Author: Jana Vasković MD • Reviewer: Alexandra Osika
Reading time: 17 minutes
Terminal boutons of axon (Bulbuli terminales axonis); Image: Paul Kim
Neurotransmitters are substances which neurons use to communicate with one another and with their target tissues in the process of synaptic transmission (neurotransmission).
Neurotransmitters are synthetized in and released from nerve endings into the synaptic cleft. From there, neurotransmitters bind to receptor proteins in the cellular membrane of the target tissue. The target tissue gets excited, inhibited, or functionally modified in some other way.
There are more than 40 neurotransmitters in the human nervous system; some of the most important are acetylcholine, norepinephrine, dopamine, gamma-aminobutyric acid (GABA), glutamate, serotonin, and histamine.
In this article, we are going to discuss the mechanism of neurotransmission, the classification of neurotransmitters, and some clinical notes about disorders associated with both excess and shortage of some neurotransmitters.
Key facts about neurotransmitters
Glutamate (Glu) Acetylcholine (ACh) Histamine Dopamine (DA) Norepinephrine (NE); also known as noradrenaline (NAd) Epinephrine (Epi); also known as adrenaline (Ad)
gamma-Aminobutyric acid (GABA) Serotonin (5-HT) Dopamine (DA)
Dopamine (DA) Serotonin (5-HT) Acetylcholine (ACh) Histamine Norepinephrine (NE)
Releasing hormones from hypothalamus Oxytocin (Oxt) Vasopressin; also known as antidiuretic hormone (ADH)
Mechanism of neurotransmission
Neurons communicate with their target tissues at synapses into which they release chemical substances called neurotransmitters (ligands). As this communication is mediated with chemical substances, the process is called chemical neurotransmission and happens within chemical synapses.
Each synapse consists of the:
- Presynaptic membrane – membrane of the terminal bouton (axon ending) of the presynaptic nerve fiber
- Postsynaptic membrane – membrane of the target cell
- Synaptic cleft – a gap between the presynaptic and postsynaptic membranes
Inside the terminal bouton of the presynaptic nerve fiber, numerous vesicles that contain neurotransmitters are produced and stored. When the presynaptic membrane is depolarized by an action potential, calcium voltage-gated channels open (found in the membranes of the terminal buttons). This leads to an influx of calcium ions into the terminal bouton, which changes the state of certain membrane proteins in the presynaptic membrane, and results in exocytosis of neurotransmitters from the terminal bouton into the synaptic cleft.
Neurotransmitters are an important part of the nervous system. Learn more about the anatomy of the nervous system with our beginner-friendly quizzes and labeled digrams.
After crossing the synaptic cleft, neurotransmitters bind to their receptors on the postsynaptic membrane. Once the neurotransmitter binds to its receptor, the ligand-gated channels of the postsynaptic membrane either open or close. These ligand-gated channels are ion channels, and their opening or closing alters the permeability of the postsynaptic membrane to calcium, sodium, potassium, and chloride ions. This leads to a stimulatory or inhibitory response.
Learn more about membrane potentials and action potentials, their phases, and how do we get excitatory or inhibitory responses to action potentials with our study materials:
If a neurotransmitter stimulates the target cell to an action, then it is an excitatory neurotransmitter acting in an excitatory synapse. On the other hand, if it inhibits the target cell, it is an inhibitory neurotransmitter acting in an inhibitory synapse. So, the type of the synapse and the response of the target tissue depends on the type of neurotransmitter. Excitatory neurotransmitters cause depolarization of the postsynaptic cells and generate an action potential; for example acetylcholine stimulates muscle contraction. Inhibitory synapses cause hyperpolarization of the target cells, leading them farther from the action potential threshold, thus inhibiting their action; for example GABA inhibits involuntary movements.
The neurotransmitter released into the synaptic cleft acts for a very short duration, only minutes or even seconds. It is either destroyed by enzymes, such as acetylcholine esterase, or is reabsorbed into the terminal button of the presynaptic neuron by reuptake mechanisms and then recycled. The best-known neurotransmitters responsible for such fast, but short-lived excitatory action are acetylcholine, norepinephrine, and epinephrine while GABA is the major inhibitory neurotransmitter.
Repeated synaptic activities can have long-lasting effects on the receptor neuron, including structural changes such as the formation of new synapses, alterations in the dendritic tree, or growth of axons. An example of this is the learning process – the more you study and repeat, the more synapses are created in your brain and enable you to retrieve that information when needed.
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Besides neurotransmitters, there are other synapse-associated chemical substances called the neuromediators (neuromodulators). Neuromodulation differs to neurotransmission by how long the substance acts on the synapse. Neuromodulators aren’t reabsorbed as quickly by presynaptic neurons or broken down by enzymes. Instead, they spend a significant amount of time in cerebrospinal fluid, influencing (modulating) the activity of several other neurons in the brain. The best known neuromodulators are also neurotransmitters, such as dopamine, serotonin, acetylcholine, histamine, and norepinephrine.
