Acetylcholine (ACh) is a neurotransmitter present in vertebrates and insects. It plays a role in memory formation, arousal, attention and certain forms of learning in the CNS. It is the neurotransmitter in all autonomic ganglia and the final neurotransmitter of the parasympathetic nervous system. It is also the neurotransmitter at the neuromuscular junction, the synapse between motor neurons and skeletal muscle. Acetylcholine is produced in cholinergic neurons by the enzyme choline acetyltransferase from choline and acetyl coenzyme A. Acetylcholine receptors can be G-protein linked muscarinic receptors or nicotinic ligand-gated ion channels. Acetylcholine is quickly broken down by the enzyme acetylcholinesterase in the synaptic cleft. Several groups of various drugs and substances affects acetylcholine system: Cholinesterase inhibitors used to treat dementia, anticholinergics used to treat parkinsonism, certain antidepressants and antipsychotics, and nicotine, to mention a few.
Acetylcholine production and release
Acetylcholine (ACh) is produced in cholinergic neurons from the precursors choline and acetyl coenzyme A (ACoA) by the enzyme choline acetyltransferase (ChAT), with coenzyme A as a byproduct. Choline is an important nutrient found in food, but certain amounts can also be produced in the body from the α-amino acid serine with vitamin B12 and folate as cofactors. Acetyl coenzyme A is produced in mitochondria during glycolysis and fatty acid oxidation. Acetylcholine is packed into synaptic vesicles by the vesicular acetylcholine transporter (VAChT). Acetylcholine is stored until a neuronal impulse signals its release into the synaptic cleft, where it can bind to a range of muscarinic or nicotinic acetylcholine receptors.
Acetylcholine termination of action and metabolism
Acetylcholine’s signaling action in the synaptic cleft is quickly terminated by enzymatic destruction. Acetylcholinesterase (AChE) is present in high amount in cholinergic synapses and converts acetylcholine to choline (Ch) and acetate (A). The enzyme is also present inside cholinergic neruons, in red blood cells, platelets, lymphocytes, the gut and skeletal muscle. Butyrylcholinesterase (BuChE), which is sometimes referred to as “pseudocholinesterase”, is also able to break down acetylcholine into choline and acetate. Butyrylcholinesterase is found in glial cells, liver, plasma, gut and skeletal muscle. AChE is the key enzyme for inactivating ACh in cholinergic synapses, but BuChE can take on this activity if ACh diffuses to nearby astroglia. A choline transporter (ChT) on cholinergic neurons moves choline back into the presynaptic neuron for resynthesis into acetylcholine. No acetylcholine transporter exists due to the quick enzymatic breakdown of acetylcholine.
Acetylcholine receptors are divided into two major subtypes, muscarinic receptors and nicotinic receptors. These subtypes are thus named as muscarinic receptors are stimulated by the mushroom alkaloid muscarine and nicotinic receptors are stimulated by the tobacco alkaloid nicotine. Muscarine receptors are all G-protein linked receptors, while nicotinic receptors are all ligand-gated excitatory ion channels. Nicotinic receptors are blocked by curare, while many muscarinic receptors are blocked by so-called anticholinergics, e.g. atropine and scopolamine. There are five different muscarinic receptors, named M1-M5. Nicotinic receptors are made up of five subunits arranged around a central pore and are classified as muscle- or neuronal-type depending on their primary site of expression. A huge number of possible variations exists. Four important configurations are mentioned below. Positive allosteric modulators (PAMs) have been identified for nicotinic cholinergic receptors in the brain, including the cholinesterase inhibitor galantamine.
Muscarine 1 cholinergic receptor (M1-receptor)
M1-receptors are postsynaptic and important to the regulation of memory function and arousal in the CNS. M1-receptors also mediate slow exitatory postsynaptic potential at postganglionic nerves, which increases the likelihood of triggering an action potential. M1-receptors are also found in exocrine glands. They are Gq protein coupled receptors, which activates phospolipase C, producing the second messengers DAG and IP3, with increased intracellular calcium as one of the downstream results, making it an exitatory receptor.
Muscarine 2 cholinergic receptor (M2-receptor)
M2-receptors are presynaptic autoreceptors, providing negative feedback to the cholinergic neuron. They are Gi/o protein coupled receptors, which results in decreased amounts of the second messenger named cAMP in the cell, making it an inhibitory receptor. M2 receptors are also located in the heart, where its function is to return the hearth to normal sinus rhythm and function after sympathetic stimulation.
Muscarine 3/4/5 cholinergic receptor (M3/M4/M5-receptor)
M3 & M5 are Gq protein coupled receptors like the M1-receptor, while M4 is a Gi/o protein coupled receptors like the M2 receptor. M3-receptors are expressed at many locations, including blood vessels and in the lungs, and may mediate some of the peripheral side effects from anticholinergics.
Nicotinic (∝1)2β1δε and (α1)2βδγ cholinergic receptor
Nicotinic (∝1)2β1δε and (α1)2βδγ-receptors are muscle type receptors found in the neuromuscular junction between an alpha motor neuron and skeletal muscle fiber. They are responsible for the end plate potentials, or depolarization, of skeletal muscle.
Nicotinic (∝4)2(β2)3 cholinergic receptor
Nicotinic (∝4)2(β2)3 receptors are ganglion type receptors found in autonomic ganglia, both sympathetic and parasympathetic, that mediate the excitatory postsynaptic potential.
Nicotinic (∝4)2(β2)3 cholinergic receptor
Nicotinic receptors made up of two α4 and three β2 subunits, (α4)2(β2)3-receptors, are postsynaptic receptors that play an important role in regulating dopamine release in the nucleus accumbens. It is likely the primary receptor causing the rewarding effects of nicotine.
