Neuronal responses mediated by activation of the non-NMDA receptors: Potentiation by nootropes

Abstract

Experiments on superfused slices of rat hippocampus showed that the nootropic drugs pyracetam, ethymizol, ambocarb, and nooglutil increase the amplitude of populational EPSP (pEPSP) of neurons of the dentate gyrus evoked by electrical stimulation of the perforant pathway (PP). Nootropes exert no effect on the process of presynaptic glutamate liberation from the PP axons, but increase the chemosensitivity of the postsynaptic AMPA/kainate receptors mediating EPSP generation in the dentate gyrus neurons. Inhibitors of protein kinase (A-buthamide) and guanylatecyclase (methylene blue) do not modify the effects of nootropes. The nootrope-induced potentiation of pEPSP does not develop against the background of the application of calmodulin inhibitor W-7. In the presence of protein kinase inhibitor C, polymixin B, nootropes reversibly depress pEPSP in the dentate gyrus neurons. Blocking of the NMDA receptor ionic channels by ketamine and of the voltage-dependent T-type calcium channels by Ni2+ does not significantly modify the effects of nootropic drugs. A blocker of Ca2+-ATPase of the Ca2+ stores sodium orthovanadate, potentiates the effects of nootropes. Dantrolene, which disrupts Ca2+ liberation from the non-mitochondrical depots, blocks the effects of nootropes and diminishes pEPSP depression evoked by nootropes in the presence of polymixin B. On the basis of presented data, it is supposed that nootropic drugs assist Ca2+ liberation from the neuronal depots and activate calmodulin-dependent protein kinase and protein kinase C. Protein kinases phosphorylate the intracellular domains of the AMPA/kainate receptors, and this process results in an increase in their sensitivity to excitatory amino acids.