Abstract The 5‐HT4 partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5‐HT4 receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5‐HT4 receptors enhances the release of acetylcholine and calcitonin gene related peptide from stimulated nerve terminals. This action strengthens neurotransmission in prokinetic pathways, enhancing gastrointestinal motility. The knockout of 5‐HT4 receptors in mice not only slows gastrointestinal activity but also, after 1 month of age, increases the age‐related loss of enteric neurons and decreases the size of neurons that survive. 5‐HT4 receptor agonists, tegaserod and RS67506, increase numbers of enteric neurons developing from precursor cells and/or surviving in culture; they also increase neurite outgrowth and decrease apoptosis. The 5‐HT4 receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5‐HT4‐mediated. 5‐HT4 receptor agonists, therefore, are neuroprotective and neurotrophic for enteric neurons. Because the age‐related decline in numbers of enteric neurons may contribute to the dysmotilities of the elderly, the possibility that the neuroprotective actions of 5‐HT agonists can be utilized to prevent the occurrence or worsening of these conditions should be investigated.

2007-05-01·Autonomic neuroscience : basic & clinical4区 · 医学

Wood creosote prevents CRF-induced motility via 5-HT3 receptors in proximal and 5-HT4 receptors in distal colon in rats

4区 · 医学

Article

作者: Takahashi, Toku ; Kuge, Tomoo ; Fujino, Kazunori ; Ataka, Koji ; Fujimiya, Mineko

Wood creosote has been used as an herbal medicine against acute diarrhea caused by food poisoning and has an inhibitory effect on colonic motility and enterotoxin-induced ion secretion. Since no previous studies have examined the effects of wood creosote on stress-induced alteration of colonic motility, we examined the effects on the colonic motility altered by intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF), which is a key mediator in responses to stress. We recorded motor activity in proximal and distal colon of unrestrained conscious rats via two manometory catheters. The frequencies of phase III-like contraction and the % motor indices in both proximal and distal colon were measured. At the same time the number of fecal pellets excreted was counted. I.c.v. injection of CRF increased the motor activity in both proximal and distal colon, and these effects were completely antagonized by i.c.v. injection of a selective CRF type 1 antagonist but not by a CRF type 2 antagonist. Changes in colonic motility induced by CRF were reversed by intravenously administered wood creosote. Intraluminal administration of the 5-HT(3) receptor antagonist granisetron, or the 5-HT(4) receptor antagonist SB 204070 blocked the increase in colonic motility induced by i.c.v. injection of CRF. Wood creosote prevented the increase in colonic motility induced by the 5-HT(3) receptor agonist SR57227A in the proximal colon, while it prevented the increase in colonic motility induced by the 5-HT(4) receptor agonist RS67506 in the distal colon. These results indicate that wood creosote prevents the increase in colonic motility induced by CRF via 5-HT(3) receptors in the proximal colon, and via 5-HT(4) receptors in the distal colon, suggesting that wood creosote might be useful to treat stress-induced diarrhea.

2004-01-01·Journal of pharmacological sciences3区 · 医学

Failure of Repeated Electroconvulsive Shock Treatment on 5-HT4-Receptor-Mediated Depolarization Due To Protein Kinase A System in Young Rat Hippocampal CA1 Neurons

3区 · 医学

ArticleOA

作者: Sasa, Masashi ; Ishihara, Kumatoshi

We previously demonstrated that repeated electroconvulsive shock (ECS) treatment enhanced serotonin (5-HT)(1A)- and 5-HT(3)-receptor-mediated responses in hippocampal CA1 pyramidal neurons. The electrophysiological studies were performed to elucidate the effects of ECS treatment on depolarization, which was an additional response induced by 5-HT, and the second messenger system involved in this depolarization of hippocampal CA1 neurons. Both application of 5-HT (100 microM) induced depolarization of the membrane potential in the presence of 5-HT(1A)-receptor antagonists. This depolarization was mimicked by 5-HT(4)-receptor agonists, RS 67506 (1-30 microM) and RS 67333 (0.1-30 microM), in a concentration-dependent manner. 5-HT- and RS 67333-induced depolarization was attenuated by concomitant application of RS 39604, a 5-HT(4)-receptor antagonist. H-89, a protein kinase A (PKA) inhibitor, inhibited 5-HT-, RS 67506-, and RS 67333-induced depolarizations, while forskolin (10 microM), an activator of adenylate cyclase, induced depolarization. Furthermore, RS 67333-induced depolarization was not significantly different between hippocampal slices prepared from rats administered ECS once a day for 14 days and those from sham-treated rats. These findings suggest that 5-HT(4)-receptor-mediated depolarization is caused via the cAMP-PKA system. In addition, repeated ECS-treatment did not modify 5-HT(4)-receptor functions in contrast to 5-HT(1A)- and 5-HT(3)-receptor functions.

100 项与 RS-67506 相关的药物交易

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