The modulatory influence of aniracetam, a drug which reversibly modifies the kinetic properties of AMPA-type glutamate receptors, on synaptic responses is reported to be detectably changed by the induction of long-term potentiation (LTP). The present study used hippocampal slices to examine three issues arising from this result. First, possible contributions of inhibitory currents and postsynaptic spiking to the aniracetam/LTP interaction were investigated with infusions of GABA receptor antagonists and topical applications of tetrodotoxin. Second, tests were carried out to determine if the altered response to aniracetam is sufficiently persistent to be a plausible substrate for the extremely stable LTP effect. Third, the nature of the change responsible for the aniracetam/LTP interaction was explored with waveform analyses and a kinetic model of the AMPA receptor. The following results were obtained. LTP reduced the effect of aniracetam on the amplitude but increased its effect on the decay time constant of field EPSPs recorded under conditions in which local spiking and inhibitory responses were blocked. The LTP-induced change in the effect of aniracetam was extremely stable in that it was still evident 75 min after induction of potentiation. Finally, the waveform distortions introduced by LTP and aniracetam could be corrected by uniform stretching of the responses, suggesting that the changes introduced by each of the manipulations are unitary in nature. These distortions and the interactions between them could be reproduced in the AMPA receptor model by representing LTP as an acceleration of channel gating kinetics.
Copyright 1998 Elsevier Science B.V.