Serotonin, a crucial neurotransmitter synthesized by enterochromaffin cells, plays a cardinal role in regulating gastrointestinal (GI) motility. With over 90% of the body's total serotonin in the GI tract, its influence on digestive processes is profound. Serotonin is swiftly released upon various stimuli, such as food boluses or certain drugs, triggering intrinsic sensory neurons in the myenteric plexus and extrinsic vagal and spinal sensory neurons. This leads to the activation of the peristaltic reflex, a wave-like muscle contraction that propels food along the digestive tract.

The Enteric Nervous System (ENS), a complex network of neurons within the walls of the GI tract, is replete with diverse serotonin receptors, including 5-HT_1p, 5-HT₄, and 5-HT₃. 5-HT_1p and 5-HT₄ receptors on intrinsic sensory neurons, while 5-HT₃ receptors on extrinsic neurons are implicated in the peristaltic reflex.

Additionally, serotonin receptor activation also stimulates the release of other neurotransmitters. For instance, activated 5HT₁ receptors at the gastric fundus generate nitric oxide (NO), which results in smooth muscle relaxation. Another example is 5-HT4 receptors on excitatory motor neurons. When stimulated, they enhance acetylcholine (ACh) release at neuromuscular junctions, leading to high-amplitude propagating contractions (HAPC) in the proximal colon. These are characterized by contractions in longitudinal muscles and relaxation of circular muscles.

Recognizing the pivotal role of serotonin receptors in GI motility has paved the way for developing serotonin receptor agonists as potential therapeutic agents for GI disorders. Cisapride (Propulsid), tegaserod (Zelnorm), and prucalopride (Resolor) are typical examples of serotonin receptor agonists. However, cisapride can lead to fatal cardiac arrhythmias and is available only via a limited-access protocol in the United States. Also, tegaserod is only available as an emergency investigational new drug.

Prucalopride, a high-affinity 5-HT4 agonist, has been approved for chronic constipation treatment in women, mainly in Europe and Canada. By increasing the strength and number of colonic HAPCs, prucalopride reduces fecal transit time through the colon. However, its use can lead to adverse effects such as nausea, abdominal pain, and diarrhea.