Reversal of long-term potentiation (LTP) by physiological stimulation was tested in the CA1 field of hippocampal slices. In control medium, a one minute episode of 5 Hz (theta frequency) stimulation beginning 1-3 min after LTP had no effect on the degree of potentiation measured 30 min later. However, in the presence of norepinephrine (200 microM), 5 Hz stimulation reduced LTP by about 30%. Theta frequency stimulation was only effective when administered within 10 min of LTP induction and had no lasting effects on non-potentiated synapses. Stimulation at 1 Hz did not reverse LTP and stimulation at 10 Hz was no more effective than 5 Hz stimulation. LTP could be nearly completely reversed by theta frequency stimulation when potentiation was induced by milder and more naturalistic stimulation patterns. Under these conditions, LTP reversal was blocked by an antagonist of adenosine A1 receptors. These results suggest that the hippocampal theta rhythm promotes both the induction of LTP and its subsequent reversal with the latter process involving activation of adenosine receptors. Reversal of LTP may function to refine or sharpen recently encoded representations.