Previous experiments with wheatgerm agglutinin, an inhibitor of ionotropic quisqualate receptor desensitization, suggest that desensitization regulates quisqualate receptor-mediated synaptic transmission and excitotoxicity. Using whole-cell recordings from cultured postnatal rat hippocampal neurons, we have examined the wheatgerm agglutinin effect in further detail and compared it to other lectins. Wheatgerm agglutinin and other lectins belonging to the glucose/mannose, N-acetylglucosamine, and sialic acid classes inhibited desensitization. However, wheatgerm agglutinin was the most effective and had the most rapid onset of action. The inhibition was dose-dependent, and it was reduced and reversed by N-acetylglucosamine and N-acetylneuraminic acid. Treating neurons with neuraminidase, which cleaves sialic acid residues from the surface of cells, also diminished the effect. These results suggest that wheatgerm agglutinin reversibly inhibits ionotropic quisqualate receptor desensitization by interacting with carbohydrate residues on or near the quisqualate receptor complex. Future studies using the lectins may help to clarify the functional role of carbohydrate chains on the ionotropic quisqualate receptor.