1.About Acetylcholine. What Does Acetylcholine Do?
If dopamine is “ the molecule of motivation”, acetylcholine would be best described as the “memory molecule” as it helps you learn, focus, stay alert and convert short term memory into long term memory. Acetylcholine is the key neurotransmitter 1) in the autonomic nervous system (which includes the parasympathetic “rest and digest” branch, the sympathetic nervous system involved in “fight or flight “ reaction and the enteric nervous system, which is your” second brain” in the gut)-thus playing a key role in digestion, cardiovascular function, respiration, sweating and reproduction. 2) at the neuromuscular junction (between the motor nerve and skeletal muscle), thus playing an essential role in muscle and nerve functions and 3) in the brain, being found throughout the brain but particularly important in the hippocampus and temporal lobes. It was the first neurotransmitter to be discovered, and labeled the vagus stuff, as it mimics the electric stimulation of the vagus nerve [1].
While Parkinson’s disease is known to be associated with dopamine deficiency, Alzheimer’s disease and myasthenia gravis are linked with acetylcholine deficiency. Yet, a shortage of this neurotransmitter is also found in MS, Parkinson’s disease and many other conditions affecting the brain and/or the gut.
Choline is the precursor of acetylcholine, and combines with an acetyl group (a byproduct of sugar metabolism) to form acetylcholine.
Choline + Acetyl Co-A—> Acetylcholine (+ Co A). Key enzyme involved in this reaction: Choline acetyl transferase.
After being used for various processes in the body, acetylcholine is broken down to form acetic acid and choline
Acetylcholine + H20—> Acetic acid + Choline. Key enzyme involved in this reaction: acetylcholinesterase. Drugs called acetylcholinesterase inhibitors (AChEI) inhibit this enzyme from breaking down acetylcholine, thus increasing both the level and duration of action of the neurotransmitter acetylcholine.
There are two types of acetylcholine (aka cholinergic) receptors: muscarinic (very important in the brain) and nicotinic receptors.
Technical: Nicotinic receptors bind nicotine and are blocked by curare (tubocurarine). They are linked to ionic channels; mediate neurotransmission at neurons, ganglia, interneurons and the motor endplate. Their response is brief and fast and mediate excitation in target cells. Muscarinic receptors bind muscarine and are blocked by atropine. Are linked to 2nd messenger systems through G proteins mediate neurotransmission at neurons and effector organs (ie heart, smooth muscle fibres and glands). Their response is slow and prolonged. Are both pre and postsynaptic where nicotinic receptors are postsynaptic only [2],[3].
Symptoms of Low Acetylcholine (Acetylcholine Deficiency Symptoms)
Symptoms of low acetylcholine (mental/emotional symptoms)
Memory loss (particularly visual and verbal memory) and memory lapses
Slow digestion and poor digestion: constipation, food intolerances, digestive symptoms
Excessive or frequent urination
High cholesterol levels
High blood pressure
High blood sugar levels
Dry eyes and mouth
Abnormal sweating
Excessive, frequent urination
*not all the symptoms above must be present; these symptoms may be caused by other conditions as well. The low acetylcholine symptoms list above gives you an idea of what happens if you have a shortage of this neurotransmitter.
Diseases associated with acetylcholine deficiency: mild deficiencies can be associated with hyper and hypothyroidism, learning difficulties, high blood pressure and high cholesterol levels, ADHD, diabetes, heart disease and fatty liver. Moderate deficiencies are found in MS, Parkinson’s disease, depression, seizures, severe anemia. Severe deficiencies of this neurotransmitter are seen in strokes and of course- Alzheimer’s disease. Myastenia gravis is an autoimmune disease of the neuromuscular junction in which the receptors for acetylcholine are destroyed.
3.Acetylcholine Deficiency Causes
Above you can see the acetylcholine deficiency symptoms and related diseases. But what are the root causes of low acetylcholine ?
Sugar imbalances is a big factor. Insulin is essential for brain health and production of acetylcholine itself. I wrote in this article about diabetes type III (in the brain) which is associated with Alzheimer’s, Parkinson’s and MS. Western type (high fat high sugar diet) also contributes to impairments along acetylcholine pathway[4] .
Stress- especially chronic stress- depletes the body of acetylcholine [5].
