1. The effects of diazoxide (DZ) on synaptic transmission and upon responses to exogenously applied glutamate agonists were examined in cultured hippocampal neurons. 2. DZ reversibly increased the peak amplitude of evoked excitatory postsynaptic currents (EPSCs) to 150 +/- 100% of control and prolonged the EPSC decay time constant (tau) from 5.9 +/- 1.2 ms to 14 +/- 6.2 ms (240% of control). 3. Peak and steady-state glutamate (Glu) and quisqualate (QA) currents activated by exogenous application were dramatically increased by DZ at concentrations which did not influence N-methyl-D-aspartate (NMDA), kainate (KA), or GABA currents. These effects were rapidly and completely reversible. Active and passive membrane properties were unaffected by DZ. 4. Inhibitory postsynaptic currents (IPSCs) were unaffected by the same DZ concentrations. 5. These experiments indicate that desensitization plays an important role in terminating excitatory transmission between mammalian central neurons. DZ and perhaps related compounds will ultimately help us identify the regions of the AMPA/KA receptor responsible for desensitization.