Reversal of long-term potentiation by low-frequency stimulation is often referred to as depotentiation. However, it is not clear whether depotentiation induced by low-frequency stimulation and long-term depression (LTD) induced by similar stimuli are distinct phenomena. We have performed a series of experiments in area CA1 of rat hippocampal slices in which a single pattern of theta-burst (TB) stimulation (Larson, et al., 1986; Staubli and Lynch, 1987) was found to produce either LTP or reversal of LTP depending on the intensity of the stimulation. TB stimulation (10 trains consisting of 4 pulses at 100 Hz, 200 msec apart) delivered at test pulse-intensity induced LTP. However, the same stimulation delivered at a higher intensity (10 times that of the test pulse, evoking a maximal response) did not induce LTP or depression of control responses, but produced lasting depression of previously potentiated responses. This reversal of LTP (TB depotentiation) was observed when the stimulus was delivered between 0.5 and 110 min after induction of LTP. TB depotentiation was reversible, cumulative and saturable when high-intensity TB trains were delivered in succession. TB depotentiation was also blocked by antagonists at NMDA receptors. Low-frequency (1 Hz) stimulation induced LTD, indicating that responses were not already maximally depressed. In addition, high-intensity TB stimulation did not reverse LTD. These results suggest that depotentiation induced by maximal TB stimulation and LTD induced by low-frequency stimulation are distinct phenomena, yet share some characteristics common to forms synaptic plasticity mediated by NMDA receptor activation.