Interleukin-1beta at doses of 32 and 100 ng/side, injected bilaterally into the dorsal hippocampus of rats, significantly increased the working memory errors in a three-panel runway setup, whereas interleukin-1beta at doses affecting working memory errors had no effect on the number of errors in the first trial or the latency. The increase in working memory errors induced by intrahippocampal administration of 100 ng/side interleukin-1beta was significantly decreased by concurrent injection (300 ng/side) of the interleukin-1 receptor antagonist. The cholinesterase inhibitor physostigmine at a dose of 3.2 microg/side and D-cycloserine (1.0 and 10 microg/side), which is a partial agonist acting at the glycine binding site of the NMDA receptor/channel complex, reduced the increase in working memory errors induced by 100 ng/side interleukin-1beta. These results suggest that interleukin-1beta causes disruptions of septohippocampal cholinergic and glutamatergic transmission via its high-affinity receptor, which underlie the impairment of working memory.