Carbachol can potentiate N-methyl-D-aspartate responses in the rat hippocampus by a staurosporine and thapsigargin-insensitive mechanism.
Experiments were performed to investigate the mechanism underlying the potentiation of N-methyl-D-aspartate (NMDA) responses by carbachol (CCh) in the CA1 region of rat hippocampal slices. CCh (300 nM) potentiated responses to NMDA, but not to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), in a readily reversible manner. Potentiation occurred in slices treated with 200 nM tetrodotoxin and perfused with Mg(2+)-free medium. It also occurred in slices treated with either staurosporine (1 microM), which is a potent inhibitor of a variety of protein kinases including protein kinase C (PKC), or thapsigargin (10 microM), which depletes intracellular Ca2+ stores by preventing their refilling. However, CCh-induced potentiation was abolished in slices perfused with Ca(2+)-free medium. These data suggest that low concentrations of CCh can acutely potentiate NMDA responses in the hippocampus by a Ca(2+)-sensitive process that is probably independent of both the activation of PKC and the release of Ca2+ from intracellular stores. This mechanism is similar to that underlying the potentiation of NMDA responses by the metabotropic glutamate receptor (mGluR) agonist, aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD).
Harvey
J
J
Department of Pharmacology, Medical School, University of Birmingham, UK.
Balasubramaniam
R
R
Collingridge
G L
GL
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects; D019311:Staurosporine; D013729:Terpenes / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D019284:Thapsigargin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000470:Alkaloids; D011976:Receptors, Muscarinic; D013729:Terpenes; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D019284:Thapsigargin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002217:Carbachol; D011493:Protein Kinase C; D019311:Staurosporine