Differential action of NMDA antagonists on cholinergic neurotoxicity produced by N-methyl-D-aspartate and quinolinic acid.
1. Injections of N-methyl-D-aspartate (NMDA) and quinolinic acid (Quin), agonists that activate NMDA receptors, into the rat nucleus basalis magnocellularis (nbM) produced a dose-related decrease in cholineacetyltransferase (ChAT) activity in the cerebral cortex and amygdala 7 days after injection. 2. In order to examine the possibility that NMDA and Quin activate different sub-types of NMDA receptors to produce central cholinergic neurotoxicity, the sensitivity of these agonists to the action of three different NMDA receptor antagonists, 2-amino-7-phosphonoheptanoate (AP-7), 7-chlorokynurenate and dizolcipine (MK801) was examined by injecting a fixed dose of NMDA (60 nmol) or Quin (120 nmol) in combination with different doses of the antagonists into the nbM. 3. Both AP-7 (0.6-15 nmol) and 7-chlorokynurenate (3.75-200 nmol), which block the NMDA receptor recognition site and glycine modulatory site respectively, produced a dose-related attenuation of the NMDA or Quin-induced decrease in ChAT activity in both the cortex and amygdala. Both antagonists showed a greater potency against the action of NMDA than against Quin. 4. MK801 (2-200 nmol), an NMDA receptor-linked channel blocker, attenuated the Quin and NMDA response only at a high dose. Unlike AP-7 and 7-chlorokynurenate, MK801 did not exhibit a consistent difference in its potency as an antagonist against NMDA and Quin. 5. The differential antagonist actions of AP-7 or 7-chlorokynurenate against NMDA and Quin-induced cholinergic neurotoxicity suggest that the excitotoxic actions of these two agonists are mediated via distinct NMDA receptor sub-types. The NMDA- and Quin-sensitive receptors appear to differ with respect to properties of the receptor recognition and glycine modulatory sites that are associated with these receptors.
Pawley
A C
AC
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Flesher
S
S
Boegman
R J
RJ
Beninger
R J
RJ
Jhamandas
K H
KH
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C031231:2-amino-7-phosphonoheptanoic acid; C057013:7-chlorokynurenic acid