Nonpeptide Neurotransmitters effects on motility and associated medications

Cholinergics – Acetylcholine (ACh)

Primary stimulant of GI motility
Synthesized by choline acetyltransferase in parasympathetic neurons
Receptors:
- M2: ↓ cAMP → excitation
- M3: ↑ Ca²⁺ → contraction
Terminated by acetylcholinesterase
Also increases secretions, dilates arterioles, and releases enteric hormones
Medications:
- Atropine, Dicyclomine – IBS-D
- Bethanechol – Gastroparesis, GER
- Neostigmine, Pyridostigmine – Colonic pseudo-obstruction

Adrenergics – Norepinephrine

Primary inhibitor of GI motility
Synthesized by tyrosine hydroxylase and dopamine β-hydroxylase
Receptors:
- α1: ↑ Ca²⁺ → sphincter contraction
- α2: ↓ ACh release
- β: ↑ cAMP → smooth muscle relaxation
Terminated by reuptake and monoamine oxidase
Also constricts arterioles and inhibits secretion
Medications: Adrenergic drugs may cause GI side effects

Serotonin (5-HT)

Stimulates GI transit and motor patterns
Synthesized by tryptophan hydroxylase
Receptors:
- 5-HT3: Excitatory ligand-gated channels
- 5-HT4: GPCRs promoting motility
Terminated by serotonin reuptake transporter
Also mediates secretion, vasodilation, and pain perception
Medications:
- Alosetron, Cilansetron – IBS-D
- Ondansetron, Granisetron – Nausea/Vomiting
- Metoclopramide – Delayed gastric emptying
- Tegaserod, Cisapride – Withdrawn due to CV risks
- Prucalopride, Naronapride, Velusetrag – Investigational

Dopamine

Inhibits esophageal and gastroduodenal motility
Synthesized by tyrosine hydroxylase
Receptors: D2 (↓ cAMP → relaxation)
Terminated by dopamine transporter
Also suppresses cholinergic activity and activates CNS vomiting center
Medications:
- Metoclopramide – D2 antagonist
- Domperidone – Peripheral D2 antagonist

Nitric Oxide (NO)

Inhibitory neurotransmitter for sphincter relaxation
Synthesized by NO synthase
Receptors: NO-sensitive guanylyl cyclase (↑ cGMP)
Terminated rapidly as a free radical
Also regulates secretion, blood flow, and immunity
Medications: Inhaled NO has no significant GI effects

Purinergics – ATP, ADP, Adenosine

Inhibit smooth muscle via fast IJP
Receptors:
- P2X: Excitatory ionotropic
- P2Y: Inhibitory GPCRs
Terminated by uptake or hydrolysis
Also mediate secretion and vasoconstriction
Medications: Clopidogrel binds purinoceptors; GI effects unclear

Amino Acids – GABA and Glutamate

GABA

Modulates colonic peristalsis
Receptors:
- GABAA/C: Excitatory
- GABAB: Inhibitory
Medications:
- Baclofen – ↓ transient LES relaxations
- Lesogaberan – Investigational

Glutamate

Enhances cholinergic motility
Receptors:
- NMDA: ↑ NO-dependent ACh release
- Metabotropic: ↑ vagal tone
Medications: Monosodium glutamate – Off-label for gastroparesis

GI Neurotransmitters and Medications

Nonpeptide Neurotransmitters Modulating GI Motility

Neurotransmitter	Medication(s)	Mechanism of Action	Clinical Use/Indication
Acetylcholine	Atropine, Dicyclomine	Muscarinic receptor antagonists (M2/M3)	IBS-D (reduce motility and secretions)
Acetylcholine	Bethanechol	Muscarinic receptor agonist (M3)	Gastroparesis, GER (enhance motility)
Acetylcholine	Neostigmine, Pyridostigmine	Acetylcholinesterase inhibitors (↑ ACh availability)	Acute colonic pseudo-obstruction (Ogilvie syndrome)
Norepinephrine	Adrenergic drugs (varied)	α1: sphincter contraction; α2: ↓ ACh release; β: smooth muscle relaxation	May cause constipation, ileus, sphincter dysfunction
Serotonin (5-HT)	Alosetron, Cilansetron	5-HT3 receptor antagonists	IBS-D (reduce motility and visceral sensitivity)
Serotonin (5-HT)	Ondansetron, Granisetron	5-HT3 receptor antagonists	Nausea and vomiting (central and enteric blockade)
Serotonin (5-HT)	Metoclopramide	5-HT4 agonist; 5-HT3 and D2 antagonist	Delayed gastric emptying, nausea
Serotonin (5-HT)	Tegaserod, Cisapride	5-HT4 receptor agonists	IBS-C, gastroparesis (withdrawn due to CV risk)
Serotonin (5-HT)	Prucalopride, Naronapride, Velusetrag	Selective 5-HT4 receptor agonists	Chronic idiopathic constipation, gastroparesis (investigational)
Dopamine	Metoclopramide	D2 receptor antagonist	Gastroparesis, nausea (central and peripheral effects)
Dopamine	Domperidone	Peripheral D2 receptor antagonist	Gastroparesis (fewer CNS effects; risk of prolactinemia)
Nitric Oxide	—	Activates guanylyl cyclase → ↑ cGMP → smooth muscle relaxation	Sphincter relaxation; no significant GI drug interactions
Purinergics (ATP, ADP)	Clopidogrel	P2Y receptor antagonist (antiplatelet)	Unknown GI effects; theoretical modulation of purinoceptors
GABA	Baclofen	GABAB receptor agonist	GERD (reduces transient LES relaxations)
GABA	Lesogaberan	GABAB receptor agonist (investigational)	GERD (fewer CNS effects)
Glutamate	Monosodium glutamate	NMDA and metabotropic receptor activation	Gastroparesis (off-label use)