The effect of different glutamate‐receptor antagonists on the induction of cortical spreading depression of Leao and of cortical anoxic membrane depolarization were investigated in the anaesthetized rat. Spreading depression (SD), elicited by mechanical stimulation of the cortical surface, was inhibited by the non‐competitive N‐methyl‐d‐aspartate (NMDA)‐receptor blocker, (±)‐5‐methyl‐10,11‐dihydro‐SH‐dibenzo(a, d)‐cyclo‐hepten‐5,10‐imine maleate (dizocilpine or MK‐801), (0. 30 μmol kg^‐1 (0. 10 mg kg ^‐1)), and the competitive NMDA‐receptor antagonists; cis‐4‐phosphonomethyl‐2‐piperidine carboxylate (CGS 19755), (3.36 μmol kg^‐1 (0.75 mg kg^‐1)), d‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentenoic acid (CGP 40116), (1.20 μmol kg^‐1 (0.25 mg kg^‐1)) and its carboxylester CGP 43487, (6.30 μmol kg^‐1 (1.50 mg kg^‐1)). The α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepripriate (AMPA)‐receptor blocker, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(F) quinoxaline (NBQX), administered as an intravenous dose of 29.76 and 89.29 μmol kg^‐1 (10 & 30 mg kg^‐1), which is sufficient to block seizures and protect against ischaemic brain damage, did not inhibit spreading depression. None of the drugs utilized inhibited the anoxic membrane depolarization. The data demonstrate that NMDA‐receptor activation is essential for the initiation and propagation of spreading depression, while activation of AMPA‐receptors is not obligatory. The observed initiation and propagation of SD, during AMPA‐receptor blockade, suggest that activation of voltage‐operated ion channels may contribute to release the magnesium block of the NMDA‐receptor operated channel and to the initiation of SD.