Acetylcholine (often abbreviated ACh) (Figure 1) is an organic, polyatomic ion that acts as a neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS) and the only neurotransmitter used in the motor division of the somatic nervous system (sensory neurons use glutamate and various peptides at their synapses). Acetylcholine is also the principal neurotransmitter in all autonomic ganglia. In cardiac tissue, acetylcholine neurotransmission has an inhibitory effect, which lowers heart rate. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle.
Acetylcholine 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. Acetylcholine was also the first neurotransmitter to be identified.
Acetylcholine has functions both in the peripheral nervous system (PNS) and in the central nervous system (CNS) as a neuromodulator. In the peripheral nervous system, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system. In the central nervous system, acetylcholine and the associated neurons form the cholinergic system.
When acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens ligand-gated sodium channels in the cell membrane. Sodium ions then enter the muscle cell, initiating a sequence of steps that finally produce muscle contraction. Although acetylcholine induces contraction of skeletal muscle, it acts via a different type of receptor (muscarinic, see Figure 2) to inhibit contraction of cardiac muscle fibers.
In the autonomic nervous system, acetylcholine is released in the following sites: all pre- and post-ganglionic parasympathetic neurons, all pre-ganglionic sympathetic neurons, some post-ganglionic sympathetic fibers, and pseudomotor neurons to sweat glands
In the central nervous system, ACh has a variety of effects as a neuromodulator of plasticity, arousal, and reward. ACh has an important role in the enhancement of sensory perceptions when we wake up and in sustaining attention. Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with Alzheimer's disease. ACh has also been shown to promote REM sleep.
In the cerebral cortex, tonic ACh inhibits layer 4 neurons, the main targets of thalamocortical inputs while exciting pyramidal cells in layers 2/3 and 5. This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer 5 excitatory microcircuits. As a result, these layer-specific effects of ACh might function to improve the signal:noise ratio of cortical processing. At the same time, acetylcholine acts through nicotinic receptors (Figure 3) to excite certain groups of inhibitory interneurons in the cortex, which further dampen cortical activity.
One well-supported function of ACh in the cortex is increased responsiveness to sensory stimuli, a form of attention. Phasic increases of ACh during visual, auditory, and somatosensory stimulus presentations have been found to increase the firing rate of neurons in the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned, animals' ability to detect visual signals was robustly and persistently impaired. In that same study, an animals' ability to correctly reject non-target trials was not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli.
ACh has been implicated in reporting expected uncertainty in the environment based both on the suggested functions listed above and results recorded while subjects perform a behavioral cuing task. Reaction time difference between correctly cued trials and incorrectly cued trials, called the cue validity, was found to vary inversely with ACh levels in primates with pharmacologically and surgically altered levels of ACh. The result was also found in Alzheimer’s disease patients and smokers after nicotine (an ACh agonist) consumption.
Creation of ACh
Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus Basilis of Meynert in the basal forebrain. 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. Certain neurotoxins work by inhibiting acetylcholinesterase, leading to excess acetylcholine at the neuromuscular junction. This results in the paralysis of the muscles needed for breathing and stopping the beating of the heart.