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.
1. It has been suggested that an NMDA1 receptor subtype might be activated by N-methyl-D-aspartate (NMDA) and ibotenate and an NMDA2 subtype by NMDA or quinolinate, and that the NMDA2 site might be more susceptible to blockade by kynurenic acid. 2. 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. 3. 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 much greater than quinolinate greater than ibotenate = NMDA. 4. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to approximately 40% of the toxin-alone condition. 5. 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 x equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 x equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. 6. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.
Department of Psychology, University of St Andrews, Fife.
P
P
Winn
T W
TW
Stone
M
M
Latimer
M H
MH
Hastings
A J
AJ
Clark
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D007051:Ibotenic Acid; D007608:Kainic Acid; D007736:Kynurenic Acid; D008297:Male; D016202:N-Methylaspartate; D017378:Quinolinic Acid; D011805:Quinolinic Acids; D016318:Quisqualic Acid; D051381:Rats
D011805:Quinolinic Acids; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D016318:Quisqualic Acid; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D007608:Kainic Acid