The discriminative stimulus effects of N-methyl-D-aspartate glycine-site ligands in NMDA antagonist-trained rats.

RATIONALE

Many N-methyl-D-aspartate (NMDA) antagonists produce phencyclidine (PCP)-like side effects that limit their clinical utility. NMDA glycine-site antagonists may be less likely to produce these effects than other site-selective NMDA antagonists.

OBJECTIVES

The objective of the study is to compare the discriminative stimulus effects of novel NMDA glycine-site drugs to those of channel blocking and competitive NMDA antagonists.

MATERIALS AND METHODS

Drug discrimination studies were performed in separate groups of rats trained with saline vs. PCP (2 mg/kg i.p.) or the competitive antagonist NPC 17742 (4 mg/kg i.p.) using a standard two-lever operant conditioning procedure under an FR32.

RESULTS

Neither the partial glycine-site agonists aminocyclopropane carboxylic acid methyl ester and (+)-HA-966 nor the antagonists L701,324; MDL 100,458; MDL 100,748; MDL 103,371; MDL 104,472; MDL 105,519; MRZ 2/571; MRZ 2/576; and ACEA 0762 produced >50% PCP-lever selection, though all were tested over a sufficient dose range to produce response rate decreasing effects. All of the antagonists, except MDL 100,458 and MDL 100,748, were also tested for NPC 17742-like effects, producing somewhat more variable results than in PCP-trained rats. ACEA-0762 produced full substitution for NPC 17742, whereas MDL 105,519 produced no substitution. The remaining compounds engendered between 20% and 80% drug-lever selection.

CONCLUSION

These results provide evidence that NMDA glycine-site partial agonists and antagonists generally do not produce discriminative stimulus effects similar to those of representative NMDA channel blockers or competitive antagonists. This suggests that these NMDA glycine-site antagonists should be less likely to produce the undesirable behavioral side effects seen in clinical trials with many other NMDA antagonists.