From Citizendium
Jump to navigation Jump to search
This article is developing and not approved.
Main Article
Related Articles  [?]
Bibliography  [?]
External Links  [?]
Citable Version  [?]
This editable Main Article is under development and subject to a disclaimer.

Template:Drugbox The chemical compound acetylcholine, often abbreviated as ACh, was the first neurotransmitter to be identified. It is a chemical transmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in many organisms including humans. Acetylcholine is the neurotransmitter in all autonomic ganglia.


(CC) Image: David E. Volk
Structure of acetylcholine.

Acetylcholine is an ester of acetic acid and choline with chemical formula CH3COOCH2CH2N+(CH3)3. This structure is reflected in the systematic name, 2-(acetyloxy)-N,N,N-trimethylethanaminium.

Acetylcholine (ACh) was first identified in 1914 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi who initially gave it the name vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work.

Later work showed that when acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens ligand gated sodium channels in the membrane. Sodium ions then enter the muscle cell, stimulating muscle contraction. Acetylcholine, while inducing contraction of skeletal muscles, instead induces decreased contraction in cardiac muscle fibers. This distinction is attributed to differences in receptor structure between skeletal and cardiac fibers. Acetylcholine is also used in the brain, where it tends to cause excitatory actions. The glands that receive impulses from the parasympathetic part of the autonomic nervous system are also stimulated in the same way.

Synthesis and Degradation

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Organic mercurial compounds have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyl transferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.

Normally, the enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. The devastating effects of organophosphate-containing nerve agents (e.g. Sarin gas) are due to their irreversible inactivation of this enzyme. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands and central nervous system; victims commonly die of suffocation as they cannot contract their diaphragm. Other organophosphates and some carbamates are effective insecticides because they inhibit acetylcholinasterase in insects. On the other hand, since a shortage of acetylcholine in the brain has been associated with Alzheimer's disease, some drugs that inhibit acetylcholinesterase are used in the treatment of that disease.

Release sites

Botulin acts by suppressing the release of acetylcholine; where the venom from a black widow spider has the reverse effect.

  • all preganglionic autonomic fibers including:
    • all preganglionic sympathetic fibers
    • all preganglionic parasympathetic fibers
    • preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion. On stimulation by acetylcholine, it releases adrenaline and noradrenaline.
  • all postganglionic parasympathetic fibers
  • some postganglionic sympathetic fibers
    • secretory fibers to sweat glands
    • vasodilator fibers to blood vessels of skeletal muscles

Acetylcholine Receptors

For more information, see: Acetylcholine receptor.

There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). They are named for the ligands used to discover the receptors.

Nicotinic receptors

Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and chloride ions. They are stimulated by nicotine and acetylcholine and blocked by curare. Most peripheral AChRs are nicotinic, such as those on the heart and blood vessels or at the neuromuscular junction. They are also found in wide distribution through the brain, but in relatively low numbers.

Muscarinic receptors

Muscarinic receptors are metabotropic and affect neurons over a longer time frame. They are stimulated by muscarine and acetylcholine, and blocked by atropine. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Extracts from the plant included this compound, and its action on muscarinic AChRs that increased pupil size was used for attractiveness in many European cultures in the past. Now, ACh is sometimes used during cataract surgery to produce rapid constriction of the pupil. It must be administered intraocularly because corneal cholinesterase metabolizes topically administered ACh before it can diffuse into the eye. It is sold by the trade name Miochol-E (CIBA Vision). Similar drugs are used to induce mydriasis (dilation of the pupil) in cardiopulmonary resuscitation and many other situations.


Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Cholinesterase inhibitors, an example of enzyme inhibitors, increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents (Sarin and VX nerve gas) or pesticides (organophosphates and the carbamates). Clinically they are used to reverse the action of muscle relaxants, to treat myasthenia gravis and in Alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain).

