Pentobarbital-like discriminative stimulus effects of N-methyl-D-aspartate antagonists

The discriminative stimulus effects of competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists were compared in rats trained to discriminate sodium pentobarbital (5.0 mg/kg i.p.) from saline under a two-lever fixed ratio 32 schedule of food reinforcement. The competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) substituted for pentobarbital at doses that did not disrupt rates of responding. The proposed competitive NMDA antagonist NPC 12626 [2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid] also substituted for pentobarbital. The benzodiazepine antagonist Ro15-1788 did not antagonize the pentobarbital-like discriminative stimulus effects of CPP. The noncompetitive NMDA antagonists phencyclidine and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] produced a maximum average of only 42 and 38%, respectively, pentobarbital-lever responding at doses that also substantially reduced response rates. These results suggest that the competitive NMDA antagonists CPP and NPC 12626 share discriminative stimulus properties with pentobarbital. However, the pentobarbital-like discriminative stimulus effects of CPP are probably not mediated through interaction with benzodiazepine receptors sensitive to Ro15-1788. In addition, because phencyclidine and MK-801 did not fully substitute for pentobarbital, these results provide further evidence for differences in the discriminative stimulus properties of competitive and noncompetitive NMDA antagonists.