Norepinephrine (NE) release measured by microdialysis from probes positioned in the prefrontal cortex of anesthetized rats was increased when N-methyl-D-aspartate (NMDA) was contained in the microdialysis medium. NE release increased by a factor of 3.6 compared to prior baseline levels when 1 mM NMDA was applied for 30 min. This increase was largely reversible, and when a second stimulation was applied using aconitine (0.3 mM, 30 min), which acts on voltage-sensitive sodium channels, a second evoked release of NE was observed, of a similar magnitude as that evoked by NMDA. Dizocilpine (300 nM), which blocks cation channels associated with NMDA receptors, prevented the NMDA-elicited NE increase but not the aconitine-elicited increase.