Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists.

The glycine site (MRZ 2/570 and L-701,324), and uncompetitive (MRZ 2/579) NMDA receptor antagonists inhibited morphine-produced behaviors related to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects of glycine/NMDA antagonists were not dose-dependent. Mice which were morphine-free for 3 days still displayed a significant severity of the withdrawal syndrome when challenged again with naloxone. This extinction of a residual morphine dependence was markedly diminished by treatment with similar doses of NMDA receptor antagonists at the test following the wash-out period. The rewarding impact of morphine was investigated in rats using the place preference (CPP) paradigm. All NMDA receptor antagonists (2.5-10 mg/kg) inhibited both the acquisition and expression of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA receptor antagonists given for 3 days after the end of conditioning did not influence the extinction of morphine-induced CPP. Microdialysis studies revealed that the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA receptor antagonist. These data suggest that novel glycine site and uncompetitive NMDA receptor antagonists may have therapeutic potential in the treatment of opioid abuse.