Field potential recordings were made from area CA1 of hippocampal slices from young adult rats to study the effects of repeated tetanic stimulation on the development of LTP. Stimulation was applied to the Schaffer collateral afferents, and field excitatory postsynaptic potentials were recorded in stratum radiatum. Theta-burst stimulation (TBS) resulted in variable amounts of long-term potentiation (LTP), depending on how many trains of stimulation were delivered. Peak amounts of LTP occurred after 8-16 trains of TBS, but virtually no LTP occurred after 24 or 32 trains of TBS. There was thus an inverted U-shaped relation between the amount of TBS and the degree of LTP. The temporal spacing of TBS trains was important for observing the lack of LTP after 32 trains ("over-stimulation"). If the trains were grouped into blocks of 8, with 10 min between blocks, LTP occurred normally. This finding suggests that a time-dependent LTP reversal process was occurring during the massed presentation of TBS trains. Over-stimulation inhibited for 60-90 min the subsequent induction of LTP by a normally efficient LTP-inducing protocol. This effect was input specific and dependent on activation of N-methyl-D-aspartate (NMDA) receptors. Lowering extracellular [Ca2+] from 2.5 to 2.0 mM, or adding the L-type calcium channel antagonist nimodipine, had only a small protective effect on the lack of LTP induced by 32 trains of TBS. Addition of an NMDA receptor antagonist to the bath solution shortly after the beginning of the over-stimulation protocol gave significantly more protection. Administration of an adenosine (A1) receptor antagonist during over-stimulation permitted robust LTP to occur, indicating that A1 receptor activation during TBS contributes to the depotentiation process. These findings confirm previous findings in the dentate gyrus that repeated afferent tetanization within a narrow time frame can lead to a loss or reversal of LTP. Activation of adenosine receptors appears to trigger this effect.