Other associated chemical substances include neurohormones. They are synthesized in neurons and secreted into the bloodstream which carries them to distant tissues. The best examples are the hypothalamic releasing hormones oxytocin and vasopressin.
Neurotransmitters can be classified as either excitatory or inhibitory.
Classification of neurotransmitters
Excitatory neurotransmitters function to activate receptors on the postsynaptic membrane and enhance the effects of the action potential, while inhibitory neurotransmitters function to prevent an action potential. In addition to the above classification, neurotransmitters can also be classified based on their chemical structure:
- Amino acids – GABA, glutamate
- Monoamines – serotonin, histamine
- Catecholamines (subcategory of monoamines) – dopamine, norepinephrine, epinephrine
The following are the most clearly understood and most common types of neurotransmitters.
Acetylcholine (ACh) is an excitatory neurotransmitter secreted by motor neurons that innervate muscle cells, basal ganglia, preganglionic neurons of the autonomic nervous system, and postganglionic neurons of the parasympathetic and sympathetic nervous systems.
Key facts about the acetylcholine (ACh)
Excitatory in all cases except in the heart (inhibitory)
Motor neurons, basal ganglia, preganglionic neurons of the autonomic nervous system, postganglionic neurons of the parasympathetic nervous system, and postganglionic neurons of the sympathetic nervous system that innervate the sweat glands
Regulates the sleep cycle, essential for muscle functioning
Its main function is to stimulate muscle contraction. However, the only exception to this, where acetylcholine is an inhibitory neurotransmitter, is at the parasympathetic endings of the vagus nerve. These inhibit the heart muscle through the cardiac plexus.
It is also found in sensory neurons and in the autonomic nervous system, and has a part in scheduling the “dream state” while an individual is fast asleep. Acetylcholine plays a vital role in the normal functioning of muscles. For example, poisonous plants like curare and hemlock cause paralysis of muscles by blocking the acetylcholine receptor sites of myocytes (muscle cells). The well-known poison botulin works by preventing vesicles in the terminal bouton from releasing acetylcholine, thus leading to paralysis of the effector muscle.
Norepinephrine (NE), also known as noradrenaline (NAd), is an excitatory neurotransmitter produced by the brainstem, hypothalamus, and adrenal glands and released into the bloodstream. In the brain it increases the level of alertness and wakefulness.
Key facts about the norepinephrine (NE)
Brainstem, hypothalamus, and adrenal glands
Increases the level of alertness and wakefulness, stimulates various processes of the body
In the body, it is secreted by most postganglionic sympathetic nerves. It acts to stimulate the processes in the body. For example, it is very important in the endogenous production of epinephrine. Norepinephrine has been implicated in mood disorders such as depression and anxiety, in which case its concentration in the body is abnormally low. Alternatively, an abnormally high concentration of it may lead to an impaired sleep cycle.
Also known as adrenaline (Ad), epinephrine (Epi) is an excitatory neurotransmitter produced by the chromaffin cells of the adrenal gland. It prepares the body for the fight-or-flight response. That means that when a person is highly stimulated (fear, anger etc.), extra amounts of epinephrine are released into the bloodstream.
Key facts about the epinephrine (Epi)
Chromaffin cells of the medulla of adrenal gland
The fight-or-flight response (increased heart rate, blood pressure, and glucose production)
This release of epinephrine increases heart rate, blood pressure, and glucose release from the liver (via glycogenolysis). In this way, the nervous and endocrine systems prepare the body for dangerous and extreme situations by increasing nutrient supply to key tissues.
Dopamine (DA) is a neurotransmitter secreted by the neurons of the substantia nigra. It is considered a special type of neurotransmitter because its effects are both excitatory and inhibitory. Which effect depends on the type of receptor that dopamine binds to.
Key facts about dopamine
Both excitatory and inhibitory
Inhibits unnecessary movements, inhibits the release of prolactin, and stimulates the secretion of growth hormone
As a part of the extrapyramidal motor system which involves the basal ganglia, dopamine is important for movement coordination by inhibiting unnecessary movements. In the pituitary gland, it inhibits the release of prolactin, and stimulates the secretion of growth hormone.
Dopamine deficiency related to the destruction of the substantia nigra leads to Parkinson’s disease. Increased activity of dopaminergic neurons contributes to the pathophysiology of psychotic disorders and schizophrenia. Drug and alcohol abuse can temporarily increase dopamine levels in the blood, leading to confusion and the inability to focus. However, an appropriate secretion of dopamine in the bloodstream plays a role in the motivation or desire to complete a task.
gamma-Aminobutyric acid (GABA) is the most powerful inhibitory neurotransmitter produced by the neurons of the spinal cord, cerebellum, basal ganglia, and many areas of the cerebral cortex. It is derived from glutamate.