Sleeping problems (lack of sleep, or low quality sleep)
Low fat diet and nutrient deficiencies. Low fat diets are also low in choline. Vegetarian and vegans therefore are at higher risk for acetylcholine deficiency. Vitamin B1, B5, magnesium deficiencies also correlate with low acetylcholine.
Prescription drugs : antidepressants, anti-anxiety, antihistamine, antacids, antibiotics, anti inflammatory drugs(NSAIDs) have anticholinergic effects (lower acetylcholine levels). Of course, anticholinergic drugs, too will lower acetylcholine levels
Toxins : from mercury [6],[7] and other heavy metals [8], [9] in food and chemicals in water, to smoke and electromagnetic radiation- they can all have a negative impact on acetylcholine levels [10].
4.Acetylcholine and The Brain, Inflammation and Immune System. Acetylcholine Deficiency and MS
Acetylcholine in the Brain: What does acetylcholine do in the brain? Acetylcholine plays a major role in memory and learning. Most studies focused on its importance in learning and short term memory [11], but is also the main neurotransmitter that converts short term memory into long term memory. Along with GABA, glutamate and norepinephrine, acetylcholine is very important for memory consolidation [12],[13]. Many nootropics (smart drugs, cognitive enhancers) specifically work by boosting acetylcholine. Technical: blockade of muscarinic cholinergic receptors by drugs such as scopolamine impairs new memories, but not the retrieval of previously stored memories, plus impair working memory for some stimuli. On the other hand drugs that activate nicotinic receptors improve the encoding of new information [14].
Acetylcholine (as well as dopamine) regulates neurogenesis (the formation of new neurons) in the hippocampus [15],[16] and also enhances synapse plasticity (increased connections between brain cells) [17]. Acetylcholine is heavily involved in myelination and scientists are currently researching ways to manipulate acetylcholine signaling to promote myelin repair. Technical : Myelinating glia express all the major types of muscarinic and nicotinic ACh receptors; acetylcholinesterase and butyrylcholinesterase are highly expressed in white matter [18].
Could acetylcholine be a secret cause of MS? Possibly. Acetylcholine fights inflammation, autoimmunity and degeneration. MS is associated with acetylcholine deficiency. Acetylcholine/cholinergic system can reduce inflammatory response by lowering inflammatory markers and increase T reg cells [19],[20]. Technical: autonomic regulation of local and systemic inflammation through so called “the cholinergic anti-inflammatory pathway’ is a mechanism consisting of the vagus nerve and its main neurotransmitter, acetylcholine (technical: this process is dependent on the nicotinic acetylcholine receptor alpha7 subunit) [21],[22].
Impairments along acetylcholine pathways and low levels of this neurotransmitter seem to be involved in neurodegeneration, being found in neurodegenerative diseases such as MS, Alzheimer’s disease, Parkinson’s and Huntington’s disease [23]. MS (RR type) had been associated with dysregulation of acetylcholine levels in the immune cells [24] and low levels of acetylcholine correlate with increased proinflammatory markers in RRMS [25].
MS was also associated with significant loss of myelin in hippocampus (where acetylcholine is a key neurotransmitter) and reduced acetylcholine synthesis/ acetylcholine deficiency [26],[27]. There is a cross talk between acetylcholine and the immune system [28] which explains why healthy levels of acetylcholine are needed to improve immune system function.
Although different acetylcholine receptors will have different (sometimes opposing effects), this neurotransmitter is overall considered providing neuromodulation (rather than stimulation) in the brain (technical : neuromodulation is done by influencing neuronal excitability and synaptic transmission, promoting synaptic plasticity and coordinating the firing of neurons) [29]. In the peripheral organs, acetylcholine is the main stimulating (excitatory) neurotransmitter. \
Acetylcholine works closely with other neurotransmitters, as it regulates the levels and activities of serotonin, dopamine and other neuropeptides (therefore modulates both immune response and neurotransmission) [30]. For example stimulation of nicotinic receptors can increase the release of glutamate, GABA, dopamine (DA), acetylcholine, norepinephrine, and serotonin [31]. Acetylcholine modulates the function of hypothalamus, thus influencing the control of body temperature (thermoregulation), sleep, food intake, the function of endocrine glands, and ability to adapt to stress [32]. Acetylcholine promotes healthy sleep, being particularly important during REM sleep (when its levels are high, while serotonin and dopamine are low).
