Concanavalin A, cyclothiazide, and aniracetam, ligands that modulate desensitization at glutamate receptors, were tested for their actions on responses at kainate-preferring receptors in dorsal root ganglion (DRG) neurons and at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring receptors in hippocampal neurons. In DRG neurons concanavalin A blocked desensitization produced by either kainate or 5-chlorowillardiine and strongly potentiated the peak amplitude of responses to both agonists. However, in hippocampal neurons concanavalin A produced only weak potentiation of responses to kainate and 5-chlorowillardiine, and after treatment with lectin responses to 5-chlorowillardiine remained strongly desensitizing. In contrast, cyclothiazide completely blocked desensitization produced by 5-chlorowillardiine in hippocampal neurons and strongly potentiated responses to kainate; the action of aniracetam was similar but much weaker. In DRG neurons cyclothiazide and aniracetam had no effect on desensitization and instead produced weak inhibition of responses to kainate. The different sensitivities of native AMPA- and kainate-preferring glutamate receptors to cyclothiazide and concanavalin A should prove useful for the differentiation of glutamate receptor subtypes in other areas of the central nervous system.