In the CA1 region of adult guinea pig hippocampal slices, long trains of theta frequency (5 Hz) stimulation produced a small enhancement of basal synaptic transmission but depressed the strength of synaptic transmission at synapses that had recently undergone long-term potentiation (LTP). Five hertz stimulation delivered immediately prior to high-frequency stimulation also inhibited the subsequent induction of LTP. The depression of potentiated synapses by 5 Hz stimulation (depotentiation) was blocked by 2-amino-5-phosphonovalerate and was observed only during the early phases of LTP. Furthermore, the protein phosphatase inhibitors okadaic acid and calyculin A blocked both depotentiation and the ability of 5 Hz stimulation to inhibit subsequent LTP, suggesting that protein phosphatases are involved in the ability of 5 Hz stimulation to modulate synaptic plasticity in the CA1 region of the hippocampus.