Differential effects of 5-HT3 receptor antagonism on working memory failure due to deficiency of hippocampal cholinergic and glutamatergic transmission in rats

The muscarinic acetylcholine receptor antagonist scopolamine significantly increased 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 3.2 μg/side into the dorsal hippocampus. Concurrent infusion of the selective and potent 5-hydroxytryptamine₃ (5-HT₃) receptor antagonist Y-25130 (0.32 and 1.0 μg/side) significantly attenuated the increase in working memory errors induced by intrahippocampal 3.2 μg/side scopolamine. Intrahippocampal Y-25130 (1.0 μg/side) by itself did not affect working memory errors. On the other hand, intrahippocampal administration of the competitive NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) at 32 ng/side caused a significant increase in the number of working memory errors. However, Y-25130 at 1.0 μg/side did not affect the increase in working memory errors when infused intrahippocampally together with 32 ng/side CPP. These results suggest that antagonism of hippocampal 5-HT₃ receptors is ineffective against working memory failure resulting from blockade of NMDA receptor-mediated neurotransmission, but that it can compensate deficiency of septohippocampal cholinergic activity involved in working memory function of rats.