Abstract The concentration-response relationship of membrane currents induced by l-homocysteic acid was studied on mouse embryonic hippocampal neurons in culture ( n = 56). In the majority of neurons two phases in the dose-response relationship could be distinguished. The first was characterized by responses to 3–100 μM l-homocysteic acid which desensitized with a time-constant > 1 s in a concentration-dependent manner and were antagonized by 30 μM d- l-2-amino-5-phosphonovaleric acid indicating activation of the N-methyl- d-aspartate receptors. At higher concentrations of l-homocysteic acid this component was strongly depressed. The second phase was characterized by sustained responses that were concentration-dependent (1 mM l-homocysteic acid maximum concentration tested) and were not blocked by d- l-2-amino-5-phosphonovaleric acid indicating activation of non-N-methyl- d-aspartate receptors. Eight neurons did not exhibit these two-phase characteristics in the concentration-response relationship at the beginning of the recording. The magnitude of responses to l-homocysteic acid was positively related to concentration and the responses were partially blocked by d- l-2-amino-5-phosphonovaleric acid. In these neurons, however, repeated applications of l-homocysteic acid at concentrations 30 μM up to 300 μM resulted in a long-lasting, three- to four-fold increase of the membrane current. This increase was completely blocked by d- l-2-amino-5-phosphonovaleric acid (50–100 μM) suggesting that it was produced by activation of receptors. It is suggested that the long-lasting increase of the membrane current after repeated l-homocysteic acid application reflects long-term changes in the mechanisms involved in controlling N-methyl- d-aspartate receptors from an intracellular site in which Ca 2+ plays an important but not an exclusive role.