Seizures and brain injury in neonatal rats induced by 1S,3R-ACPD, a metabotropic glutamate receptor agonist

J. W. McDonald, A. S. Fix, J. P. Tizzano, D. D. Schoepp

Research output: Contribution to journalArticle

Abstract

The role of metabotropic excitatory amino acid receptors in seizures and brain injury was examined using the selective metabotropic agonist 1S,3R- ACPD [(1S,3R)-1-aminocyclopentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats. Systemic administration of 1S,3R-ACPD produced dose-dependent convulsions (ED50 = 16 mg/kg, i.p.) that were stereoselective for the active metabotropic ACPD isomer, since 1S,3R-ACPD was less potent (ED50 = 93 mg/kg, i.p.). 1S,3R-ACPD-induced seizures were antagonized by systemic administration of dantrolene, an inhibitor of intracellular calcium mobilization, but not by the ionotropic glutamate antagonists MK-801 or GYKI- 52466. As indexed by hemispheric brain weight differences 5 d postinjection, unilateral intrastriatal injection of 1S,3R-ACPD (0.1-2.0 μmol/μl), but not 1R,3S-ACPD, produced dose-dependent brain injury (maximal effect of 3.4 ± 0.5% damage). 1S,3R-ACPD brain injury occurred in the absence of prominent behavioral convulsions. Histologic and ultrastructural examination of 1S,3R- ACPD-injected rat brains revealed swelling and degeneration of select neurons at 4 hr postinjection, but little evidence of injured neurons 5 d later. 1S,3R-ACPD-mediated brain injury was not attenuated by systemic administration of the NMDA antagonist MK-801 or the AMPA antagonist GYKI- 52466. However, cointrastriatal injection of dantrolene reduced the severity of 1S,3R-ACPD injury by 88 ± 7%. These studies indicate that seizures and neuronal injury can be elicited by the selective activation of metabotropic glutamate receptors in perinatal rats, and these effects of 1S,3R-ACPD involve the mobilization of intracellular calcium stores.

Original languageEnglish (US)
Pages (from-to)4445-4455
Number of pages11
JournalJournal of Neuroscience
Volume13
Issue number10
DOIs
StatePublished - 1993

Keywords

  • 1S,3R-ACPD (1-amino-cyclopentane-1,3-dicarboxylic acid)
  • brain injury
  • dantrolene
  • excitatory amino acid
  • glutamate
  • metabotropic glutamate receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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