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

John W. McDonald, Andrew S. Fix, Joseph P. Tizzano, Dairyle D. Schoepp

Research output: Contribution to journalArticle

Abstract

The role of metabotropic excitatory amino acid receptors inseizures 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. Sys temic administration of 1S,3R-ACPD produced dose-dependent convulsions (ED5O = 16 mg/kg, i.p.) that were stereoselective for the active metabotropic ACPD isomer, since 1R,3S-ACPD was less potent (ED50, = 93 mg/kg, i.p.). 1S,3R-ACPD-induced seizures were antagonized by systemic administration of dantrotene, 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 de-generation 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
StatePublished - 1993
Externally publishedYes

Fingerprint

Excitatory Amino Acid Agonists
Dicarboxylic Acids
Metabotropic Glutamate Receptors
Brain Injuries
Seizures
Dizocilpine Maleate
Dantrolene
Calcium
Neurons
Excitatory Amino Acid Antagonists
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Injections
Brain Edema
Wounds and Injuries
Glutamate Receptors
N-Methylaspartate
Weights and Measures
Brain

Keywords

  • 1S
  • 3R-ACPD (1-amino-cyclopentane-1,3-di-carboxylic acid)
  • Brain injury
  • Dantrolene
  • Excitatory amino acid
  • Glutamate
  • Metabotropic glutamate receptors

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

McDonald, J. W., Fix, A. S., Tizzano, J. P., & Schoepp, D. D. (1993). Seizures and brain injury in neonatal rats induced by 1 S,3A-ACPD, a metabotropic glutamate receptor agonist. Journal of Neuroscience, 13(10), 4445-4455.

Seizures and brain injury in neonatal rats induced by 1 S,3A-ACPD, a metabotropic glutamate receptor agonist. / McDonald, John W.; Fix, Andrew S.; Tizzano, Joseph P.; Schoepp, Dairyle D.

In: Journal of Neuroscience, Vol. 13, No. 10, 1993, p. 4445-4455.

Research output: Contribution to journalArticle

McDonald, JW, Fix, AS, Tizzano, JP & Schoepp, DD 1993, 'Seizures and brain injury in neonatal rats induced by 1 S,3A-ACPD, a metabotropic glutamate receptor agonist', Journal of Neuroscience, vol. 13, no. 10, pp. 4445-4455.
McDonald, John W. ; Fix, Andrew S. ; Tizzano, Joseph P. ; Schoepp, Dairyle D. / Seizures and brain injury in neonatal rats induced by 1 S,3A-ACPD, a metabotropic glutamate receptor agonist. In: Journal of Neuroscience. 1993 ; Vol. 13, No. 10. pp. 4445-4455.
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