Abstract Spermine-induced neurotoxicity and its pharmacological manipulation was studied in the rat striatum in vivo. Spermine (50, 100, 250 nmol) was injected into the striatum and the volume of damage quantified by computer-based image analysis. Spermine produced a dose-dependent increase in the volume of damage. Co-administration of MK-801 ((+[-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclo-hepten-5,10-imine maleate; dizocilpine, 60 nmol), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (25, 40 nmol) and pretreatment with pentobarbital (40 mg/kg, i.p.[ significantly reduced the volume of damage induced by 100 nmol spermine. MK-801 (30 nmol) was also effective in reducing the damage induced by 50 nmol spermine. Treatment with a specific inhibitor of nitric oxide synthase, N ω-nitro- l-arginine methyl ester (50 mg/kg, i.p. twice daily for 10 days) was ineffective. These results suggest an involvement of both N-methyl- d-aspartate (NMDA) and non-NMDA glutamate receptors in the cascade of spermine-induced neurotoxicity.