HIPPOCAMPAL lesions impair spatial learning in the watermaze(1). Drugs that antagonize N-methyl-D-aspartate (NMDA)-receptor activity, which is required for long-term potentiation (LTP) at various hippocampal synapses(2-4), block LTP and impair watermaze learning(4-6). This has led to the hypothesis that NMDA receptors, through their involvement in LTP, may be necessary for spatial(4-11) and other forms of learning(12,13). We examined this hypothesis using NPC17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptano acid), a potent and specific antagonist of NMDA receptors(14-17). Here we report that NPC17742 completely blocked dentate gyrus LTP but did not prevent normal spatial learning in rats that had been made familiar with the general task requirements by non-spatial pretraining. Although these results do not rule out a contribution of NMDA-mediated dentate LTP to spatial learning, they indicate that this form of LTP is not required for normal spatial learning in the watermaze.