Acetylcholine

Acetylcholine is a neurotransmitter that is thought to play a role in many human diseases including myalgic encephalomyelitis and postural orthostatic tachychardia syndrome.

Function
Acetylcholine is used in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervous system. It plays an important role in regulating the inflammatory response and is used at the neuromuscular junction by motor neurons in order to activate muscles.

In the central nervous system, acetylcholine modulates arousal and temperature regulation, is important for attention, memory and motivation, and may play a role in central fatigue.

General Function Summary
As a neurotransmitter, acetylcholine is produced in nerve cells. Any cell that produces or is affected by acetylcholine is called cholinergic. In the nervous system, acetylcholine typically travels from the axon to the dendrite of the next nerve cell across the synaptic cleft. In muscle cells, it travels to the receptors on the muscle fiber, called the motor end plate. Acetylcholine can activate receptors, such as the nicotonic receptors or muscarinic receptors. These receptors can also be activated by, or blocked by, other molecules such as nicotine and muscarine. Muscarinic receptors are typically found in the parasypathetic nervous system, whereas nicotonic receptors are found in the central nervous system, peripheral nervous system, and neuromuscular junctions. Nicotonic receptors are classified as ligand-gated ion channels - when activated they open and allow ions like K+, Na+, and Ca+ to move in or out of the cell. Muscarinic receptors exert their effects on cells via a secondary messenger system.

Closing of the gate is completed by Acetylcholinesterase ( AChE) which catalyzes the breakdown of acetylcholine into choline and acetic acid, which allows the ion gate to close. Each molecule of AChE can degrade about 25,000 molecules of acetylcholine (ACh) per second. If the AChE molecule is blocked, breakdown of ACh will not be completed and the gate will remain open. If the AChE is blocked on a muscle fiber, the fiber will remain contracted. Various duration and strength AChE blockers exist. Short-duration or reversible AChE blockers have been developed as medications, as short-term blocking of AChE can allow the ion gates to stay open longer and increase ACh availability. Long-duration and irreversible AChE blockers, including Nerve Gas, can cause various symptoms up to and including paralysis and death.

Immune system
The vagus nerve speaks directly to the immune system via acetylcholine.

Acetylcholine plays a role in innate immunity through nicotinic acetylcholine receptors and in the adaptive immune response via M3 muscarinic acetylcholine receptors (M3R).

Muscarinic receptors
Knockout mice, that is mice lacking the gene that encodes for M3R, had impaired response to bacterial infection, while normal mice given a muscarinic agonist (to increase the activity of M3R) had enhanced production of IL-13 and IFN-γ. Another study used a muscarinic agonist and an antagonist (reduce activity) and found antagonist suppressed the immune response while the agonist exaggerated it.

Mast cells
Several studies suggest a relationship between autonomic nervous system dysfunction and mast cell activation via acetylcholine.

One study found that acetylcholine via muscarinic receptors strongly inhibited the release of histamine in mucosal mast cells. The activity of acetylcholinesterase, an enzyme that breaks down acetylcholine, was found to be significantly increased in 64% of patients experiencing flares of ulcerative colitis.

Myasthenia Gravis
Autoantibodies to acetylcholine receptors alpha subunit have been found in patients with myasthenia gravis. These cross react with herpesvirus glycoprotein D. Antibodies to acetylcholine receptor and HSV-1 antigens crossreact.

B cells from myasthenia gravis patient stimulated in vitro by Epstein-Barr virus (EBV) produced acetylcholine autoantibodies. Ongoing EBV infection of the thymus has been posited as a causative agent for the production of aceytlcholine receptor autoantibodies in myasthenia gravis.

Sjögren's syndrome
Autoantibodies against muscarinic acetylcholine receptor on exocrine glands were found in patients with Sjögren's syndrome.

Chronic fatigue syndrome
Since at least the 1990s it has been theorized that CFS might be associated with abnormalities of acetylcholine neurotransmission. To test this hypothesis, a provocation study was performed using the acetylcholinesterase inhibitor pyridostigmine. The results did indicate that CFS patients' hypothalamuses are hypersensitive to cholinergic stimulation relative to matched healthy controls. These results mirror similar, highly replicated findings showing that CFS patients' hypothalamuses are hypersensitive to serotonergic stimulation as well (see Buspirone challenge test).

A 2003 study of 60 CFS patients found that 53.3% had detectable autoantibodies against the M1 muscarinic acetylcholine receptor. In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4 muscarinic acetylcholine receptors, as well as ß2 adrenergic receptors. A 2016 Australian study found that ME/CFS patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for M3 muscarinic acetylcholine receptors.

Several small clinical trials have been performed to assess the benefit of treatment with acetylcholinesterase inhibitors in CFS; one using pyridostigmine and another using galantamine. Both trials showed improvement of symptoms on the treatment. The exact mechanism or mechanisms by which AChE inhibition might help in CFS are unclear due to how widely represented acetylcholine-responsive tissues are in the brain, (neuro)musculature, cranial and pre-ganglionic spinal autonomic nerves, vasculature, and peripheral C-fibers. Additionally, AChE inhibitors such as pyridostigmine are able to stimulate growth hormone secretion, and both CFS and POTS patients have been shown to have disturbed growth hormone levels.

Anecdotally, some ME/CFS patients have tried pyridostigmine (trade name Mestinon), with some success. A work in progress study of exercise intolerance in preload failure found that Mestinon improved exercise tolerance, but the study has not yet been published.

Postural orthostatic tachycardia
A small study of postural orthostatic tachycardia syndrome in children found that 24.39% of patients had acetylcholine receptor autoantibodies. A small study of adult patients found elevated α1, β1 and β2 adrenergic receptor autoantibodies. A small randomized crossover design trial found that patients with postural orthostatic tachychardia improved with Mestinon.

Increasing and decreasing acetylcholine
Many classes of drugs including benzodiazepines, opiods, anesthetics, and some antihistimanes such as Benadryl are anticholinergic. During exercise, levels of acetylcholine drop.

Acetylcholinesterase inhibitors
Acetylcholinesterase is an enzyme that breaks down acetylcholine. Acetylcholinesterase inhibitors block or downregulate the activity of acetylcholinesterase; in turn, because there is less enzyme breaking down acetylcholine, the amount of circulating acetylcholine increases.

The following compounds are acetylcholinesterase inhibitors:
 * pyridostigmine (Mestinon) - A peripheral AChE inhibitor, pyridostigmine is unable to cross the blood brain barrier due to its chemical structure.
 * huperzine A (crosses blood-brain barrier)
 * galantamine - A central/peripheral AChE inhibitor. While prescription only in some countries, galantamine is available over the counter in the United States.
 * blueberries

Research studies related to ME/CFS

 * 2004, Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome - (Abstract)

Learn more

 * 2003, The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation, Molecular Medicine, 2003 May-Aug; 9(5-8): 125–134.
 * 2011, Video - "Is acetylcholine toxicity the cause of CFS?"
 * 24 February 2015, Scientists uncover new role for neurotransmitter that helps fight infection, Imperial College London News