We investigated the role of kainate receptor activation in modulating the influx of Ca2+ coupled to the exocytotic release of glutamate in rat hippocampal synaptosomal fractions (P2). In whole hippocampus synaptosomes stimulation with domoic acid increased the intracellular free Ca2+ concentration ([Ca2+]i) in a dose-dependent manner with an EC50 of 0.16 microM, whereas the EC50 for kainate was 0.86 microM and for (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) was 43.04 microM. Stimulation of the synaptosomes with 10 microM domoic acid induced Ca(2+)-dependent release of endogenous glutamate. Also, in synaptosomes isolated from the CA3 sub-region of the hippocampus the domoic acid-induced release of glutamate was higher than that from the dentate gyrus (221.3%), from the CA1 (188.1%) or from the whole hippocampal synaptosomes (131.5%). These results support the existence of a presynaptic kainate receptor which may control the exocytotic release of glutamate in the CA3 sub-region of the rat hippocampus.