Acetylcholine is a hot topic within the realm of memory enhancement. It is a neurotransmitter that is critical for the everyday functioning of the brain: particularly in the areas of movement, learning & memory, and sleep quality. Check out this post to learn about the receptors, function, and health effects of this key neurotransmitter.
What Is Acetylcholine?
Definition & Discovery
Acetylcholine was first discovered in 1914, and was in fact the first of the brain’s major neurotransmitters to be identified [1, 2].
Acetylcholine was first studied for its role in regulating wakefulness and sleep. However, since its initial discovery it has been associated with a wide variety of different important functions and roles throughout the brain and the rest of the body [1, 2].
It is believed that choline — the chemical and metabolic precursor to acetylcholine — was originally used by single-celled organisms billions of years ago to create their protective outer cell layers (membranes). Since this earliest biological function, its role has since been expanded over the course of evolution to become involved in a wide range of important functions including muscular control, sleep regulation, and even higher cognitive functions, such as learning and memory [3, 4].
Acetylcholine is synthesized from acetyl-coenzyme A (which comes from glucose) and choline, with the help of an enzyme called choline acetyltransferase [5]. However, unlike many other neurotransmitters, acetylcholine is created (synthesized) within the connections between neurons (the neural synapses), rather than inside neurons themselves [3].
Function
One of the central functions of acetylcholine is to trigger muscle movements, which it does by stimulating the synapses where the nervous system connects to the muscular system (neuromuscular junctions, or “NMJs”) [3].
However, this role is not just limited to controlling the muscles that move the body around: for example, acetylcholine and histamine interact together to contract muscles in the lungs, which enables breathing (respiration) [6, 7].
While it plays a large and complex variety of roles throughout the brain, acetylcholine is most commonly associated with certain cognitive functions, such as memory and attention. It is also believed to play a role in promoting the phase of sleep associated with dreaming (REM sleep) [8, 9, 10].
Acetylcholine Receptors
Acetylcholine can act on the two different types of receptors in the body: nicotinic and muscarinic.
- Nicotinic receptors got their name because nicotine activates them. They help transmit signals in the brain and activate skeletal muscles. The famous poison curare blocks them and causes paralysis [11]
- Muscarinic receptors are in all other parts of the body: in the heart, gut, glands, and brain. Muscarine is a mushroom poison that overactivates them. Abnormal activity of these receptors is thought to contribute to addiction, schizophrenia, and Huntington’s disease [12, 13, 14, 15].
What Does Acetylcholine Do?
Roles and Effects:
1) Learning and Memory
Several different lines of scientific evidence suggest that acetylcholine plays a crucial role in learning and memory.
For example, acetylcholine is believed to be critically involved in the development and progression of several common neurodegenerative diseases that involve memory impairments, such as dementia and Alzheimer’s disease. In fact, some of the memory-related symptoms of these disorders appear to correlate with reduced levels and activity of acetylcholine — especially in certain brain regions known to play a key role in memory, such as the hippocampus [8].
For this reason, drugs that increase acetylcholine are commonly used by medical practitioners to treat patients with Alzheimer’s [16, 17].
Scopolamine — a drug that is known to block acetylcholine activity — has been reported to impair the acquisition of new information and memories, according to several studies in both humans and animals [18, 19].
In monkeys, disruption of the brain’s supply of acetylcholine — especially in the cerebral cortex and hippocampus — has been reported to impair the acquisition of factual information (during a discrimination learning task), and also reportedly produces memory impairments comparable to human amnesia [20, 21].
Although the precise mechanisms involved in acetylcholine’s effects on memory are complex and not yet fully-understood, some researchers believe that it plays a central role in synaptic plasticity, the biological mechanism which allows neurons to store new information and memories by modifying the way they connect to each other [22].
Due to its potential role in stimulating learning and memory, some researchers have investigated whether using dietary supplements or other compounds to increase acetylcholine levels might influence cognitive functioning.
Although this research is in a relatively early stage, some studies have reported some interesting preliminary findings. For example, according to one observational study in almost 1,400 people, higher dietary intake of choline was associated with slightly better cognitive performance (especially verbal and visual memory) [23].
Relatedly, one small-scale trial in 24 healthy male volunteers reported that supplementation with 500-1,000mg of CDP-choline may have improved a variety of cognitive processes (including working memory and verbal memory). However, this effect was only observed in people whose normal (“baseline”) cognitive performance was already relatively below-average. By contrast, people with “average” levels of cognitive performance showed no effects from choline supplementation, while high-performing subjects actually got worse [24]!
