D-cycloserine, a glycine site agonist, reverses working memory failure by hippocampal muscarinic receptor blockade in rats.

D-Cycloserine, a partial agonist at the glycine binding site on the NMDA receptor/channel complex, did not affect the number of errors (attempts to pass through two incorrect panels of the three-panel gates at four choice points) in the working memory task with a three-panel runway setup, when injected bilaterally at 1 or 10 microg/side into the dorsal hippocampus. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine (3.2 microg/side) significantly increased the number of working memory errors. The increase in working memory errors induced by intrahippocampal 3.2 microg/side scopolamine was significantly reduced by concurrent infusion of 1 and 10 microg/side D-cycloserine. These results suggest that positive modulation of the NMDA receptor/channel through activation of the glycine site can compensate dysfunction of hippocampal cholinergic neurotransmission involved in working memory function.