The objective of this study was to evaluate the role of beta-adrenergic receptors in modulating associative long-term potentiation (LTP) induced at CA1 synapses. Two independent Schaffer collateral pathways were stimulated in hippocampal slices. The field EPSP (fEPSP) response evoked in one pathway (the weak pathway) was small, whereas a large response, usually 80-90% of the maximum, was evoked in the strong pathway. After recording of the baseline fEPSP evoked at 0.033 Hz, LTP of the weak pathway could be associatively induced by paired stimulation of the weak and strong pathways 100 times at 6 sec intervals, with stimulation of the weak pathway preceded 3-10 msec. However, pairing protocols with an interval between stimulation of the two pathways >10 msec resulted in no LTP. The induced LTP was NMDA receptor dependent, because 50 microm D,L-APV blocked its induction. Bath application of 1 microm isoproterenol enhanced LTP by increasing the window of the stimulation interval up to 15 msec but did not affect the magnitude of the LTP induced by pairing protocols with intervals <10 msec. Similar results were obtained when the experiments were repeated using whole-cell recording. These results suggest that activation of beta-adrenergic receptors can enhance associative LTP by increasing the width of the time window rather than the magnitude of the LTP. Enhancement of LTP by beta-adrenergic receptors was blocked in slices by pretreatment with inhibitors of protein kinase A or mitogen-activated protein kinase, suggesting that these signaling cascades are involved in this process.