Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1987 Mar;84(6):1689–1693. doi: 10.1073/pnas.84.6.1689

Paradoxical anticonvulsant activity of the excitatory amino acid N-methyl-D-aspartate in the rat caudate-putamen.

L Turski, B S Meldrum, E A Cavalheiro, L S Calderazzo-Filho, Z A Bortolotto, C Ikonomidou-Turski, W A Turski
PMCID: PMC304502  PMID: 3550795

Abstract

We used limbic seizures induced in rats by systemic injection of the cholinergic agonist pilocarpine (380 mg/kg; i.p.) to study the neuronal pathways within the basal ganglia that modulate seizure threshold. N-Methyl-D-aspartate (N-Me-D-Asp) is an excitatory amino acid derivative that is a powerful convulsant agent when injected into the cerebral cortex, amygdala, or hippocampus in rats. Bilateral microinjections of N-Me-D-Asp into the caudate-putamen, however, protected against limbic seizures induced by pilocarpine (injected systemically), with an ED50 of 0.7 nmol (range 0.5-1.0 nmol). Lesioning the caudate-putamen (by bilateral microinjection of the excitotoxin ibotenate) converted subconvulsant doses of pilocarpine into convulsant ones. The anticonvulsant action of N-Me-D-Asp in the caudate-putamen was reversed by blocking gamma-aminobutyrate-mediated inhibition in the substantia nigra pars reticulata or in the entopeduncular nucleus. The results suggest that the caudate-putamen and its gamma-aminobutyrate-dependent efferent pathways modulate the threshold for seizures in the limbic forebrain.

Full text

PDF
1689

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. De Sarro G., Meldrum B. S., Reavill C. Anticonvulsant action of 2-amino-7-phosphonoheptanoic acid in the substantia nigra. Eur J Pharmacol. 1984 Oct 30;106(1):175–179. doi: 10.1016/0014-2999(84)90692-7. [DOI] [PubMed] [Google Scholar]
  2. Fink R. P., Heimer L. Two methods for selective silver impregnation of degenerating axons and their synaptic endings in the central nervous system. Brain Res. 1967 Apr;4(4):369–374. doi: 10.1016/0006-8993(67)90166-7. [DOI] [PubMed] [Google Scholar]
  3. HAYASHI T. A physiological study of epileptic seizures following cortical stimulation in animals and its application to human clinics. Jpn J Physiol. 1952 Nov;3(1):46–64. doi: 10.2170/jjphysiol.3.46. [DOI] [PubMed] [Google Scholar]
  4. Hosokawa S., Kato M., Kuroiwa Y. Topographical distribution of propagation of seizure activity in the basal ganglia during focal motor seizures in the monkey. Neurosci Lett. 1983 Jul 15;38(1):29–33. doi: 10.1016/0304-3940(83)90105-2. [DOI] [PubMed] [Google Scholar]
  5. Iadarola M. J., Gale K. Substantia nigra: site of anticonvulsant activity mediated by gamma-aminobutyric acid. Science. 1982 Dec 17;218(4578):1237–1240. doi: 10.1126/science.7146907. [DOI] [PubMed] [Google Scholar]
  6. Köhler C., Schwarcz R. Comparison of ibotenate and kainate neurotoxicity in rat brain: a histological study. Neuroscience. 1983 Apr;8(4):819–835. doi: 10.1016/0306-4522(83)90013-1. [DOI] [PubMed] [Google Scholar]
  7. La Grutta V., Sabatino M., Gravante G., La Grutta G. Effects of caudate nucleus on paroxysmal activity in hippocampus of cat. Electroencephalogr Clin Neurophysiol. 1985 Nov;61(5):416–421. doi: 10.1016/0013-4694(85)91033-8. [DOI] [PubMed] [Google Scholar]
  8. McNamara J. O., Galloway M. T., Rigsbee L. C., Shin C. Evidence implicating substantia nigra in regulation of kindled seizure threshold. J Neurosci. 1984 Sep;4(9):2410–2417. doi: 10.1523/JNEUROSCI.04-09-02410.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Patel S., Millan M. H., Mello L. M., Meldrum B. S. 2-Amino-7-phosphonoheptanoic acid (2-APH) infusion into entopeduncular nucleus protects against limbic seizures in rats. Neurosci Lett. 1986 Feb 28;64(2):226–230. doi: 10.1016/0304-3940(86)90105-9. [DOI] [PubMed] [Google Scholar]
  10. Racine R. J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281–294. doi: 10.1016/0013-4694(72)90177-0. [DOI] [PubMed] [Google Scholar]
  11. Turski L., Cavalheiro E. A., Schwarz M., Turski W. A., De Moraes Mello L. E., Bortolotto Z. A., Klockgether T., Sontag K. H. Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Brain Res. 1986 Apr 9;370(2):294–309. doi: 10.1016/0006-8993(86)90484-1. [DOI] [PubMed] [Google Scholar]
  12. Turski L., Cavalheiro E. A., Sieklucka-Dziuba M., Ikonomidou-Turski C., Czuczwar S. J., Turski W. A. Seizures produced by pilocarpine: neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. Brain Res. 1986 Nov 19;398(1):37–48. doi: 10.1016/0006-8993(86)91247-3. [DOI] [PubMed] [Google Scholar]
  13. Turski L., Cavalheiro E. A., Turski W. A., Meldrum B. S. Excitatory neurotransmission within substantia nigra pars reticulata regulates threshold for seizures produced by pilocarpine in rats: effects of intranigral 2-amino-7-phosphonoheptanoate and N-methyl-D-aspartate. Neuroscience. 1986 May;18(1):61–77. doi: 10.1016/0306-4522(86)90179-x. [DOI] [PubMed] [Google Scholar]
  14. Turski L., Meldrum B. S., Jones A. W., Watkins J. C. Anticonvulsant action of stereoisomers of gamma-glutamylaminomethylsulphonic acid in mice. Eur J Pharmacol. 1985 May 8;111(2):279–283. doi: 10.1016/0014-2999(85)90769-1. [DOI] [PubMed] [Google Scholar]
  15. Turski W. A., Cavalheiro E. A., Bortolotto Z. A., Mello L. M., Schwarz M., Turski L. Seizures produced by pilocarpine in mice: a behavioral, electroencephalographic and morphological analysis. Brain Res. 1984 Nov 12;321(2):237–253. doi: 10.1016/0006-8993(84)90177-x. [DOI] [PubMed] [Google Scholar]
  16. Turski W. A., Cavalheiro E. A., Schwarz M., Czuczwar S. J., Kleinrok Z., Turski L. Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav Brain Res. 1983 Sep;9(3):315–335. doi: 10.1016/0166-4328(83)90136-5. [DOI] [PubMed] [Google Scholar]
  17. Turski W. A., Czuczwar S. J., Kleinrok Z., Turski L. Cholinomimetics produce seizures and brain damage in rats. Experientia. 1983 Dec 15;39(12):1408–1411. doi: 10.1007/BF01990130. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES