Editing Acetylcholine (section)

==Functions==
[[File:Acetylcholine Pathway.png|thumb|Acetylcholine pathway.]]

Acetylcholine functions in both the [[central nervous system]] (CNS) and the [[peripheral nervous system]] (PNS). In the CNS, cholinergic projections from the [[basal forebrain]] to the [[cerebral cortex]] and [[hippocampus]] support the [[Cognition|cognitive]] functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.<ref>{{cite book | vauthors = Waxenbaum JA, Reddy V, Varacallo M | chapter = Anatomy, Autonomic Nervous System |date=2023 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK539845/ | title = StatPearls |access-date=6 April 2023 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30969667 }}</ref><ref name= "Sam_2023" />

===Cellular effects===
{{Main|Acetylcholine receptor}}

[[File:Cholinergic synapse.svg|class=skin-invert-image|thumb|right|Acetylcholine processing in a synapse. After release acetylcholine is broken down by the enzyme [[acetylcholinesterase]].]]
Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating [[receptor (biochemistry)|receptors]] located on the surface of cells. There are two main classes of acetylcholine receptor, [[nicotinic acetylcholine receptor|nicotinic]] and [[muscarinic acetylcholine receptor|muscarinic]]. They are named for chemicals that can selectively activate each type of receptor without activating the other: [[muscarine]] is a compound found in the mushroom ''[[Amanita muscaria]]''; [[nicotine]] is found in tobacco.

[[Nicotinic acetylcholine receptor]]s are [[ligand-gated ion channel]]s permeable to [[sodium]], [[potassium]], and [[calcium]] ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by [[curare]], the neuronal-type by [[hexamethonium]]. The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system.

[[Muscarinic acetylcholine receptor]]s have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as [[G protein-coupled receptor]]s, meaning that they exert their effects via a [[second messenger system]]. The M1, M3, and M5 subtypes are [[Gq alpha subunit|G<sub>q</sub>]]-coupled; they increase intracellular levels of [[inositol trisphosphate|IP<sub>3</sub>]] and [[calcium]] by activating [[phospholipase C]]. Their effect on target cells is usually excitatory. The M2 and M4 subtypes are [[Gi alpha subunit|G<sub>i</sub>/G<sub>o</sub>]]-coupled; they decrease intracellular levels of [[cyclic adenosine monophosphate|cAMP]] by inhibiting [[adenylate cyclase]]. Their effect on target cells is usually inhibitory. Muscarinic acetylcholine receptors are found in both the central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands.

===Neuromuscular junction===
[[File:The Muscle Contraction Process.png|thumb|400px|Muscles contract when they receive signals from motor neurons. The neuromuscular junction is the site of the signal exchange. The steps of this process in vertebrates occur as follows: (1) The action potential reaches the axon terminal. (2) Calcium ions flow into the axon terminal. (3) Acetylcholine is released into the [[synaptic cleft]]. (4) Acetylcholine binds to postsynaptic receptors. (5) This binding causes ion channels to open and allows sodium ions to flow into the muscle cell. (6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which induces muscle contraction. Labels: A: Motor neuron axon B: Axon terminal C: Synaptic cleft D: Muscle cell E: Part of a Myofibril]]
{{main|Neuromuscular junction}}
Acetylcholine is the substance the nervous system uses to activate [[skeletal muscle]]s, a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to [[smooth muscle tissue]], which is involved in a range of involuntary activities such as movement of food through the gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by [[motor neuron]]s located in the [[spinal cord]] or, in a few cases, the [[brainstem]]. These motor neurons send their [[axons]] through [[motor nerve]]s, from which they emerge to connect to muscle fibers at a special type of [[chemical synapse|synapse]] called the [[neuromuscular junction]].

When a motor neuron generates an [[action potential]], it travels rapidly along the nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes acetylcholine to be released into the space between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Sodium ions then flow into the muscle cell, initiating a sequence of steps that finally produce [[muscle contraction]].

Factors that decrease release of acetylcholine (and thereby affecting [[P-type calcium channel]]s):<ref name="Miller">{{cite book|veditors = Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL|title=Miller's Anesthesia| edition = 7th |date=1 January 2009|publisher=Elsevier Health Sciences|isbn=978-0-443-06959-8|pages=343–47}}</ref>

# [[Antibiotics]] ([[clindamycin]], [[polymyxin]])
# Magnesium:&nbsp;antagonizes P-type calcium channels
# [[Hypocalcemia]]
# [[Anticonvulsant]]s
# [[Diuretic]]s ([[furosemide]])
# [[Eaton-Lambert syndrome]]: inhibits P-type calcium channels
# [[Myasthenia gravis]]
# [[Botulinum toxin]]: inhibits SNARE proteins

[[Calcium channel blocker]]s (nifedipine, diltiazem) do not affect P-channels. These drugs affect [[L-type calcium channel]]s.

