Neocortical preparations have proven highly resistant to the induction of long-term potentiation (LTP), and we have only recently determined the conditions sufficient for the induction of neocortical LTP in the adult, freely moving rat. The stimulation trains must be spaced and repeated over a period of days in order to reach asymptotic levels of potentiation. Here we show that, within these constraints, the neocortex is actually highly responsive. LTP could be induced with as few as one brief high frequency train per day or with extremely low-intensity stimulation trains. We also provide evidence for a critical role for N-methyl-D-aspartate (NMDA) receptor activation in LTP induction in this preparation, and demonstrate that this LTP is input-specific. Control pathways showed no potentiation effects. LTP was found in a monosynaptic and two polysynaptic components (average latencies to peak: 8.1, 15.2 and 20.0 ms) and in the superimposed population spikes. Although LTP could be induced with one train per day or with low-intensity trains, larger and longer-lasting potentiation effects could be induced by increasing the number of trains delivered per session, the number of sessions over which trains were delivered, or the pulse intensity of the trains. The LTP decayed slowly and was still evident 5 weeks later. Administration of the competitive NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid blocked the induction of LTP in a dose-dependent fashion and appeared to unmask a depression of both the population spikes and a polysynaptic component. These results indicate that the neocortex is highly sensitive to LTP induction procedures, as long as the stimulation trains are spaced and applied over a period of days. They are also consistent with the view that the neocortex must operate with a slow learning rate to reduce interference effects in memory.