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.

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
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.

Anecdotally, some ME/CFS patients have tried Mestinon, an aceytlcholinesterase inhibitor that increases circulating acetylcholine and is used to treat myasthenia gravis, 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) (does not cross blood-brain barrier. Active in peripheral nervous system.)
 * huperzine A (crosses blood-brain barrier)
 * 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