In this study we have examined the neurotoxic effects of folic acid (FA), alone or in combination with selected excitotoxins using in vitro preparations of chick retina. Folic acid alone at concentrations of up to 10 mM had no effect. Co-incubation of 10 mM FA with 2 microM kainic acid (KA) protected all cell types susceptible to KA toxicity, namely amacrine and bipolar cells. At lower concentrations the protective effect of FA to susceptible cell types was found to be dose-dependent. The rank order of cells which are protected by FA, in order of the lowest concentration of FA required, was amacrine, inner bipolar and outer bipolar cells. The effect of FA against KA is a very weak one, as a 130-400-fold concentration of FA is required to protect amacrine cells from KA and a 1000-5000-fold dose of FA required to protect bipolar cells. However, FA (2 mM) also protects susceptible retinal neurons from the neurotoxic effects of 40 microM N-methyl-DL-aspartic acid (NMDLA) and 60 microM quinolinic acid (QUIN); only requiring respectively 50 and 33 times the concentration of FA. Interestingly 10 mM FA had little effect against 40 microM quisqualic acid (QUIS). Thus FA antagonizes the effects of KA, NMDLA, QUIN and to a small extent QUIS. Although its action may be mediated through several receptor types, FA appears to be a more potent antagonist of the N-methyl-D-aspartic acid (NMDA)-preferring than the KA-preferring or QUIS-preferring receptor.