OBJECTIVE To study the effect of intrahippocampal infusion of interleukin-6 (IL-6) on active avoidance in rats and the possible involvement of nitric oxide (NO). METHODS Using a shuttle-box model, the effects of bilaterally intrahippocampal infusion of IL-6 3.2, 16, and 80 ng as well as sodium nitroprusside (SNP) 400 ng on active avoidance were studied on d 8 after administration. The levels of nitrite as an index of NO in the hippocampus were detected using a fluorometric assay 24 h after infusion of IL-6 3.2 or 80 ng. RESULTS IL-6 16 and 80 ng impaired the acquisition performance of active avoidance by prolonging the latency of avoidance in training, but not the retention performance in testing. IL-680 ng and SNP 400 ng also resulted in a marked impairment in acquisition performances by decreasing the rate of avoidance, but not in retention performances. IL-680 ng markedly elevated the nitrite levels from 10.6 +/- 0.7 in control rats to 13.6 +/- 2.0 (nmol/g wet wt) (P < 0.01). IL-6 3.2 ng had no effect on active avoidance nor on nitrite levels. CONCLUSIONS Intrahippocampal infusion of IL-6 impaired learning acquisition of active avoidance in rats.