Acutely dissociated neurons from the superficial layers of the medial entorhinal cortex of the rat were studied under voltage clamp using the whole-cell patch-clamp configuration. Neurons from the medial entorhinal cortex exhibit a tetrodotoxin (TTX)-resistant Na+ current (I(TTX-R); IC50 almost-equal-to 146 nM), in addition to the normal TTX-sensitive Na+ current (I(TTX-S); IC50 almost-equal-to 6 nM). I(TTX-R) was found in both putative stellate and putative pyramidal neurons from the medial entorhinal cortex. I(TTX-R) is kinetically indistinguishable from I(TTX-S), but can be distinguished from I(TTX-S) based on its enhanced sensitivity to block by Cd2+, La3+, and Zn2+. I(TTX-R) is kinetically and pharmacologically similar to the TTX-resistant Na+ current found in cardiac muscle.