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 Mg2+-free medium. It also occurred in slices treated with either staurosporine (1 muM), which is a potent inhibitor of a variety of protein kinases including protein kinase C (PKC), or thapsigargin (10 muM), which depletes intracellular Ca2+ stores by preventing their refilling. However, CCh-induced potentiation was abolished in slices perfused with Ca2+-free medium. These data suggest that low concentrations of CCh can acutely potentiate NMDA responses in the hippocampus by a Ca2+-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).