A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N‐methyl‐d‐aspartate or quisqualate, and the effects on toxicity of 2‐amino‐5‐phosphonovaleric acid and kynurenic acid in the rat

Philip Winn, Trevor W. Stone, Mary Latimer, Michael H. Hastings, Andrew J.M. Clark

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Abstract

It has been suggested that an NMDA1receptor subtype might be activated by N‐methyl‐d‐aspartate (NMDA) and ibotenate and an NMDA2subtype by NMDA or quinolinate, and that the NMDA2site might be more susceptible to blockade by kynurenic acid. Experiments were carried out to examine the ability of 2‐amino‐5‐phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain. Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate ≫ quinolinate > ibotenate = NMDA. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to ∼40% of the toxin‐alone condition. The antagonistic properties of kynurenate were dose‐dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 × equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 × equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.
Original languageEnglish
Pages (from-to)904-908
Number of pages5
JournalBritish Journal of Pharmacology
Volume102
Issue number4
DOIs
Publication statusPublished - 30 Apr 1991

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Quisqualic Acid
Kynurenic Acid
Quinolinic Acid
Kainic Acid
Acids
Toxic Actions
Basal Forebrain
Neurons
Injections

Keywords

  • 2‐amino‐5‐phosphonovaleric acid (AP5)
  • basal forebrain
  • excitatory amino acid receptors
  • kynurenic acid
  • lesions
  • neurotoxic amino acids

Cite this

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title = "A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N‐methyl‐d‐aspartate or quisqualate, and the effects on toxicity of 2‐amino‐5‐phosphonovaleric acid and kynurenic acid in the rat",
abstract = "It has been suggested that an NMDA1receptor subtype might be activated by N‐methyl‐d‐aspartate (NMDA) and ibotenate and an NMDA2subtype by NMDA or quinolinate, and that the NMDA2site might be more susceptible to blockade by kynurenic acid. Experiments were carried out to examine the ability of 2‐amino‐5‐phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain. Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate ≫ quinolinate > ibotenate = NMDA. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to ∼40{\%} of the toxin‐alone condition. The antagonistic properties of kynurenate were dose‐dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 × equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 × equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.",
keywords = "2‐amino‐5‐phosphonovaleric acid (AP5), basal forebrain, excitatory amino acid receptors, kynurenic acid, lesions, neurotoxic amino acids",
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AU - Winn, Philip

AU - Stone, Trevor W.

AU - Latimer, Mary

AU - Hastings, Michael H.

AU - Clark, Andrew J.M.

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AB - It has been suggested that an NMDA1receptor subtype might be activated by N‐methyl‐d‐aspartate (NMDA) and ibotenate and an NMDA2subtype by NMDA or quinolinate, and that the NMDA2site might be more susceptible to blockade by kynurenic acid. Experiments were carried out to examine the ability of 2‐amino‐5‐phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain. Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate ≫ quinolinate > ibotenate = NMDA. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to ∼40% of the toxin‐alone condition. The antagonistic properties of kynurenate were dose‐dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 × equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 × equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.

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