Spermidine, a positive modulator of the NMDA receptor, facilitates extinction and prevents the reinstatement of morphine-induced conditioned place preference in mice

Rationale Individuals with opioid use disorders often relapse into drug-seeking behavior after recalling memories linked to the drug use experience. Improving extinction efficacy has been used as a strategy to treat substance use disorders and suppress relapse. Although N-methyl-D-aspartate receptor (NMDAr) agonists facilitate acquisition, consolidation, and extinction, no study has addressed whether spermidine (SPD), a natural polyamine ligand of the NMDA receptor, facilitates the extinction and reinstatement of morphine-induced conditioned place preference (CPP). Objectives and methods The aim of the present study was to investigate the effect of SPD, an NMDAr agonist, on the extinction and reinstatement of morphine-induced CPP in mice. Adult male albino Swiss mice received saline (0.9% NaCl) or morphine (5 mg/kg) intraperitoneally (i.p.) and were respectively confined to a black or a white compartment for 30 min for four consecutive days for CPP induction. SPD (10-30 mg/kg, i.p.) or ifenprodil (NMDAr antagonist, 0.1-1 mg/kg, i.p.) were injected 15 min before extinction training. Results SPD and ifenprodil facilitated the extinction of morphine-induced CPP. SPD treatment during the extinction period impaired reinstatement induced by a priming dose of morphine (1.25 mg/kg). Ifenprodil (0.1 mg/kg) prevented the facilitatory effect of spermidine on the extinction of morphine-induced CPP but did not prevent reinstatement induced by morphine. Conclusions These results suggest that SPD facilitated the extinction of morphine-induced CPP by modulating the polyamine binding site of the NMDA receptor. Our findings reveal important effects of SPD and ifenprodil on the re-exposure-induced decrease in morphine-induced CPP, which may be promising for developing novel pharmacological strategies to treat opioid use disorder.