Multiple mechanisms underlying nootropic drug-induced enhancement of neuronal responses mediated by activation of glutamate NMDA-type receptors

Abstract

Nootropic drugs of various chemical structure (pyracetam, dimethylaminoethanol, ethymisol, and ambocarb) possessing antiamnesic activity were found to increase depolarization evoked by L-aspartate and the EPSP late components evoked by dorsal roots stimulation (DR-EPSP). Experiments were performed on motoneurons of the lumbar region of isolated frog spinal cord superfused with Mg2+-free saline. When ionic channels of NMDA-glutamate receptors were blocked with ketamine and Mg2+, the nootropic substances did not affect DR-EPSP and motoneuronal depolarization evoked by L-glutamate. Butamid, a protein kinase A inhibitor, blocked the ethymisol and pyracetam effects, whereas polymixin B, a protein kinase C inhibitor, blocked the ambocarb effect. Trifluoroperazine, a calmodulin inhibitor, blocked the effect of dimethylaminoethanol. Proline inhibited only the pyracetam effect. These results indicate that the NMDA-potentiating activity of the above nootropic drugs may be based on both intracellular phosphorylation of NMDA receptor-channel complexes, as mediated by protein kinases, and allosteric enhancement of affinities of these complexes to excitatory amino acids.