Effects of competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists in rats trained to discriminate NMDA from saline.

Competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists and other central nervous system depressants were assessed for their ability to antagonize the discriminative stimulus effects of NMDA in rats trained under a standard two-lever fixed ratio schedule of food reinforcement. The competitive NMDA antagonists, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate and NPC 12626 [2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate], dose-dependently antagonized NMDA-lever selection at doses that did not affect rates of responding. Conversely, the noncompetitive NMDA antagonists, phencyclidine, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] and (+)-N-allylnormetazocine, as well as pentobarbital and diazepa, all reduced response rates dose-dependently without antagonism of NMDA-lever responding. In stimulus generalization tests, NPC 12626 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate at doses higher than those required to antagonize NMDA, often elicited NMDA-lever responding. The mechanisms underlying the similarities in the interoceptive stimuli produced by NMDA and its competitive antagonists remain to be determined. These results indicate that although competitive NMDA antagonists antagonize effects of NMDA without concomitant behavioral disruption, noncompetitive NMDA antagonists and central nervous system depressants are behaviorally disruptive at doses that do not antagonize NMDA. The results provide further evidence for differences in the behavioral profiles of competitive and noncompetitive NMDA antagonists.