Several non-competitive
NMDA receptor ion channel blockers, competitive
NMDA antagonists and compounds acting at other sites on the
NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of
dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive
NMDA receptor antagonist,
dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for
dizocilpine with a rank order of potency of
dizocilpine > TCP > (-)-MK-801 > SKF 10,047 >
dextrorphan > PCP. There was a positive correlation between the potencies of the compounds that substituted for
dizocilpine and their previously reported affinities for the [3H]
dizocilpine binding site of the
NMDA receptor ion channel. Compounds 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 inhibitor,
cocaine, and the GABAA receptor agonists,
diazepam and
phenobarbital, failed to substitute fully for
dizocilpine. However, like the
ion channel blockers, the competitive
NMDA antagonists,
CGS 19755,
NPC 17742, (+/-)
CPP and
LY 233536 dose-dependently substituted for
dizocilpine. 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 antagonists substituted for
dizocilpine is in accordance with other behavioral data (e.g.,
ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive
NMDA blockers.