In patches excised from CA1 pyramidal cells, peak amplitudes of currents evoked by brief glutamate pulses grew progressively smaller over a series of high-frequency pulses. This decline was eliminated by cyclothiazide, a drug previously shown to block AMPA receptor desensitization. In hippocampal slices, synaptically evoked bursts exhibited an increase from the first to the second response, presumably due to facilitation of transmitter release, but the subsequent responses gradually declined in amplitude. Cyclothiazide attenuated or reversed this decline; after normalization to the first response, the amplitudes of the later responses to a 50 Hz series of afferent stimulation were increased by 20-25% in regular recording medium and by as much as 40% when transmitter release was enhanced in a high-calcium medium. The effect of cyclothiazide was greatly diminished when the stimulation frequency was reduced to 33 or 25 Hz. Comparable results were obtained in slices in which NMDA, GABAA, and GABAB receptors were blocked. The ampakine drug CX516 which has only a minor influence on desensitization kinetics did not differentially facilitate the later responses to high-frequency afferent stimulation. These results suggest that the desensitization of AMPA receptors contributes importantly to synaptic activity when afferents are repetitively activated at high-frequency.