===Autonomic nervous system===

[[File:1503 Connections of the Parasympathetic Nervous System.jpg|thumb|right|Components and connections of the [[parasympathetic nervous system]].]]
The [[autonomic nervous system]] controls a wide range of involuntary and unconscious body functions. Its main branches are the [[sympathetic nervous system]] and [[parasympathetic nervous system]]. Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action; the phrase often invoked to describe it is [[fight-or-flight response|fight-or-flight]]. The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion, and reproduction; the phrase often invoked to describe it is "rest and digest" or "feed and breed". Both of these aforementioned systems use acetylcholine, but in different ways.

At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia, which send output projections to virtually every tissue of the body. In both branches the internal connections, the projections from the central nervous system to the autonomic ganglia, use acetylcholine as a neurotransmitter to innervate (or excite) ganglia neurons. In the parasympathetic nervous system the output connections, the projections from ganglion neurons to tissues that do not belong to the nervous system, also release acetylcholine but act on muscarinic receptors. In the sympathetic nervous system the output connections mainly release [[noradrenaline]], although acetylcholine is released at a few points, such as the [[sudomotor]] innervation of the sweat glands.

==== Direct vascular effects ====
Acetylcholine in the [[Serum (blood)|serum]] exerts a direct effect on [[vascular tone]] by binding to [[Muscarinic acetylcholine receptor|muscarinic receptor]]s present on vascular [[endothelium]]. These cells respond by increasing production of [[nitric oxide]], which signals the surrounding smooth muscle to relax, leading to [[vasodilation]].<ref name="pmid15649880">{{cite journal | vauthors = Kellogg DL, Zhao JL, Coey U, Green JV | title = Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin | journal = J. Appl. Physiol. | volume = 98 | issue = 2 | pages = 629–32 | date = February 2005 | pmid = 15649880 | doi = 10.1152/japplphysiol.00728.2004 | s2cid = 293055 }}</ref>

===Central nervous system===
[[File:Nucleus basalis of Meynert - intermed mag.jpg|thumb|right|[[Micrograph]] of the [[nucleus basalis]] (of Meynert), which produces acetylcholine in the CNS. [[LFB stain|LFB-HE stain]].]]
In the central nervous system, ACh has a variety of effects on plasticity, arousal and [[reward system|reward]]. ACh has an important role in the enhancement of alertness when we wake up,<ref name="pmid16183137">{{cite journal | vauthors = [[Barbara E. Jones|Jones BE]] | title = From waking to sleeping: neuronal and chemical substrates | journal = Trends Pharmacol. Sci. | volume = 26 | issue = 11 | pages = 578–86 | date = November 2005 | pmid = 16183137 | doi = 10.1016/j.tips.2005.09.009 }}</ref> in sustaining attention <ref name="pmid10808142">{{cite journal | vauthors = Himmelheber AM, Sarter M, Bruno JP | title = Increases in cortical acetylcholine release during sustained attention performance in rats | journal = Brain Res Cogn Brain Res | volume = 9 | issue = 3 | pages = 313–25 | date = June 2000 | pmid = 10808142 | doi = 10.1016/S0926-6410(00)00012-4 }}</ref> and in learning and [[memory]].<ref name="pmid6431311">{{cite journal | vauthors = Ridley RM, Bowes PM, Baker HF, Crow TJ | title = An involvement of acetylcholine in object discrimination learning and memory in the marmoset | journal = Neuropsychologia | volume = 22 | issue = 3 | pages = 253–63 | date = 1984 | pmid = 6431311 | doi = 10.1016/0028-3932(84)90073-3  | s2cid = 7110504 }}</ref>

Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated with [[Alzheimer's disease]].<ref name="pmid10071091">{{cite journal | vauthors = Francis PT, Palmer AM, Snape M, Wilcock GK | title = The cholinergic hypothesis of Alzheimer's disease: a review of progress | journal = J. Neurol. Neurosurg. Psychiatry | volume = 66 | issue = 2 | pages = 137–47 | date = February 1999 | pmid = 10071091 | pmc = 1736202 | doi = 10.1136/jnnp.66.2.137  }}</ref> ACh has also been shown to promote [[Rapid eye movement sleep|REM]] sleep.<ref name="pmid21238497">{{cite journal | vauthors = Platt B, Riedel G | title = The cholinergic system, EEG and sleep | journal = Behav. Brain Res. | volume = 221 | issue = 2 | pages = 499–504 | date = August 2011 | pmid = 21238497 | doi = 10.1016/j.bbr.2011.01.017  | s2cid = 25323695 }}</ref>

