What is the role of acetylcholine (ACh) neurotransmitter in the nervous system?

Role of Acetylcholine Neurotransmitter

Acetylcholine (ACh) is a critical regulatory neurotransmitter that functions throughout the central, peripheral, and autonomic nervous systems, acting both as a direct neurotransmitter and as a modulator of other neurotransmitters, with no mammalian physiological process able to commence without its participation. 1

Distribution and Fundamental Functions

• ACh operates across all major divisions of the nervous system: central nervous system (CNS), peripheral nervous system, and both sympathetic and parasympathetic branches of the autonomic system 1
• In the CNS specifically, ACh modulates cognitive functions including long-term and short-term memory, limbic activation, and alertness 1
• Beyond neurotransmission, ACh regulates cell proliferation during embryogenesis and controls neuron and glial cell survival and differentiation 2

Receptor-Mediated Effects

ACh exerts its physiological effects through two distinct receptor classes, each producing different clinical manifestations:

Muscarinic Receptor Actions

• Cardiovascular effects: Initial sympathetic hyperstimulation (tachycardia, hypertension) followed by muscarinic activation causing bradycardia, heart block, QT prolongation, arrhythmias, and hypotension 3
• Respiratory system: Laryngeal and upper airway irritation, bronchorrhea, bronchospasm, and pulmonary edema 3
• Gastrointestinal tract: Hypermotility causing nausea, vomiting, abdominal cramps, and severe diarrhea 3
• Secretory glands: Excessive lacrimation, salivation, and perspiration (the latter secondary to ganglionic stimulation) 3
• Urinary tract: Urinary incontinence 3
• Visceral smooth muscle and cardiac muscle are influenced through muscarinic hyperstimulation 3

Nicotinic Receptor Actions

• Skeletal muscle effects: Involuntary fasciculation followed by weakness and flaccid paralysis 3
• Respiratory muscle paralysis occurs through nicotinic effects 3
• Autonomic ganglia are affected through nicotinic hyperstimulation 3
• Constant nicotinic receptor activation generates involuntary skeletal muscle contractions followed by complete depolarization-like block 3

Central Nervous System Functions

• Sleep regulation: ACh plays a key role in transitions between sleep phases, with slow-wave sleep requiring low ACh concentrations while rapid-eye-movement (REM) sleep is associated with high ACh levels 4
• Cognitive and behavioral modulation: ACh influences cognition, sleep, arousal, motivation, reward, and pain processing 5
• CNS accumulation effects: When ACh accumulates in the CNS, it causes anxiety, disorientation, general convulsions, and coma 3

Synthesis and Regulation

• Neurons cannot synthesize choline, which must be derived from the diet and delivered through the bloodstream 6
• Presynaptic choline transport supports ACh production and release through a unique high-affinity choline transporter critical for neurotransmitter release 6
• ACh hydrolysis by acetylcholinesterase breaks down ACh into choline and acetyl coenzyme A, with approximately 50% of choline recovered by the high-affinity transporter for reuse 6
• Choline must be incorporated and stored into phospholipids in the brain to serve for ACh biosynthesis 6

Clinical Significance in Disease States

• Neurodegenerative diseases: Altered ACh levels or modified receptor expression and function occur in Alzheimer's, Parkinson's, and Huntington's diseases, with cognitive, behavioral, and motor disabilities correlating to cholinergic circuit dysfunction 2
• Psychiatric disorders: Cholinergic dysfunction has been described in schizophrenia 2
• Inflammatory modulation: ACh functions as a modulator of inflammation both within and outside the nervous system, with altered function potentially representing an additional pathogenetic mechanism in diseases like multiple sclerosis 2
• Brainstem abnormalities: Medullary serotonergic system dysfunction involving ACh interactions has been implicated in up to 70% of SIDS cases, with prenatal nicotine exposure altering nicotinic acetylcholine receptor expression in brainstem regions important for autonomic function 3

Developmental and Non-Neuronal Roles

• Prenatal exposure effects: Cigarette smoke or nicotine exposure during fetal development alters nicotinic acetylcholine receptor expression in brainstem areas important for autonomic function and increases vulnerability to sudden infant death syndrome 3
• Non-neuronal tissues: ACh and its receptors are distributed in many tissues beyond the nervous system, with emerging physiological roles in various pathologies 2