Abstract
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-HT4receptor 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-HT4receptors 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.
Footnotes
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Send reprint requests to: Dr. Machiko Matsumoto, Department of Pharmacology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. E-mail:mbird{at}med.hokudai.ac.jp
- Abbreviations:
- 5-HT
- serotonin
- SC 53116
- 1-(S)-1-exo-4-amino-5-chloro-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-2-methoxybenzamide
- GR 113808
- [1-[2-(methylsulphonylamino)ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate
- BIMU 1
- endo-N-(8-methyl-8-azabicyclo[3.2.1]-oct-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1 carboxamine
- BIMU 8
- endo-N-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H-benzimidalol-1 carboxamide
- RS 67333
- 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone
- RS 17017
- 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)-1-pentanone
- ACh
- acetylcholine
- LTP
- long-term potentiation
- LTPm
- muscarinic long-term potentiation
- Received August 8, 2000.
- Accepted November 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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