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.