Stimulation of dopamine release from cultured rat mesencephalic cells by naturally occurring excitatory amino acids: involvement of both N-methyl-D-aspartate (NMDA) and non-NMDA receptor subtypes.

: In rat mesencephalic cell cultures, L-glutamate at concentrations ranging from 100 μM to 1 mM stimulated release of [3H]dopamine that was attenuated by the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 6,7-dinitroquinoxalinedione, but not by the selective NMDA receptor antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801; 10 μM) and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (300 μM). Even at 1 mM glutamate, this release was Ca2+ dependent. These observations suggest that the release was mediated by a non-NMDA receptor. Only release stimulated by a lower concentration (10 μM) of glutamate was inhibited by MK-801 (10 μM), indicating that glutamate at this concentration activates the NMDA receptor. By contrast, L-aspartate at concentrations of 10 μM to 1 mM evoked [3H]dopamine release that was completely inhibited by MK-801 (10 μM) and was also Ca2+ dependent (tested at 1 and 10 mM aspartate). Thus, effects of aspartate involved activation of the NMDA receptor. Sulfur-containing amino acids (L-homocysteate, L-homocysteine sulfinate, L-cysteate, L-cysteine sulfinate) also evoked [3H]dopamine release. Release evoked by submillimolar concentrations of these amino acids was attenuated by MK-801 (10 μM), indicating involvement of the NMDA receptor. Higher concentrations of the sulfur-containing amino acids (≥1 μM L-homocysteate, ≥ 1 mM L-homocysteine sulfinate, ≥ 10 mM L-cysteate, ≥ 10 mM L-cysteine sulfinate) evoked [3H]dopamine release that was Ca2+ dependent (largely Ca2+ dependent for 10 mM L-cysteine sulfinate) and inhibited by 6,7-dinitroquinoxalinedione (100 μM), but unaffected by MK-801 (10 or 100 μM). Thus, like glutamate, higher concentrations of the sulfur-containing amino acids interact with non-NMDA receptors, while non-NMDA receptor involvement was not observed with aspartate.