Based on these initial findings, it is likely that acetylcholine has an important role to play in cognition, learning and memory — although the conflicting evidence suggests that its role is complex, and is not as simple as “more acetylcholine = better”!
2) Controlling the Sleep-Wake Cycle
When acetylcholine was first discovered, it was being studied primarily for its role in the regulation of the sleep-wake cycle [1, 2]. Today, acetylcholine is still one of the main neurotransmitters believed to be responsible for stimulating wakefulness (along with other important neurotransmitters and hormones, such as orexin, histamine, norepinephrine, and dopamine) [1, 10].
For example, some studies have reported that the activity of acetylcholine neurons is significantly increased during waking, whereas the activity of these same neurons is suppressed during certain stages of sleep (such as slow-wave sleep, or SWS) [10].
Some researchers have proposed that the wakefulness-promoting effects of acetylcholine may be involved in the “stimulating” effects of certain drugs that increase the activity this neurotransmitter, such as amphetamines and other stimulant drugs like modafinil and cocaine. Conversely, the effects of sleep-promoting (“sedative/hypnotic”) drugs, such as zolpidem (Ambien) and various antihistamines, may partially come from their ability to reduce acetylcholine activity [10].
Relatedly, animal studies in rats have reported that the sedative/hypnotic drugs zolpidem (Ambien), diazepam, and eszopiclone may induce their effects by stimulating GABA receptors that (in turn) suppress acetylcholine release by the brainstem [1].
Acetylcholine’s role in sleep- and wakefulness-related behaviors may also tie into its role in learning and memory. For example, while acetylcholine activity is generally suppressed during many stages of sleep, acetylcholine levels have been reported to increase during REM sleep — one of the most important stages of sleep for storing (“consolidating”) new memories [25, 26, 27, 28].
3) Attention and Alertness
Historically, acetylcholine has been thought to be mainly important in learning and short-term memory functions. However, more recent studies have provided support for acetylcholine’s role in attention and alertness [29].
For example, one animal study reported that acetylcholine levels in the brain increased significantly when rats were placed into an environment that required high degrees of sustained attention (high attentional effort). Furthermore, increasing the difficulty of the attention task (by adding distracting stimuli) further increased acetylcholine levels. Based on these findings, the authors of this study concluded that acetylcholine may play a direct role in stimulating attention and focus [9].
Relatedly, one study of 60 healthy adult women aged 40-60 reported improvements in attention after 28 days of supplementation with CDP-choline, a compound that is believed to increase acetylcholine levels throughout the brain [30].
While these early results are promising, much more research will be needed to confirm whether acetylcholine supplementation can consistently influence memory abilities in healthy human users.
4) Inflammation
Acetylcholine is also believed to be involved in inflammation. In fact, its influence on inflammation is so significant that it even has a biological pathway named after it, called the “cholinergic anti-inflammatory pathway” [31].
Pro-inflammatory cytokines are produced by cells of the immune system in response to injury or infection. These cytokines, in turn, initiate a chain of effects that recruit a variety of inflammatory cells to the site of infection in order to contain it.
The cholinergic anti-inflammatory pathway is currently believed to provide a sort of “braking” effect on this immune response. This may protect the body against the tissue damage that can occur if an acute inflammatory response spreads beyond the local tissues to affect the kidney, liver, lungs, or other major organs [32].
For example, according to one animal study, increased acetylcholine levels were associated with reduced inflammation in the intestinal gut mucosa — possibly due to the activation of alpha-7 nicotinic acetylcholine receptors (α7nAChRs), which inhibit the release of pro-inflammatory cytokines [31].
Relatedly, according to studies of inflammation-related health conditions (such as IBD), acetylcholine has also been reported to reduce the levels of other pro-inflammatory cytokines, such as IL-6, IL1B, and TNF-a [31].
Additionally, specific sub-types of acetylcholine receptors — such as alpha-7 nicotinic acetylcholine receptors, or “α7nAChRs” for short — have been reportedly found on a number of different immune system cell types, including macrophages, monocytes, and mast cells. Some researchers have proposed that acetylcholine may reduce inflammation by inhibiting these immune cells [31].
Other systems involved in anti-inflammatory mechanisms, such as vagus nerve stimulation, are also believed to be activated by acetylcholine [31]. Decreased vagus nerve activity has been reported in studies of inflammatory bowel disease (IBD), and may in part result from reduced anti-inflammatory stimulation from acetylcholine [31].
However, the precise role of acetylcholine in overall inflammation is not fully clear, and is probably more complex than some of the above findings may suggest. For example, some studies have reported that acetylcholine (again acting via nAChRs) also suppresses the production of antiinflammatory cytokines, such as IL-10.
