The ionic mechanisms underlying the action of excitatory amino acids were investigated in the rat motor cortex. Ion-selective microelectrodes were attached to micropipettes such that their tips were very close and local changes in extracellular concentration of sodium, calcium, and potassium ions elicited through ionophoretic applications of glutamate (Glu) and of its agonists N-methyl-D-aspartate (NMDA), quisqualate (Quis), and kainate (Ka) were measured. These agents produced moderate increases in [K+]o (up to 13 mM) but, in contrast, substantial tetrodotoxin-insensitive decreases in [Na+]o (maximally of 60 mM). NMDA-induced sodium responses could be blocked by manganese, while the Quis- and Ka-induced responses were not. Quis and Ka produced increases in [Ca2+]o or biphasic responses while NMDA, even with small doses, induced each time drastic decreases in [Ca2+]o (maximally of 1.15 mM), which could be attenuated or blocked by manganese but not by organic calcium channel blockers. NMDA responses could be abolished by reduced doses of 2-amino-phosphonovalerate. The largest Glu- and NMDA-induced calcium responses were observed in the superficial cortical layers, but such maxima disappeared after selective degeneration of pyramidal tract neurons. All amino acids produced sizeable reductions in the extracellular space volume. The following can be concluded. (i) All the excitatory amino acids tested induce an increased permeability to sodium and potassium ions. (ii) In addition, the NMDA-operated channels have specifically a large permeability for calcium, although calcium ions contribute only by less than 10% to the NMDA-induced inward currents.(ABSTRACT TRUNCATED AT 250 WORDS)