Effect of cholinergic activation by physostigmine on working memory failure caused in rats by pharmacological manipulation of hippocampal glutamatergic and 5-HTergic neurotransmission

The muscarinic receptor antagonist scopolamine significantly increased the number of errors in the working memory task with a three-panel runway setup, when injected bilaterally at 3.2 mu g/side into the dorsal hippocampus. The increase in working memory errors induced by intrahippocampal 3.2 mu g/side scopolamine was reduced by concurrent injection of the cholinesterase inhibitor physostigmine (1.0 and 3.2 mu g/side). However, physostigmine (3.2 mu g/side) did not affect an increase in working memory errors induced by intrahippocampal injection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) at 32 ng/side. Likewise, physostigmine (3.2 mu g/side) was ineffective in reducing an increase in working memory errors caused by intrahippocampal administration of the 5-hydroxytryptamine(1A) (5-HT1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) at 10 mu g/side. These results suggest that the septohippocampal cholinergic activity is necessary for normal working memory processes, but that cholinergic activation neither compensates loss of hippocampal NMDA receptor-mediated neurotransmission nor counteracts the overstimulation of hippocampal 5-HT1A receptors in terms of working memory function.