Therefore, more research will still be needed to understand exactly how acetylcholine either increases or decreases the inflammatory response in different contexts.
5) Protecting Against Infections
In addition to its role in inflammation, some preliminary evidence from animal research suggests that acetylcholine may have important interactions with the immune system, and may play a role in how it responds to infections.
For example, one animal study has reported that acetylcholine may inhibit the formation of “biofilms” during certain kinds of infections (such as fungal infections caused by Candida albicans) [33].
6) Helping Gut Movement
Another important function of acetylcholine is to facilitate the movement of food through the gastrointestinal tract (a process called peristalsis).
More specifically, this function is associated with acetylcholine activity within the “parasympathetic” nervous system — the part of the nervous system that is associated with the “rest-and-digest” functions (which are the counterpart to the “fight-or-flight” responses caused by the sympathetic nervous system) [34].
Specific types of acetylcholine receptor, called nicotinic acetylcholine receptors (nAChRs), are believed to be particularly involved in this process.
These receptors get their name from the fact that they are stimulated by nicotine: and the involvement of nicotine in stimulating these receptors is believed to be why up to 1 in 6 people who quit smoking report (temporary) gastrointestinal symptoms, such as constipation. The idea behind this is that because a chronic smoker’s gastrointestinal acetylcholine system is “used” to getting more nicotine-based stimulation from tobacco, it may become less able to function properly once this extra source of stimulation is removed, thereby resulting in impaired digestive processes (such as constipation symptoms) [35].
Additionally, some antidepressant drugs (monoamine reuptake inhibitors) that are able to inhibit these nicotinic acetylcholine receptors have been commonly reported to cause constipation as a potential side-effect. Some such antidepressant medications include [36]:
- Desipramine (Norpramin)
- Fluoxetine (Prozac)
- Citalopram (Celexa)
- Sertraline (Zoloft)
- Reboxetine (Edronax)
- Venlafaxine (Effexor)
- Paroxetine (Paxil)
- Imipramine (Tofranil)
- Clomipramine (Anafranil)
- Amitriptyline
7) Reducing Pain
Some evidence also suggests that acetylcholine may also be involved in mediating the perception of pain, and that targeting this system may potentially help treat pain.
For example, some research has reported that the Alzheimer’s disease medication donepezil — which primarily acts by increasing acetylcholine levels — produces a dose-dependent pain-relieving effect in human patients, and may also have some efficacy as a preventative treatment for the symptoms of migraines [37].
Relatedly, a systematic review of multiple cell- and animal-based studies concluded that higher levels of acetylcholine in the spinal cord are generally associated with pain relief, whereas reducing acetylcholine activity (such as by blocking its receptors) often results in increased sensitivity to pain [38].
Although the exact mechanisms behind these potential effects are not fully understood yet, early evidence from various studies in both humans and animals suggests that nicotinic and muscarinic types of acetylcholine receptors are each likely involved in these potential pain-related effects [39, 38].
8) Improving Blood Flow
According to some early cell-based studies, acetylcholine may play a role in regulating blood circulation — specifically, by stimulating the production of nitric oxide, a compound that controls blood pressure by relaxing the blood vessels (vasodilation) throughout the cardiovascular system [40].
Some preliminary findings also suggest that muscarinic acetylcholine receptors, in particular, may be especially relevant to the potential cardiovascular functions of acetylcholine [40].
9) Hormone Balance
Finally, some research also suggests that acetylcholine activity has an influence on the production or secretion of various hormones throughout the body and brain.
For example, some studies have reported that acetylcholine levels are correlated with the secretion of hormones such as prolactin and growth hormone from the pituitary gland. Although the full mechanisms are not known yet, some researchers believe that a significant amount of acetylcholine’s effects on hormones may come from its ability to influence neural activity in the hypothalamus, a brain region that is widely believed to be heavily involved in hormone regulation [41, 42].
Takeaway
Acetylcholine is the main neurotransmitter of the “rest-and-digest” or parasympathetic nervous system. As a central messenger of this response, acetylcholine counteracts “fight-or-flight” tendencies and drives cholinergic activity in the body.
The brain makes acetylcholine from choline, which is commonly found in food.
Science has revealed a lot about the function of acetylcholine since its discovery over a century ago. From alertness to cognition to digestion, acetylcholine plays diverse roles.
Experimental studies suggest it might also have pain-relieving, anti-inflammatory, and hormone-balancing properties, but further research is needed to confirm this.
