Acetylcholine

Acetylcholine Synthesis, Release, and Inactivation

• ACh is not only found in the brain, it is also a key transmitter at the neuromuscular junction and at specific synapses within the sympathetic and parasympathetic branches of the autonomic nervous system.
• ACh is synthesized from choline and acetyl CoA in a single reaction catalyzed by the enzyme choline acetyltransferase. The rate of ACh synthesis is controlled by precursor availability and is increased by cell firing.
• ACh is loaded into synaptic vesicles by the specific vesicular transporter VAChT.
• A variety of animal and bacterial toxins influence the cholinergic system either by stimulating or inhibiting ACh release. Local administration of the paralytic toxin botulinum toxin A has both medical and cosmetic uses.
• Following its release into the synapse or neuromuscular junction, ACh is rapidly degraded by the enzyme AChE.
• Much of the choline liberated from ACh breakdown is taken back up into the cholinergic nerve terminal by a choline transporter that plays a critical role in maintaining ongoing ACh synthesis.
• Drugs that block AChE cause prolongation of ACh action at postsynaptic or muscular cholinergic receptors.
• Several reversible AChE antagonists that enter the brain are currently used to treat mild to moderate Alzheimer’s disease. Other reversible antagonists that do not cross the blood–brain barrier help alleviate symptoms of the neuromuscular disorder myasthenia gravis.
• Organophosphorus compounds that block AChE irreversibly are the active ingredients of some insecticides, and similar but more potent inhibitors are the main components of dreaded nerve gases.

Organization and Function of the Cholinergic System

• Acetylcholine is an important neurotransmitter in the PNS, where it is released by motor neurons innervating skeletal muscles, by preganglionic neurons of both the parasympathetic and sympathetic branches of the autonomic nervous system, and by ganglionic parasympathetic neurons.
• In the brain, cholinergic neurons include a group of interneurons within the striatum, a diffuse system of projection neurons that constitute the basal forebrain cholinergic system (BFCS), and a group of brainstem neurons in the laterodorsal and pedunculopontine tegmental (LDTg and PPTg) nuclei.
• The BFCS plays an important role in cognitive functioning, whereas the LDTg and the PPTg exert multiple roles, including stimulation of midbrain dopamine neurons, behavioral arousal, sensory processing, and initiation of rapid-eye-movement sleep.
• Cholinergic receptors are divided into two major families: nicotinic and muscarinic receptors.
• Nicotinic receptors are ionotropic receptors comprising five subunits. When the receptor channel opens, it produces a fast excitatory response resulting from an influx of Na⁺ and Ca²⁺ ions across the cell membrane. In the brain, these receptors are located both postsynaptically, where they stimulate cell firing, and presynaptically, where they directly enhance neurotransmitter release from nerve terminals.
• Nicotinic receptors in neurons and muscles possess somewhat different subunits, and this leads to significant pharmacological differences between the two types of receptors. Some of the cognitive functions of ACh have been ascribed to activation of (α4)₂(β2)₃ or (α7)₅ nicotinic receptors.
• Ionotropic receptors, including nicotinic receptors, can exist in a closed, open, or desensitized state. Prolonged exposure to a nicotinic receptor agonist such as nicotine itself promotes conversion of the receptor to a desensitized state in which the channel will not open despite the presence of the agonist. In such a case, the receptor must be resensitized before it can be activated again. Nicotinic receptors can also cause a process of depolarization block involving temporary loss of the cell’s resting potential and an inability of the cell to generate action potentials. This is the basis for certain muscle relaxants used in medicine.
• There are five kinds of muscarinic receptors, designated M₁ through M₅, all of which are metabotropic receptors. Muscarinic receptors function through several different signaling mechanisms, including activation of the phosphoinositide second-messenger system, inhibition of cAMP synthesis, and stimulation of K⁺ channel opening.
• Muscarinic receptors are widely distributed in the brain, with particularly high densities in various forebrain structures. M₅ receptors in the VTA are believed to modulate processes of drug reward and dependence.
• Outside of the brain, muscarinic receptors are found in targets of the parasympathetic system, including the heart, secretory glands, and smooth muscle found in many internal organs. Consequently, general muscarinic agonists are called parasympathomimetic agents, whereas antagonists are considered parasympatholytic in their actions.
• M₂ receptors mediate the effects of the parasympathetic system on the heart, whereas M₃ receptors stimulate secretory responses of the sweat and salivary glands and also the insulin-secreting β-cells of the pancreas. Blockade of muscarinic receptors in the salivary glands leads to the dry mouth effect, which is a serious side effect of many drugs used to treat various psychiatric disorders.