Role of ionotropic glutamate receptors in the regulation of hippocampal norepinephrine output in vivo

In vitro evidence indicates that norepinephrine release in the mammalian hippocampus is modulated by glutamate receptors. With the use of microdialysis, we have now evaluated the role of ionotropic glutamate receptors in the regulation of hippocampal norepinephrine output in vivo. Stimulation of N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors by local administration of NMDA (1–100 μM) resulted in a concentration-dependent decrease in the extracellular concentration of norepinephrine in the hippocampus of freely moving rats, whereas the blockade of these receptors with MK801 (1–100 μM) induced a concentration-dependent increase in norepinephrine output. Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptors with AMPA (1–100 μM) resulted in a biphasic effect on the extracellular norepinephrine concentration, with a decrease in this parameter apparent at 10 μM and an increase at 100 μM. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect on norepinephrine output. The GABAA receptor antagonist bicuculline (10 μM) prevented the decrease in hippocampal norepinephrine output induced by either NMDA or 10 μM AMPA. Our results thus implicate ionotropic glutamate receptors as key regulators of norepinephrine release in the hippocampus and may therefore provide a basis for the development of new drugs for stress-related disorders.

Research Highlights
► Stimulation and blockade of NMDA receptors induced a decrease and an increase of hippocampal norepinephrine output, respectively.
► Stimulation of AMPA receptors induced a biphasic effect on the same parameter.
► The decrease induced by both NMDA and AMPA stimulation was prevented by the GABAA receptor agonist bicuculline.
► GABAergic interneurons might play a crucial role in the regulation of norepinephrine output by glutamate ionotropic receptors.