The effects of substance P and related tachykinins on intrinsic membrane properties and synaptic responses of neurons in cortical slices were determined. Substance P had no detectable effect on membrane properties of principal neurons in layer II or V of the rat medial entorhinal cortex or on neurons in either layer of the anterior cingulate cortex. Specific agonists at the neurokinin1-receptor were also without effect as were agonists at both neurokinin1- and neurokinin3-receptors. Substance P hyperpolarized a small number of principal neurons. These responses were weak and desensitized with repeated applications. Similar effects were seen with other neurokinin1-receptor agonists. Excitatory synaptic potentials mediated by either alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate- or N-methyl-D-aspartate-receptors in principal neurons of the entorhinal cortex were unaffected by substance P. Responses of entorhinal neurons to iontophoretically applied glutamate and N-methyl-D-aspartate were also unaffected. Inhibitory synaptic potentials mediated by either GABA(A)- or GABA(B)-receptors in entorhinal neurons were slightly but consistently enhanced by substance P. Neurons identified as interneurons on the basis of their firing characteristics were consistently depolarized by substance P. These responses also desensitized with repeated applications. Spontaneous epileptiform discharges evoked in entorhinal cortex by perfusion with a GABA(A)-receptor antagonist (bicuculline), were reduced in frequency and, sometimes, in duration by substance P. This effect was mimicked by other neurokinin1-receptor agonists and blocked by neurokinin1-receptor antagonists. It was also mimicked by neurokinin A but not by a specific neurokinin1-receptor agonist. The reduction in frequency of discharges was also mimicked by a GABA(B)-receptor agonist, L-baclofen, and blocked by the GABA(B)-receptor antagonist, CGP55845A. Neurokinin B, and a specific neurokinin1-receptor agonist (senktide), increased the frequency and (sometimes) duration of epileptiform discharges. Substance P could also increase frequency but this usually succeeded or preceded a decrease in frequency. The effect of neurokinin B was reduced by a metabotropic glutamate receptor antagonist. Substance P appears to have little direct effect on principal neurons of the entorhinal cortex but may hyperpolarize them indirectly by activating interneurons and releasing GABA. This indirect inhibition may be responsible for the ability of substance P to reduce the frequency of epileptiform discharges in the entorhinal cortex and may suggest that neurokinin1-receptor agonists have potential as anticonvulsant drugs.