The effects of local administration of interleukin-1 (IL-1) were studied by using an intracerebral microdialysis technique in rats. A local injection of IL-1 (3 and 10 ng) induced an elevation of norepinephrine (NE) concentration in the medial prefrontal cortex (mPFC). IL-1-receptor antagonist (800 ng) completely blocked the IL-1-induced NE increase. Diclofenac, a cyclooxygenase inhibitor (500 µM), and N-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor (100 µM), applied through the dialysis probe, did not affect the initial rise in NE levels observed 20 min after injection of IL-1 but completely suppressed the late phase of IL-1-induced NE increase at 40 min and thereafter. In contrast, local perfusion of 6-cyno-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartic acid (NMDA) glutamate-receptor antagonist (50 µM), but not DL-2-amino-5-phosphonovaleric acid, an NMDA-receptor antagonist (100 µM), blocked both phases of IL-1-induced NE increase. Furthermore, a microinjection of IL-1 elevated the extracellular concentration of glutamate in the mPFC. These findings suggest that the IL-1-induced rise in NE levels in the mPFC is caused by activation of the glutamatergic system and the glutamate-induced increases in prostanoids and NO.