The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies to the N1 receptor is the most common cause of myasthemia gravis.[1]. Over time the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine or physostigmine) are effective in treating this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the gap junction.

ACh Receptor Agonists

Direct Acting

Indirect Acting (reversible)

Reversibly inhibit the enzyme acetylcholinesterase (which breaks down acetylcholine), thereby increasing acetylcholine levels.

Indirect Acting (irreversible)

Semi-permanently inhibit the enzyme acetylcholinesterase.

Reactivation of Acetylcholine Esterase

  • Pralidoxime

ACh Receptor Antagonists

Antimuscarinic Agents (Muscarinic antagonists)

  • Atropine
  • Cimetropium
  • Dicycloverine (dicyclomine)
  • Ipratopium
  • Mebeverine
  • Otilonium
  • Pirenzipine
  • Prifinium
  • Rociverine
  • Scopolamine (hyoscine)

Ganglionic Blockers

Neuromuscular Blockers

  • Atracurium
  • Cisatracurium
  • Doxacurium
  • Metocurine
  • Mivacurium
  • Pancuronium
  • Rocuronium
  • Succinylcholine
  • Tubovurarine
  • Vecuronium

Others? / Uncategorized / Unknown

Neuromodulatory Effects

In the central nervous system, ACh has a variety of effects as a neuromodulator.

Given its prominent role in learning, ACh is naturally involved with synaptic plasticity. It has been shown to enhance the amplitude of synaptic potentials following long-term potentiation in many regions, including the dentate gyrus, CA1, piriform cortex, and neocortex. This effect most likely occurs either through enhancing currents through NMDA receptors or indirectly by suppressing adaptation. The suppression of adaptation has been shown in brain slices of regions CA1, cingulate cortex, and piriform cortex as well as in vivo in cat somatosensory and motor cortex by decreasing the conductance of voltage-dependent M currents and Ca2+-dependent K+ currents.

Acetylcholine also has other effects on excitability of neurons. Its presence causes a slow depolarization by blocking a tonically active K+ current, which increases neuronal excitability. Paradoxically, it increases spiking activity in inhibitory interneurons while decreasing strength of synaptic transmission from those cells. This decrease in synaptic transmission also occurs selectively at some excitatory cells: for instance, it has an effect on intrinsic and associational fibers in layer Ib of piriform cortex, but has no effect on afferent fibers in layer Ia. Similar laminar selectivity has been shown in dentate gyrus and region CA1 of the hippocampus. One theory to explain this paradox interprets Acetylcholine neuromodulation in the neocortex as modulating the estimate of expected uncertainty, acting counter to Norepinephrine (NE) signals for unexpected uncertainty. Both would then decrease synaptic transition strength, but ACh would then be needed to counter the effects of NE in learning a signal understood to be noisy.


  1. Lindstrom J (2002). "Autoimmune diseases involving nicotinic receptors". J. Neurobiol. 53 (4): 656–65. DOI:10.1002/neu.10106. PMID 12436428. Research Blogging.

For further reading

  • Brenner, G. M. and Stevens, C. W. (2006). Pharmacology, 2nd Edition. Philadelphia, PA: W.B. Saunders Company (Elsevier). ISBN 1-4160-2984-2
  • Canadian Pharmacists Association (2000). Compendium of Pharmaceuticals and Specialties (25th ed.). Toronto, ON: Webcom. ISBN 0-919115-76-4
  • Carlson, NR (2001). Physiology of Behavior-7th ed. Needham Heights, MA: Allyn and Bacon. ISBN 0-205-30840-6
  • Gershon, Michael D. (1998). The Second Brain. New York, NY: HarperCollins. ISBN 0-06-018252-0
  • Hasselmo, ME (1995). Neuromodulation and cortical function: Modeling the physiological basis of behavior. Behav. Brain Res. 67: 1-27 [1]
  • Yu, AJ & Dayan, P (2005). Uncertainty, neuromodulation, and attention. Neuron 46 681-692. [2]

External links