In the brainstem acetylcholine originates from the [[Pedunculopontine nucleus]] and [[laterodorsal tegmental nucleus]] collectively known as the meso[[pontine tegmentum]] area or pontomesencephalotegmental complex.<ref name="Woolf">{{cite journal | vauthors = Woolf NJ, Butcher LL | title = Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain | journal = Brain Res. Bull. | volume = 16 | issue = 5 | pages = 603–37 | date = May 1986 | pmid = 3742247 | doi = 10.1016/0361-9230(86)90134-6 | s2cid = 39665815 }}</ref><ref name="Woolf89">{{cite journal | vauthors = Woolf NJ, Butcher LL | title = Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum | journal = Brain Res. Bull. | volume = 23 | issue = 6 | pages = 519–40 | date = December 1989 | pmid = 2611694 | doi = 10.1016/0361-9230(89)90197-4 | s2cid = 4721282 }}</ref> In the basal forebrain, it originates from the [[basal optic nucleus of Meynert|basal nucleus of Meynert]] and medial [[septal nucleus]]:
* The ''pontomesencephalotegmental complex'' acts mainly on [[M1 receptor]]s in the [[brainstem]], deep [[cerebellar nuclei]], [[pontine nuclei]], [[locus coeruleus]], [[raphe nucleus]], [[lateral reticular nucleus]] and [[inferior olive]].<ref name="Woolf89"/> It also projects to the [[thalamus]], [[tectum]], [[basal ganglia]] and [[basal forebrain]].<ref name="Woolf"/>
* [[Basal optic nucleus of Meynert|Basal nucleus of Meynert]] acts mainly on [[M1 receptor]]s in the [[neocortex]].
* Medial [[septal nucleus]] acts mainly on [[M1 receptor]]s in the [[hippocampus]] and parts of the [[cerebral cortex]].

In addition, ACh acts as an important internal transmitter in the [[striatum]], which is part of the [[basal ganglia]]. It is released by cholinergic [[interneurons]]. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the [[substantia nigra]].<ref name="pmid21925242">{{cite journal | vauthors = Goldberg JA, Reynolds JN | title = Spontaneous firing and evoked pauses in the tonically active cholinergic interneurons of the striatum | journal = Neuroscience | volume = 198 | pages = 27–43 | date = December 2011 | pmid = 21925242 | doi = 10.1016/j.neuroscience.2011.08.067  | s2cid = 21908514 }}</ref><ref name="pmid15233923">{{cite journal | vauthors = Morris G, Arkadir D, Nevet A, Vaadia E, Bergman H | title = Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons | journal = Neuron | volume = 43 | issue = 1 | pages = 133–43 | date = July 2004 | pmid = 15233923 | doi = 10.1016/j.neuron.2004.06.012 |doi-access=free }}</ref>

====Memory====
Acetylcholine has been implicated in [[learning]] and [[memory]] in several ways. The anticholinergic drug [[scopolamine]] impairs acquisition of new information in humans<ref name="pmid4793334">{{cite journal | vauthors = Crow TJ, Grove-White IG | title = An analysis of the learning deficit following hyoscine administration to man | journal = Br. J. Pharmacol. | volume = 49 | issue = 2 | pages = 322–7 | date = October 1973 | pmid = 4793334 | pmc = 1776392 | doi = 10.1111/j.1476-5381.1973.tb08379.x  }}</ref> and animals.<ref name="pmid6431311"/> In animals, disruption of the supply of acetylcholine to the [[neocortex]] impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information<ref name="pmid3087582">{{cite journal | vauthors = Ridley RM, Murray TK, Johnson JA, Baker HF | title = Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs | journal = Brain Res. | volume = 376 | issue = 1 | pages = 108–16 | date = June 1986 | pmid = 3087582 | doi = 10.1016/0006-8993(86)90904-2  | s2cid = 29182517 }}</ref> and disruption of the supply of acetylcholine to the [[hippocampus]] and adjacent cortical areas produces forgetfulness, comparable to [[anterograde amnesia]] in humans.<ref name="pmid12050084">{{cite journal | vauthors = Easton A, Ridley RM, Baker HF, Gaffan D | title = Unilateral lesions of the cholinergic basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys | journal = Cereb. Cortex | volume = 12 | issue = 7 | pages = 729–36 | date = July 2002 | pmid = 12050084 | doi = 10.1093/cercor/12.7.729 | doi-access = free }}</ref>