Desensitization at AMPA/kainate receptors has been proposed to contribute to the decay of excitatory synaptic currents. We examined the action of aniracetam, wheat germ agglutinin (WGA), and concanavalin A (Con A), drugs that act via separate mechanisms to reduce desensitization evoked by L-glutamate in rat hippocampal neurons. The decay of excitatory synaptic currents, and sucrose-evoked miniature excitatory postsynaptic currents (EPSCs) was slowed 2- to 3-fold by aniracetam. In contrast, WGA increased the EPSC decay time constant only 1.3-fold and Con A had no effect. Aniracetam increased the magnitude of stimulus-evoked EPSCs 1.9-fold; variance analysis suggests a postsynaptic mechanism of action. WGA and Con A reduced EPSC amplitude via a presynaptic mechanism. Aniracetam increased the burst length of L-glutamate-activated single-channel responses. Simulations suggest that aniracetam either slows entry into a desensitized state or decreases the closing rate constant for ion channel gating.