Evidence for involvement of central 5-HT(4) receptors in cholinergic function associated with cognitive processes: behavioral, electrophysiological, and neurochemical studies.

The possible involvement of 5-HT(4) receptors in cognitive function was investigated with a view toward modulating the cholinergic neuronal system. For this purpose, behavioral, electrophysiological, and neurochemical studies were performed in rats. The behavioral study, using a passive avoidance test, demonstrated that the 5-HT(4) receptor agonist SC 53116 (10 microg/rat i.c.v.) had an ameliorative effect on the muscarinic receptor antagonist scopolamine-induced (1 mg/kg i.p.) impairment of learning. The electrophysiological study showed that SC 53116 (1 and 10 microg/rat i.c.v.) enhanced the population spike amplitude in the hippocampal CA1 field evoked by Schaffer collateral stimulation. SC 53116 (10 microg/rat i.c.v.) also augmented the tetanus-induced long-term potentiation (LTP). This augmented LTP was blocked not only by the selective 5-HT(4) receptor antagonist GR 113808 (20 microg/rat i.c.v.) but also by scopolamine (1 mg/kg i.p.). These findings suggest that the functional interaction between the serotonergic system mediated via 5-HT(4) receptors and the cholinergic system associated with cognitive processes exists in vivo. This possibility was further strengthened by neurochemical study using in vivo microdialysis; local administration of SC 53116 (10 and 100 microM) concentration-dependently enhanced the extracellular levels of acetylcholine (ACh) in the hippocampus. SC 53116-induced (10 microM) facilitation of ACh release was prevented by coperfusion of GR 113808 (10 microM). Taken together, the present findings obtained by these different approaches indicate the possibility that the 5-HT(4) receptors are involved in cognitive impairment induced by the cholinergic neuronal system.