Neurotransmitters

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.

Key facts about neurotransmitters

Excitatory Glutamate (Glu)

neurotransmitters Acetylcholine (ACh)
Histamine
Dopamine (DA)
Norepinephrine (NE); also known as noradrenaline (NAd)
Epinephrine (Epi); also known as adrenaline (Ad)

Inhibitory gamma-Aminobutyric acid (GABA)

neurotransmitters Serotonin (5-HT)
 Dopamine (DA)

Neuromodulators Dopamine (DA)

Serotonin (5-HT)
Acetylcholine (ACh)
Histamine
Norepinephrine (NE)

Neurohormones 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.

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. 

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. 

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.    

Classification

Neurotransmitters can be classified as either excitatory or inhibitory. 

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

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)

Type Excitatory in all cases except in the heart (inhibitory)

Released from 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

Functions 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

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)

Type Excitatory

Released from Brainstem, hypothalamus, and adrenal glands

Functions 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.
Epinephrine

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)

Type Excitatory

Released from Chromaffin cells of the medulla of adrenal gland

Functions 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

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

Type Both excitatory and inhibitory

Released from Substantia nigra

 Functions 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.
GABA

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)

Type Inhibitory

Released from Neurons of the spinal cord, cerebellum, basal ganglia, and many areas of the cerebral cortex

Functions 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

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)

Type Excitatory

Released from Sensory neurons and cerebral cortex

Functions 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

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)

Type Inhibitory 

Released from Neurons of the brainstem and gastrointestinal tract, thrombocytes

 Functions Regulates body temperature, perception of pain, emotions, and sleep cycle

In 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

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

Type Excitatory

Released from Hypothalamus, cells of the stomach mucosa, mast cells, and basophils in the blood

Functions 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.

Disorders associated with neurotransmitters

Alzheimer’s disease

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

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

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. 
Parkinson’s disease

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. 
Epilepsy

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.
Huntington’s disease

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

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.