DIZOCILPINE-LIKE DISCRIMINATIVE STIMULUS EFFECTS OF COMPETITIVE NMDA RECEPTOR ANTAGONISTS IN MICE

Several non-competitive NMDA receptor ion channel blockers, competitiv e NMDA antagonists and compounds acting at other sites on the NMDA rec eptor complex were examined for their ability to substitute for the di scriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor an tagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapi dly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-de pendently substituted for dizocilpine with a rank order of potency of dizocilpine>TCP>(-)-MK-801>SKF 10,047>dextrorphan>PCP. There was a pos itive correlation between the potencies of the compounds that substitu ted for dizocilpine and their previously reported affinities for the [ H-3]dizocilpine binding site of the NMDA receptor ion channel. Compoun ds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist: NBQX, the monoamine uptake inhibito r, cocaine, and the GABA(A) receptor agonists, diazepam and phenobarbi tal, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17 742, (+/-)CPP and LY 233536 dose-dependently substituted for dizocilpi ne. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antag onists substituted for dizocilpine is in accordance with other behavio ral data (e.g., ataxia, locomotor activity) documenting similarities i n the effects of non-competitive and competitive antagonists. These fi ndings are also consistent with results of clinical investigations sug gesting overlap in the behavioral and subjective profiles of competiti ve and non-competitive NMDA blockers.