To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered
dextrorphan and
dizocilpine, non-competitive
N-methyl-D-aspartic acid (
NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared.
Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of
NMDA, but also showed a broad spectrum of
anticonvulsant activities against tonic convulsions caused by
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (
AMPA),
kainic acid (KA),
bicuculline,
pentylenetetrazole or electroconvulsive shock. The
anticonvulsant action of
dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of
dextrorphan.
Dizocilpine, unlike
dextrorphan, impaired motor function at doses showing its
anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced
seizures were not antagonized by
dextrorphan.
Dextrorphan and
dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of
glutamate receptors, as death caused by
NMDA but not by
AMPA and KA was selectively and markedly inhibited by both
dextrorphan and
dizocilpine. In view of these results, the efficacy of
dextrorphan and
dizocilpine as antagonists of
convulsant effects appears to be consistent with the interpretation that a variety of
convulsants cause tonic convulsions via direct or indirect interaction with the
NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+)
binding proteins, are not directly modified by the administration of
dextrorphan, itself.