Subpopulations of gastric myenteric neurons are differentially activated via distinct serotonin receptors: Projection, neurochemical coding, and functional implications

The enteric nervous system coordinates various gut functions. Functional studies suggested that neurotransmitters and neuromodulators, one of the most prominent among them being 5-HT, may act through a specific modulation of ascending and descending enteric pathways. However, it is still mostly unknown how particular components of enteric reflex circuits are controlled. This report describes experiments aimed at identifying a differential activation of enteric pathways by 5-HT. Electrophysiological and immunohistochemical methods were combined to investigate the projection pattern and the transmitter phenotype of 5-HT-sensitive gastric myenteric neurons. Of 294 intracellularly labeled neurons, 60.5% showed responses mediated via 5-HT₃ receptors, 11.3% were 5-HT(1P)-responsive, 3.7% exhibited both 5-HT₃ and 5-HT(1P) receptor-mediated depolarization, and 24.5% were not responding to 5-HT. The 5-HT₃-responsive cells were mainly cholinergic (79%) and had ascending projections, whereas the 5-HT(1P)-responsive cells had primarily descending projections and were nitrergic (67%). Substance P- positive neurons were cholinergic; most of the cells (75%) exhibited 5-HT₃ mediated responses and had ascending projections. Muscle strip recordings supported the functional significance of the differential location of 5-HT receptor subtypes. Thus, contractile responses of gastric circular muscle strips were dose-dependently increased by a 5-HT₃ and decreased by a 5- HT(1P) agonist. Results indicated that excitatory ascending enteric pathways consisting of cholinergic, substance Pergic neurons were activated by 5-HT₃ receptors, whereas 5-HT(1P) receptors were involved in activation of inhibitory descending pathways using nitrergic neurons. This suggested that different effects of 5-HT on gastric functions are related to specific- activation of receptors located on different subsets of enteric neurons.