5.Acetylcholine and The Neuromuscular Junction (NMJ)
What does acetylcholine do in the NMJ? Acetylcholine at the neuromuscular junction — and its impact on nerves and muscles. Neuromuscular junction (NMJ) is a complex structure that serves to communicate the electrical impulse from the neuron to the muscle to produce contraction. The main messenger (neurotransmitter) here is acetylcholine. ACh has excitatory actions at the neuromuscular junction (nicotinic receptors involved) [34],[35]. Acetylcholine is a fast-acting, point-to-point neurotransmitter at the neuromuscular junction (it is also a fast acting neurotransmitter in parasympathetic nervous system, while in the brain works mostly as a neuromodulator) [36]. It has inhibitory actions at certain smooth muscles and at cardiac muscle [37].
Acetylcholine works with other neurotransmitters to maintain normal muscle function and body’s movements. For example, when dopamine gradually depletes (think the typical condition- Parkinson’s disease) there will be an imbalance between dopamine and acetylcholine. As dopamine becomes depleted, acetylcholine increases causing the symptoms of Parkinson’s disease such as body tremors, drooling, slurred speech and mobility difficulty. MS is associated with impairment if neuromuscular junction, but the treatment -for spasticity, tremors and overactive bladder- involves drugs that inhibit acetylcholine like botulinum toxin [38]. I see a lot more cons than pros for using botulinum toxin [39].
Acetylcholine & the Autonomic Nervous System (ANS)
What does acetylcholine do in the autonomic nervous system (ANS)? ANS includes the parasympathetic “rest and digest” branch, the sympathetic nervous system involved in “fight or flight “ reaction. ANS controls cardiovascular function, respiration, digestion, sweating, urinary tract, reproduction and more. Acetylcholine is the key neurotransmitter in the parasympathetic system: it decreases heart rate, stimulates digestion dilate blood vessels increases contraction of the bladder (promotes urination), contracts the pupil and the lens to near vision.
7.Acetylcholine and The Gut
Why acetylcholine in so important in the gut? The number of neurons in the gut- the enteric nervous system (ENS) is comparable to the number of neurons in the spinal cord, therefore ENS and the gut is in fact your second brain. Acetylcholine, dopamine and serotonin are key neurotransmitters in the ENS, just like in the brain and spinal cord.
ENS is stimulated by the parasympathetic nervous system, but can also work independently ( considered as a third, distinct branch of autonomic nervous system) [40]. ENS neurons secrete acetylcholine as well as other neurotransmitters and neuropeptides. Off note, other gut cells and gut bacteria (probiotics) produce acetylcholine too). When vagus nerve (which connects the gut and the brain) is stimulated, it triggers an increase of acetylcholine release in the gut, leading to changes in the gut micro environment and modulation of the immune response [41],[42],[43].
Acetylcholine promotes gut health also because stimulates digestion: acetylcholine increases salivation, raises the motility of the stomach and gut and the secretion of various gut hormones and pancreatic enzymes and stimulates the gallbladder. This is one way to explain why acetylcholine deficiency would manifest with slow and poor digestion- constipation, bloating and food intolerances (from lack of digestive enzymes to break down proteins and abnormal levels of hormones involved in digestion).
Too Much Acetylcholine- Signs and Symptoms of Excess Acetylcholine
Too much acetylcholine is not good either, being linked with depression [44] . More specific and serious symptoms of too much acetylcholine include: increased mucus production and constriction of the bronchioles within the lungs, breathing difficulties, decreases the heart rate, dilatation of pupils, increased sweating. The extreme form of excess acetylcholine excess is called cholinergic crisis and can occur when cholinesterase inhibitor drugs are used, which are used for treating myasthenia gravis [45].
If we look into more details at muscarinic and nicotinic receptors — muscarinic signs of excess acetylcholine increase salivation, lacrimation, urination, sweating, gastrointestinal upset, nausea, vomiting and can progress to bronchospasm, blurred vision, low heart rate, low blood pressure, confusion and shock . Nicotinic effects of excess acetylcholine: Skeletal muscle initially show fasciculation (involuntary irregular, violent muscle contractions) followed by weakness and paralysis. Severe reactions can lead to ventilatory failure and death (as seen in cholinergic crisis) [46].
