Role of Acetylcholine in the Nervous System
Acetylcholine functions as both a primary neurotransmitter and a critical neuromodulator throughout the central, peripheral, and autonomic nervous systems, controlling neuromuscular transmission, cognitive functions, and autonomic regulation through muscarinic and nicotinic receptor activation. 1
Fundamental Neurotransmission Mechanisms
Acetylcholine operates at the neuromuscular junction where approximately 500,000 ACh-filled vesicles are stored in presynaptic nerve terminals, releasing neurotransmitter across a 30-nm synaptic gap to bind with up to 10,000 acetylcholine receptors per μm² on the muscle fiber sarcolemma. 1
Acetylcholinesterase in the synaptic cleft rapidly hydrolyzes acetylcholine into choline and acetate, terminating muscle contraction and preventing continuous receptor stimulation. 1
Choline acetyltransferase (ChAT) synthesizes acetylcholine in neuronal cytoplasm, with choline availability serving as the rate-limiting factor for ACh production. 2
Receptor Systems and Physiological Effects
Muscarinic Receptor Actions
Muscarinic receptor activation controls visceral smooth muscle, cardiac muscle, and secretory glands, producing effects including:
- Cardiovascular: Bradycardia, heart block, QT prolongation, arrhythmias, and hypotension 1
- Respiratory: Bronchorrhea, bronchospasm, and increased airway secretions 1
- Gastrointestinal: Hypermotility causing nausea, vomiting, abdominal cramps, and severe diarrhea 1
- Secretory: Excessive lacrimation, salivation, and perspiration 1
- Urinary: Urinary incontinence 1
Nicotinic Receptor Actions
Nicotinic receptor stimulation affects autonomic ganglia and skeletal muscle, producing:
- Initial involuntary fasciculations followed by weakness and flaccid paralysis 1
- Respiratory muscle paralysis 1
- Initial sympathetic hyperstimulation causing tachycardia and hypertension before muscarinic effects dominate 1
Central Nervous System Modulation
Acetylcholine in the CNS modulates cognitive functions including long-term and short-term memory, limbic activation, and alertness, altering neuronal excitability and inducing synaptic plasticity. 3, 4
ACh coordinates firing of neuronal networks throughout the brain, potentiating behaviors adaptive to environmental stimuli while decreasing responses to non-urgent ongoing stimuli. 4
Central accumulation of ACh causes anxiety, disorientation, generalized convulsions, and coma in pathological states. 1
Clinical Significance in Neurological Disorders
Receptor Dysregulation States
Up-regulation of acetylcholine receptors increases sensitivity to ACh and decreases sensitivity to neuromuscular blocking agents, occurring in motor neuron lesions, burns, muscle atrophy from disuse, severe trauma, or prolonged ICU neuromuscular blockade. 1
Down-regulation manifests as increased sensitivity to neuromuscular blocking agents, exemplified by myasthenia gravis where antibodies to acetylcholine receptors reduce functional receptor density. 1
Cholinergic Dysfunction in Neurodegenerative Disease
Altered ACh levels and modified receptor expression occur in Alzheimer's, Parkinson's, and Huntington's diseases, with cognitive, behavioral, and motor disabilities correlating to cholinergic circuit dysfunction. 5
- Cholinesterase inhibitors (donepezil, galantamine, rivastigmine) remain first-line treatment for Alzheimer's disease, working through reversible inhibition of acetylcholinesterase to increase ACh concentration. 6, 2
Pathological Acetylcholine Excess
Organophosphate pesticides and nerve agents (e.g., sarin) irreversibly bind and inhibit acetylcholinesterase, causing rapid ACh accumulation at muscarinic and nicotinic receptors with intense postsynaptic cholinergic stimulation. 1
Critical Management Algorithm
Immediate atropine administration (1-2 mg IV for adults, 0.02 mg/kg for children) serves as gold standard therapy, doubling the dose every 5 minutes until bronchorrhea, bronchospasm, and bradycardia resolve. 7
Pralidoxime (2-PAM) or obidoxime must be given promptly (1-2 g IV initially, then 400-600 mg/hour maintenance) to reactivate acetylcholinesterase before irreversible "aging" occurs. 7
Benzodiazepines (midazolam 0.05-0.1 mg/kg IV or diazepam 0.2 mg/kg IV) control seizures and facilitate mechanical ventilation. 1, 7
Critical Pitfall
Avoid succinylcholine and mivacurium for intubation in organophosphate poisoning, as these agents are metabolized by cholinesterase and will have prolonged, unpredictable effects. 7 All cholinesterase inhibitors used therapeutically (neostigmine, pyridostigmine, edrophonium) similarly prolong neuromuscular blockade with these agents. 6
Non-Neuronal Acetylcholine Functions
ACh exists in epithelial cells (airways, alimentary tract, urogenital tract), endothelial and muscle cells, and immune cells (granulocytes, lymphocytes, macrophages), regulating basic cell functions including mitosis, differentiation, cytoskeleton organization, and immune function in an autocrine and paracrine manner. 8