward dose based on the previous data. Mice were given daily i.p. injections of either agmatine or saline immediately prior to self‐administration sessions. Mice who received agmatine pre‐treatment demonstrated significantly reduced drug‐seeking compared to animals who received saline pre‐treatment. Following completion of the experiment, animals were sacrificed and perfused for molecular analysis.These data support that agmatine may have therapeutic potential in preventing opioid use disorder. Future studies will focus on comparative molecular analysis between oxycodone‐exposed mice with or without agmatine.