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 (1-100μM) 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 (1-100μM) induced a concentration-dependent increase in norepinephrine output. Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptors with AMPA (1-100μM) resulted in a biphasic effect on the extracellular norepinephrine concentration, with a decrease in this parameter apparent at 10μM and an increase at 100μM. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect on norepinephrine output. The GABA(A) receptor antagonist bicuculline (10μM) prevented the decrease in hippocampal norepinephrine output induced by either NMDA or 10μM 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.