Vol. 296, Issue 3, 676-682, March 2001

Evidence for Involvement of Central 5-HT₄ Receptors in Cholinergic Function Associated with Cognitive Processes: Behavioral, Electrophysiological, and Neurochemical Studies

Machiko Matsumoto, Hiroko Togashi, Kiyoshi Mori, Ken-ichi Ueno, Satoshi Ohashi, Taku Kojima and Mitsuhiro Yoshioka

Departments of Pharmacology (M.M., H.T., K.M., K.-i.U., S.O., M.Y.) and Anesthesiology (T.K.), Hokkaido University School of Medicine, Sapporo, Japan

The possible involvement of 5-HT₄ 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-HT₄ receptor agonist SC 53116 (10 µg/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 µg/rat i.c.v.) enhanced the population spike amplitude in the hippocampal CA1 field evoked by Schaffer collateral stimulation. SC 53116 (10 µg/rat i.c.v.) also augmented the tetanus-induced long-term potentiation (LTP). This augmented LTP was blocked not only by the selective 5-HT₄ receptor antagonist GR 113808 (20 µg/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-HT₄ 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 µM) concentration-dependently enhanced the extracellular levels of acetylcholine (ACh) in the hippocampus. SC 53116-induced (10 µM) facilitation of ACh release was prevented by coperfusion of GR 113808 (10 µM). Taken together, the present findings obtained by these different approaches indicate the possibility that the 5-HT₄ receptors are involved in cognitive impairment induced by the cholinergic neuronal system.