Metabotropic 5-HT receptor-mediated effects in the human submucous plexus

Background: Serotonin (5-HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5-HT receptors. The ionotropic 5-HT₃ receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5-HT_1P, 5-HT₄, and 5-HT₇ receptors to activate human submucous neurons. Methods: Neuroimaging using the voltage sensitive dye Di-8-ANEPPS was performed in submucous plexus preparations from human surgical specimens of the small and large intestine. We synthesized a new, stable 5-HT_1P agonist, 5-benzyloxyhydrazonoindalpine (5-BOHIP). Key Results: 5-HT evoked a fast and late-onset spike discharge in enteric neurons. The fast component was blocked by the 5-HT₃ receptor antagonist cilansetron, while the remaining sustained response was significantly reduced by the 5-HT_1P receptor antagonist 5-hydroxytryptophanyl-5-hydroxytryptophan amide (5-HTP-DP). The newly synthesized 5-HT_1P agonist 5-BOHIP induced a slowly developing, long-lasting activation of submucous neurons, which was blocked by 5-HTP-DP. We could not demonstrate any 5-HT₇ receptor-induced spike discharge based on the lack of response to 5-carboxamidotryptamine. Similarly, the 5-HT₄ agonists 5-methoxytryptamine and prucalopride evoked no immediate or late-onset spike discharge. Conclusions & Inferences: Our work demonstrated for the first time the presence of functional 5-HT_1P receptors on human submucous neurons. Furthermore, we found no evidence for a role of 5-HT₄ or 5-HT₇ receptors in the postsynaptic activation of human submucous neurons by 5-HT.