In vivo antagonism of agonist actions at N-methyl-d-aspartate and N-methyl-d-aspartate-associated glycine receptors in mouse cerebellum: Studies of 1-hydroxy-3-aminopyrrolidone-2

P. L. Wood, M. R. Emmett, T. S. Rao, S. Mick, Julie Cler, E. Oei, S. Iyengar

Research output: Contribution to journalArticlepeer-review

Abstract

Intracerebellar injections of either NMDA or d-serine dramatically elevated levels of cGMP in the cerebellum of the mouse, in vivo. These actions were both antagonized by simultaneous injection of the NMDA-associated glycine receptor antagonist, HA-966. Intracerebellar injections of d-serine were also antagonized by peripheral (s.c.) injections of HA-966, demonstrating the bioavailability of this glycine receptor antagonist. Parenteral administration of HA-966 was also effective in antagonizing the actions of intravenously injected harmaline, an activator of the cerebellar climbing fiber pathway, on cGMP in the cerebellum. An evaluation of the parenteral dose-response curve for HA-966, revealed no effect on basal activity within the cerebellum. This contrasts sharply with the abilities of both competitive and non-competitive NMDA antagonists to decrease basal levels of cGMP in the cerebellum. In summary, these studies demonstrate that HA-966 is a bioavailable antagonist of the NMDA-associated glycine receptor and that this compound can limit excessive stimulation of the NMDA receptor by exogenous application of agonist, with minimal effects on basal activity. These data suggest that antagonists of the NMDA-associated glycine receptor may be optimal therapies in the treatment of stroke and epilepsy.

Original languageEnglish (US)
Pages (from-to)675-679
Number of pages5
JournalNeuropharmacology
Volume29
Issue number7
DOIs
StatePublished - Jul 1990
Externally publishedYes

Keywords

  • CPP
  • HA-966
  • NMDA
  • cerebellar cGMP
  • d-serine
  • dexoxadrol
  • harmaline
  • mouse

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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