N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors regulating hippocampal norepinephrine release. I. Location on axon terminals and pharmacological characterization.
The effects of endogenous and exogenous agonists at excitatory amino acid receptors mediating enhancement of [3H]norepinephrine [( 3H]NE) release have been investigated using superfused rat hippocampal synaptosomes. In Mg(++)-free medium L-glutamic acid (L-Glu), L-aspartic acid (L-Asp), N-methyl-D-aspartic acid (NMDA), kainic acid, (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and quisqualic acid (QA) all increased the release of [3H]NE. L-Glu produced the largest effect. In the presence of Mg++ (1.2 mM), the effect of L-Glu decreased by about 40%; L-Asp and NMDA lost completely their activity while the effects of kainic acid, QA and AMPA did not change significantly. Similarly to NMDA, the effect of L-Asp was augmented by glycine and blocked by NMDA receptor antagonists, while it was insensitive to the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The effect of L-Glu on [3H] NE release was partly decreased by the NMDA receptor channel blocker (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cycloepten-5,10-imine (MK-801) and partly by CNQX; when present together, the two antagonists completely abolished the L-Glu effect. The QA enhancement of [3H]NE release was antagonized by CNQX but it was insensitive to other classical non-NMDA receptor antagonists.


CONCLUSIONS
1) release-enhancing NMDA and non-NMDA receptors exist on noradrenergic axon terminals of rat hippocampus; 2) L-Asp appears to be a potent selective NMDA receptor agonist while L-Glu can activate also non-NMDA receptors; 3) the NE-releasing receptor activated by QA may represent a QA/AMPA receptor subtype.
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Genova, Italy.
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D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D005971:Glutamates; D011810:Quinoxalines; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D007051:Ibotenic Acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016318:Quisqualic Acid; D008274:Magnesium; D007608:Kainic Acid; D009638:Norepinephrine