Presynaptic modulation of cholinergic and non‐cholinergic fast synaptic transmission in the myenteric plexus of guinea pig ileum

Abstract

These studies investigated receptors modulating release of mediators of fast excitatory postsynaptic potentials (fEPSPs) in guinea pig ileum myenteric plexus using electrophysiological methods. Fast EPSPs inhibited by >95% by hexamethonium (100 micromol L(-1)) were cholinergic; mixed fEPSPs were inhibited <95% by hexamethonium. Non-cholinergic fEPSPs were studied in the presence of hexamethonium. The alpha2-adrenergic receptor agonist UK 14304 inhibited cholinergic (maximum inhibition = 76%, EC(50) = 18 nmol L(-1)), mixed (81%, 21 nmol L(-1)) and non-cholinergic (76%, 44 nmol L(-1)) fEPSPs equally. The 5-HT(1) receptor agonist 5-carboxamidotryptamine inhibited cholinergic, mixed and non-cholinergic fEPSPs equally. Renzapride, increased non-cholinergic (33%) less than mixed (97%, 13 micromol L(-1)) fEPSPs. Renzapride inhibited the purely cholinergic fEPSPs (-29%) but potentiated the cholinergic component of mixed fEPSPs (39%). Prucalopride potentiated all fEPSPs equally (30-33%). 5-HT (0.1 micromol L(-1)) induced potentiation of cholinergic (75%), mixed (97%) and non-cholinergic (84%) fEPSPs was not statistically different. The potentiating effects of renzapride and 5-HT on fEPSPs were inhibited by the 5-HT(4) receptor antagonist, SB 204070 (10 nmol L(-1)). Renzapride (0.3 micromol L(-1)) blocked 5-HT-induced increases in cholinergic fEPSPs. alpha2-Adrenergic and 5-HT(1) receptors mediate inhibition of transmitter release from cholinergic and mixed terminals. 5-HT and prucalopride, acting at 5-HT(4) receptors, facilitate all fEPSPs; renzapride facilitates the cholinergic and non-cholinergic components of mixed fEPSPs but not purely cholinergic fEPSPs. Cholinergic synapses may express few 5-HT(4) receptors or a renzapride-insensitive 5-HT(4) receptor isoform.

Expression and function of 5-HT4receptors in the mouse enteric nervous system

“…5-HT 4 agonists presynaptically increase the release of ACh from electrically stimulated preparations of bowel; this effect is not blocked by the 5-HT 1P antagonist 5-HTP-DP (26 -28, 59). 5-HT 4 receptors also act presynaptically to increase the amplitude of fast EPSPs evoked by stimulating inputs to myenteric neurons (41,65,79,80), an effect that is not shared by 5-HT 1P agonists. Finally, 5-HT 1P activity has been found to stimulate submucosal IPANs (81); moreover, this effect is blocked by 5-HTP-DP and resistant to 5-HT 4 antagonists.…”

“…For example, 5-HT 4 stimulation enhances the amplitude of electrically driven twitches of longitudinal smooth muscle because it increases the release of ACh from motoneurons (27,59,86,92,94). 5-HT 4 stimulation, within the ENS is also excitatory (87) but has been analyzed mainly by using microelectrodes, which have detected an increase in the amplitude of fast EPSPs (41,65,79,93). 5-HT 4 receptor stimulation has also been reported to facilitate peristaltic reflexes by increasing the release of ACh and CGRP from activated submucosal intrinsic primary afferent neurons (IPANs) (37,(47)(48)(49)55).…”

“…To understand these functions, it is thus necessary to identify the subtypes of 5-HT receptor that are expressed in the gut and to determine their locations and actions. The 5-HT receptors that are known to be expressed by enteric neurons include 5-HT 1A (40,60,61), 5-HT 2A (13,35), 5-HT 2B (14,36), 5-HT 3 (29,67,69,102), and 5-HT 4 (26,27,41,59,65,79). In addition to these, another 5-HT receptor activity, called 5-HT 1P , has been identified in the enteric nervous system (ENS) (15,69).…”

Enteric Nervous System: Neuropathic Gastrointestinal Motility

“…Pharmacologic interest in 5-HT 4 receptors stems from specific investigative findings that enteric neurons express the mRNA transcript that encodes the 5-HT 4 receptor and that immunohistochemical methods show ENS neuronal surface expression of the receptor in mice and guinea pigs [84,85]. Exposure to 5-HT 4 receptor agonists enhances fast excitatory postsynaptic potentials at nicotinic synapses in ENS microcircuits of guinea pigs and mice [84,86,87]. Release of neurotransmitters associated with peristaltic propulsion (e.g., acetylcholine, substance P, vasoactive intestinal peptide, nitric oxide) is initiated by stimulation of 5-HT 4 receptors [88].…”

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

“…In a recent study of the development of the mouse enteric nervous system [313], almost all enteric neurons responded to ATP early at E11.5, E12.5, E15.5 and E18.5, and receptors for ATP were expressed early in E11.5 cultures, followed by the appearance of receptors to 5-hydroxytryptamine (5-HT). ATP is released together with ACh from the majority of presynaptic terminals [436].…”