Nicotinic (α7)5 cholinergic receptor
Nicotinic receptors made up of only α7 subunits, (α7)5-receptors, are found as presynaptic autoreceptors or postsynaptic heteroreceptors in the CNS. As autoreceptors they seem to facilitate the release of acetylcholine in a feed-forward release process. As heteroreceptors they facilitate the release of neurotransmitter on the neuron they are located on. α7-receptors are involved in the pro-cognitive effects of nicotine.
Cholinergic cell bodies in the brainstem project from the pedunculopontine nucleus and laterodorsal tegmental nucleus to the prefrontal cortex, basal forebrain, thalamus, hypothalamus, amygdala and hippocampus. Cholinergic cell bodies in the basal forebrain project from the basal optic nucleus of Meynert and the medial septal nucleus to the prefrontal cortex, amygdala and hippocampus and are thought to be particularly important for memory. Acetylcholine is also involved in arousal, attention and certain forms of learning in the CNS. It is the neurotransmitter found in autonomic ganglia and the final neurotransmitter of the parasympathetic nervous system. The vagus nerve innervate several ganglia in the thorax and abdomen that provide parasympathetic supply to organs in close proximity here. The pelvic splanchnic nerves arise from spinal nerve 2-4 and provide innervation of the inferior hypogastric plexus that provide parasympathetic supply to the pelvic and genital organs. Cranial nerve III, VII and IX innervate the ciliary, pterygopalatine, otic and submandibular ganglia that provide parasympathetic supply through branches of the trigeminal nerve. All motor neurons that innervate skeletal muscle are cholinergic and release neurotransmitter acetylcholine at the neuromuscular junction. The cell body of alpha motor neurons are found in the anterior grey column (also called the ventral horn) of the spinal cord, with the exception of the alpha motor neurons innervating the head and neck, which are found in the brainstem in cranial nerve motor nuclei.
Several different classes of medical (and some recreational) drugs affect the body’s acetylcholine receptors:
Cholinergic projections from the nucleus basalis of Meynert throughout the cortex are vital for mediating memory formation. Degeneration of these neurons are thought to be at least partly responsible for the memory disruption in Alzheimer’s disease. Boosting cholinergic functioning with cholinesterase inhibitors can enhance memory function in some and at least slow the decline of function in Alzheimer’s patients, at least in the early stages of the disease. Cholinesterase inhibitors can be selective for acetylcholinesterase or target both acetylcholinesterase and butyrylcholinesterase.
The term anticholinergics usually refer to muscarinic acetylcholine receptor blockers. Anticholinergics are used to treat both symptoms of Parkinson’s disease and extrapyramidal side effect of antipsychotic medications. Dopaminergic neurons in the substantia nigra project to cholinergic neurons in the striatum, where activation of postsynaptic D2-receptors inhibit the neurons and reduce the release of acetylcholine. Reduced dopaminergic innervation due to death of dopaminergic neurons in Parkinson’s disease, or due to D2-receptor antagonism from antipsychotic drugs, results in increased release of acetylcholine from these neurons. The pharmacodynamic reason for prescribing anticholinergic drugs in both instances is attempting to balance the reciprocal relationship between dopamine and acetylcholine in the brain. The incidence of side effects from anticholinergic drugs are however quite high.
Antipsychotic drugs and older antidepressants
Many antipsychotic drugs have anticholinergic properties. This can reduce the incidence of extrapyramidal side effects, but also cause to sedation and other anticholinergic side effects. Sedation can be beneficial during acute treatment, but is problematic for long-term treatment. Tricyclic antidepressants also have potent anticholinergic properties, but are now rarely used for depression due to their adverse side effect profile.
The tobacco alkaloid nicotine, a nicotinic acetylcholine receptor agonist, is one of the most addictive substances known. The rewarding effect of nicotine is mediated through (α4)2(β2)3-receptors that regulate dopamine release in the nucleus accumbens, while the stimulant effects of nicotine is mediated through (α7)5-receptors. Anticholinergics, usually called deliriants when used as a recreational drug, have low risk of addiction and are not very popular as drugs of abuse due to unpleasant hallucinations and potential lethal side effects.
Some other useful or interesting facts about acetylcholine:
Acetylcholine was the first neurotransmitter to be discovered. It was described in a paper by Otto Loewi in 1921 as vagusstoff (german for “vagus stuff”), due to its ability to mimic the effects of electrical stimulation of the vagus nerve. This finding was the final proof that synaptic transmission was chemical. Vagusstoff was later confirmed to be identical to the substance acetylcholine, which had been identified by Sir Henry Hallett Dale 7 years earlier.
The classic pneumonic for remembering the symptoms of anticholinergic poisoning goes as follows: Blind as a bat, mad as a hatter, red as a beet, hot as heat, dry as a bone, the bowel and bladder lose their tone, and the heart runs alone. It refers to blurred vision, hallucinations and delirium, flushing, hyperthermia, dry mouth and eyes, constipation and urinary retention, tachycardia and hypertension. Anticholinergic toxicity due to ingestion of drugs or plants with anticholinergic properties is surprisingly common.
Organophosphate poisoning usually occur from exposure to pesticides. Organophosphates inhibit the enzyme acetylcholinesterase, leading to an accumulation of acetylcholine in the body. Symptoms include those covered by the mnemoic DUMBBELLS for cholinergic toxicity: Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm, Emesis, Lacrimation, Lethargy and Salivation. Other symptoms include bronchorrhea, confusion, hypothermia, tachypnea, muscle fasciculations and seizures. Bradycardia, bronchorrhea and bronchospasm are the leading cause of death from organophosphate poisoning, with several hundred thousands fatalities each year. Suicide by intentional pesticide ingestion is one of the most common methods of suicide globally.
Author: Sverre Gunnarsson Larne. Last updated: June 23rd 2016.