The mechanism of adenosine 5'-triphosphate (ATP)-induced long-term potentiation (LTP) was studied pharmacologically using guinea pig hippocampal slices. Application of 10 microM ATP for 10 min transiently depressed, then slowly augmented, synaptic transmission in CA1 neurons, leading to LTP. This ATP-induced LTP was blocked by addition of an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. Furthermore, co-application of 10 microM ATP and 100 microM L-glutamate for 10 min also induced LTP, and this effect was blocked by the use of Ca2+-free solution during drug application. These results suggest that, in CA1 neurons, a co-operative effect involving extracellular ATP and the activation of NMDA receptors, which increases intracellular Ca2+ levels, is required to trigger the intracellular biological process involved in ATP-induced LTP.