1. The effects of two adamantane derivatives, 1-trimethylammonio-5-(1-adamantane-methyl-ammoniopentane dibromide) (IEM-1460) and 1-ammonio-5-(1-adamantane-methylammoniopentane dibromide) (IEM-1754) on kainate-induced currents were studied in Xenopus oocytes expressing recombinant ionotropic glutamate receptors and in freshly isolated neurones from rat hippocampal slices. 2. The adamantane derivatives caused use- and voltage-dependent block of open channels of recombinant AMPA receptors. This antagonism was dependent on receptor subunit composition; channels gated by recombinant, homomeric GluR1 and GluR3 receptors exhibited a higher sensitivity to block than those gated by receptors containing edited GluR2 subunits. In the former cases, IEM-1460 had an IC50 of 1.6 microM at a holding potential (Vh) of -80 mV and IEM-1754 was 3.8 times less potent than IEM-1460. In contrast, 100 microM IEM-1460 inhibited responses to 100 microM kainate of receptors containing edited GluR2 subunits by only 7.8 +/- 2.4% (n = 5 oocytes at a Vh of -80 mV. 3. Native AMPA/kainate receptors in isolated hippocampal cells were inhibited by adamantane derivatives in a use- and voltage-dependent manner. This antagonism was dependent on cell type: pyramidal neurones were less sensitive to IEM-1460 (IC50 = 1617 microM at Vh = -80 mV) than interneurones (IC50 = 1.6 microM at Vh = -80 mV). IEM-1460 and IEM-1754 were equipotent when applied to pyramidal neurones, but IEM-1754 was less potent (approximately 3 times) than IEM-1460 when applied to interneurones. 4. It is concluded that the presence of the edited GluR2 subunit in recombinant AMPA receptors and native AMPA/kainate receptors inhibits channel block by organic cations and that adamantane derivatives are potentially valuable tools for identifying classes of AMPA/kainate receptors and their roles in synaptic transmission.