Key facts about the gamma-aminobutyric acid (GABA)
Neurons of the spinal cord, cerebellum, basal ganglia, and many areas of the cerebral cortex
Reduces neuronal excitability throughout the nervous system
Functions of GABA are closely related to mood and emotions. It is an inhibitory neurotransmitter that acts as a brake to excitatory neurotransmitters; thus when it is abnormally low this can lead to anxiety. It is widely distributed in the brain and plays a principal role in reducing neuronal excitability throughout the nervous system.
Glutamate (Glu) is the most powerful excitatory neurotransmitter of the central nervous system which ensures homeostasis with the effects of GABA. It is secreted by neurons of the many of the sensory pathways entering the central nervous system, as well as the cerebral cortex.
Key facts about the glutamate (Glu)
Sensory neurons and cerebral cortex
Regulates central nervous system excitability, learning process, memory
Glutamate is the most common neurotransmitter in the central nervous system; it takes part in the regulation of general excitability of the central nervous system, learning processes, and memory. Thus, inappropriate glutamate neurotransmission contributes to developing epilepsy and cognitive and affective disorders.
Serotonin (5-hydroxytryptamine, 5-HT) is an inhibitory neurotransmitter that has been found to be intimately involved in emotion and mood. It is secreted by the neurons of the brainstem and by neurons that innervate the gastrointestinal tract (enteric nervous system). In addition, serotonin is found in platelets (thrombocytes) which release it during coagulation (hemostasis).
Key facts about the serotonin (5-HT)
Neurons of the brainstem and gastrointestinal tract, thrombocytes
Regulates body temperature, perception of pain, emotions, and sleep cycle
It participates in regulation of body temperature, perception of pain, emotions, and sleep cycle. An insufficient secretion of serotonin may result in decreased immune system function, as well as a range of emotional disorders like depression, anger control problems, obsessive-compulsive disorder, and even suicidal tendencies.
Histamine is an excitatory neurotransmitter produced by neurons of the hypothalamus, cells of the stomach mucosa, mast cells, and basophils in the blood. In the central nervous system, it is important for wakefulness, blood pressure, pain, and sexual behavior. In the stomach, it increases the acidity.
Key facts about the histamine
Hypothalamus, cells of the stomach mucosa, mast cells, and basophils in the blood
Regulates wakefulness, blood pressure, pain, and sexual behavior; increases the acidity of the stomach; mediates inflammatory reactions
It is involved primarily in the inflammatory response, as well as a range of other functions such as vasodilation and regulation of the immune response to foreign bodies. For example, when allergens are introduced into the bloodstream, histamine assists in the fight against these microorganisms causing itching of the skin or irritations of the throat, nose, and or lungs.
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Disorders associated with neurotransmitters
Alzheimer’s disease is a neurodegenerative disorder characterized by learning and memory impairments. It is associated with a lack of acetylcholine in certain regions of the brain.
Depression is believed to be caused by a depletion of norepinephrine, serotonin, and dopamine in the central nervous system. Hence, pharmacological treatment of depression aims at increasing the concentrations of these neurotransmitters in the central nervous system.
Schizophrenia, which is a severe mental illness, has been shown to involve excessive amounts of dopamine in the frontal lobes, which leads to psychotic episodes in these patients. The drugs that block dopamine are used to help schizophrenic conditions.
The destruction of the substantia nigra leads to the destruction of the only central nervous system source of dopamine. Dopamine depletion leads to uncontrollable muscle tremors seen in patients suffering from Parkinson's disease.
Some epileptic conditions are caused by the lack of inhibitory neurotransmitters, such as GABA, or by the increase of excitatory neurotransmitters, such is glutamate. Depending on the cause of the seizures, the treatment is aimed to either increase GABA or decrease glutamate.
Besides epilepsy, a chronic reduction of GABA in the brain can lead to Huntington’s disease. Even though this is an inherited disease related to abnormality in DNA, one of the products of such disordered DNA is the reduced ability of the neurons to take up GABA. There is no cure for Huntington’s disease, but we still can treat symptoms by pharmacologically increasing the amount of inhibitory neurotransmitters.
Myasthenia gravis is a rare chronic autoimmune disease characterized by the impairment of synaptic transmission of acetylcholine at neuromuscular junctions, leading to fatigue and muscular weakness without atrophy.
Most often, myasthenia gravis results from circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction. This inhibits the excitatory effects of acetylcholine on nicotinic receptors at neuromuscular junctions. In a much rarer form, muscle weakness may result from a genetic defect in parts of the neuromuscular junction which is inherited, as opposed to developing through passive transmission from the mother's immune system at birth or through autoimmunity later in life.
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