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

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Abstract
In rat mesencephalic cell cultures, L-glutamate at concentrations ranging from 100 .mu.M 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 .mu.M) and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (300 .mu.M). 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 concentrations (10 .mu.M) of glutamate was inhibited by MK-801 (10 .mu.M), indicating that glutamate at this concentration activates the NMDA receptor. By contrast, L-aspartate at concentrations of 10 .mu.M to 1 mM evoked [3H]dopamine release that was completely inhibited by MK-801 (10 .mu.M) 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 .mu.M), indicating involvement of the NMDA receptor. Higher concentrations of the sulfur-containing amino acids (.gtoreq.1 mM L-homocysteate, .gtoreq. 1 mM L-homocysteine sulfinate, .gtoreq. 10 mM L-cysteate, .gtoreq. 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 .mu.M), but unaffected by MK-801 (10 or 100 .mu.M). 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.