Serotonin
5-HT is a key mediator of sensory and motor function in the GI tract, and >95% of 5-HT in the body is contained within the enteric nervous system.
Here is a simplified explanation for the effects of 5HT3 antagonists and 5HT4 agonists.
One of the major roles for serotonin in the gut is thought to be regulation of the peristaltic reflex, which consists of both PROXIMAL CONTRACTION and DISTAL RELAXATION. In both cases, 5HT primarily acts on vagal afferents, which subsequently invoke a complicated reflex loop (which I simplified considerably by having the 5HT “neuron” act directly on the ACh and NANC neurons). It’s also important to consider that the phrases “smooth muscle contraction” and “GI motility” (i.e., co-ordinated muscle contractions) are not necessarily synonymous.
First, the easier to understand stuff.
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PROXIMALLY, stimulation of 5HT4 receptors à stimulation of vagal afferents à activation of interneurons containing ACh and/or CGRP à stimulation of ACh motoneurons à increased contactility.
- This means that administration of 5HT4 agonists (like CISAPRIDE and TEGASEROD) promote gastric emptying and speed up small and large bowel transit by stimulating ACh-containing motor neurons (à good things for the treatment of constipation-predominant IBS).
Now for the tough stuff.
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DISTALLY, stimulation of 5HT3 receptors à stimulation of vagal afferents à activation of interneurons containing nitric oxide or VIP à inhibition of ACh motoneurons à decreased contractility à passage of food bolus.
- This means that administration of 5HT3 antagonists (like ONDANSETRON and ALSOETRON) increase distal contraction, which interferes with the timing of the peristaltic reflex. The net result of this is a decrease in the “effectiveness” of colonic motility and an increase in total transit time (à benefits for the treatment of diarrhea-predominant IBS). During vomiting, interference with reverse peristalsis is thought to be due to a similar interruption in effective segmentation.
ABSOLUTE BOTTOM LINE:
5HT4 agonists increase GI motility (decrease transit time)
5HT3 antagonists increase contractility but decrease co-ordination (increase transit time)