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 2/5 79) NMDA receptor antagonists inhibited morphine-produced behaviors re lated to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects o f glycine/NMDA antagonists were not dose-dependent. Mice which were mo rphine-free for 3 days still displayed a significant severity of the w ithdrawal syndrome when challenged again with naloxone. This extinctio n of a residual morphine dependence was markedly diminished by treatme nt with similar doses of NMDA receptor antagonists at the test followi ng the wash-out period. The rewarding impact of morphine was investiga ted in rats using the place preference (CPP) paradigm. All NMDA recept or antagonists (2.5-10 mg/kg) inhibited both the acquisition and expre ssion of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA receptor antagonis ts given for 3 days after the end of conditioning did not influence th e extinction of morphine-induced CPP. Microdialysis studies revealed t hat the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA receptor antago nist. These data suggest that novel glycine site and uncompetitive NMD A receptor antagonists may have therapeutic potential in the treatment of opioid abuse. (C) 1998 Elsevier Science Ltd; All rights reserved.