Cholinergic and glutamatergic activation reverses working memory failure by hippocampal histamine H1 receptor blockade in rats

Intrahippocampal administration of the histamine H-1 receptor antagonist pyrilamine (3.2-32 mu g/side) but not the histamine H-2 receprtor antagonist cimetidine (1.0-10 mu g/side) increased the number of errors in the working memory task with a three-panel runway setup. The increase in working memory errors induced by intrahippocampal 32 mu g/side pyrilamine was significantly reduced by concurrent infusion of the histamine H-1 receptor agonist 2-pyridylethylamine (3.2 and 10 mu g/side). The cholinesterase inhibitor physostigmine (1.0 and 3.2 mu g/side) and D-cycloserine (0.32 and 1.0 mu g/side), the partial agonist at the glycine binding site on the NMDA receptor/channel complex, reduced the increase in working memory errors induced by intrahippocampal 32 mu g/side pyrilamine. These results suggest that the hippocampal histaminergic activity via histamine H-1 receptor is necessary for normal working memory processes and that the septohippocampal cholinergic activation and positive modulation of the NMDA receptor/channel through activation of the glycine site can alleviate dysfunction of hippocampal histamine H-1 receptor-mediated neurotransmission involved in working memory function. (C) 2000 Elsevier Science Inc. All rights reserved.