Chronic dosing with 1-aminocyclopropanecarboxylic acid, a glycine partial agonist, modulates NMDA inhibition of muscarinic-coupled PI hydrolysis in rat cortical slices.
Chronic dosing with the glycine partial NMDA agonist, 1-aminocyclopropanecarboxylic acid (ACPC) elicited an altered allosteric regulation of cortical NMDA receptor binding. The present study hypothesized that these allosteric receptor binding changes would be manifest as pharmacologically functional reductions in NMDA receptor activity following chronic ACPC dosing. NMDA inhibition of carbachol-induced phosphoinositide (PI) hydrolysis was used as a functional assay to assess NMDA receptor function in rat cerebral cortex. NMDA inhibition of stimulated PI turnover was similar in naive (46% +/- 4.5%; mean +/- SE; n = 34) and ACPC dosed rats (39% +/- 2.3%; n = 34). While ACPC reversed NMDA's inhibitory effects in naive rats (80% +/- 13%; n = 9), it was ineffective (P < 0.05) in ACPC pretreated rats (48% +/- 9.8%; n = 9). In contrast, the NMDA antagonists, MK-801 (ion channel), 7-chlorokynurenic acid (glycine site) and AP-7 (glutamate site), effectively reversed NMDA's inhibitory effects in naive and ACPC treated rats. The potency of these antagonists were unaltered by prior ACPC dosing. Thus, chronic ACPC therapy does not alter the functioning of the NMDA ion channel or glutamate receptor sites, but elicits functional tolerance to ACPC's actions in the cortical NMDA complex.
Department of Pharmaceutics, School of Pharmacy, University of Buffalo, New York 14260-1200, USA. boje@acsu.buffalo.edu
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000819:agonists; D006868:Hydrolysis; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C065594:cispentacin; D007294:Inositol; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D002217:Carbachol; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine