EFFECTS OF N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS ON DISCRIMINATIVE STIMULUS EFFECTS OF NALOXONE IN MORPHINE-DEPENDENT RATS USING THE Y-MAZE DRUG DISCRIMINATION PARADIGM

The present study assessed the ability of various site-selective N-met hyl-D-aspartate (NMDA) receptor antagonists to affect the discriminati ve stimulus properties of naloxone in morphine-dependent rats. Adult m ale Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxon e from saline using a Y-maze shock-avoidance procedure. Naloxone-appro priate responding was exhibited as a function of naloxone dose (0.01-1 .0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treat ment temporarily was discontinued (8-96 hr, peak at 24 hr). Discrimina tive stimulus effects of naloxone (0.1-3.0 mg/kg) were antagonized by morphine (10-100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1-3.0 mg/kg) or attenuate naloxone's stimulus effects (loperamide, 1-30 mg/kg). In rat s treated with the training dose of naloxone, administration of dizoci lpine (0.03-0.3 mg/kg) and D-CPPene (1-10 mg/kg) decreased levels of n aloxone-appropriate responding, whereas memantine (1-30 mg/kg), ACEA-1 021 (10 and 50 mg/kg) and eliprodil (3-30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a de crease in the occurrence of two or more of the following opioid withdr awal signs: weight loss, forelimb tremor, ptosis, diarrhea and ''wet-d og''-like shaking. Additionally, dizocilpine (0.1 mg/kg), D-CPPene (5. 6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or elip rodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morph ine treatment 24 hr after the last morphine injection. Thus, NMDA rece ptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, an d this ability depends on the type of antagonist applied.