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The discriminative stimulus effects of the N-methyl-D-aspartate (NMDA) antagonists 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and phencyclidine were assessed in a drug discrimination based on the competitive NMDA antagonist 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626). Adult male Sprague-Dawley rats were trained to discriminate NPC 12626 from saline using a standard two-lever fixed ratio 32 schedule of food reinforcement. NPC 12626 dose-dependently substituted for the training dose (20 mg/kg IP) with an ED50 of 9.5 mg/kg. The competitive NMDA antagonist CPP completely substituted for NPC 12626 (ED50 = 1.4 mg/kg IP). The non-competitive NMDA antagonist phencyclidine, as well as pentobarbital and NMDA, failed to substitute completely for NPC 12626, even at doses of these drugs that reduced response rates. These data indicate that the discriminative stimulus properties of NPC 12626 are selective and shared by CPP but not by phencyclidine, pentobarbital or NMDA. The emerging evidence for differences in the discriminative stimulus effects of competitive NMDA antagonists and phencyclidine suggests that competitive antagonists such as NPC 12626 and CPP may not have phencyclidine-like abuse liability.

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