A neurotransmitter is a chemical substance produced within the body (endogenous) responsible for a process called synaptic transmission or neurotransmission. In this article, we are going to discuss the mechanism of neurotransmission, classification of neurotransmitters, and some clinical notes about the disorders associated with both excessive and lack of some neurotransmitters.
Mechanism of neurotransmission
The transmission of impulses through synapses involves the release of endogenous chemical substances called neurotransmitters that are present within synaptic vesicles.
- A nerve impulse or an action potential reaches a terminal bouton (presynaptic terminal).
- Voltage-sensitive calcium channels are opened up so that there is an influx of calcium ions leading to a series of chemical changes.
- Synaptic vesicles pour the neurotransmitters stored in them into the synaptic cleft (gap between two synapsing surfaces, for example between two neurons or a neuron and muscle tissue) in a process called “kiss and run” recycling, thus releasing the neurotransmitter into the gap between the presynaptic surface and the postsynaptic surface.
- The postsynaptic surface becomes depolarized (under the influence of the neurotransmitter) resulting in a nerve impulse in the postsynaptic neuron, and the neurotransmitter reaches and binds onto the receptor molecules present in the postsynaptic membrane. This alters the permeability of the postsynaptic membrane to ions of calcium, sodium, potassium, and chloride leading to depolarization.
However, permeability is also dependent on the type of neurotransmitter involved. In the case of an inhibitory synapse, the presence of the neurotransmitter causes hyperpolarization of the postsynaptic membrane. The neurotransmitter released into the synaptic cleft acts only for a very short duration, minutes or even seconds. It is either destroyed by enzymes, such as acetylcholine esterase or is withdrawn into the terminal bouton of the presynaptic neuron. The best-known neurotransmitters responsible for such fast, but short-lived action are acetylcholine, noradrenaline, and adrenaline, as well as inhibitory neurotransmitters such as GABA (gamma-aminobutyric acid).
Repeated synaptic activities can have some long-lasting effect on the receptor neuron, including structural changes such as the formation of new synapses, alterations in the dendritic tree, or growth of axons. Such effects produced under the influence of chemical substances like neurotransmitters or any other synapse-associated substance are described as neuro-mediation and the chemical substances concerned are called neuromediators. Other associated chemical substances include neurohormones synthesized in neurons and poured into the bloodstream through terminals resembling synapses in structure. Similar chemical substances are also poured into the cerebrospinal fluid or into the intercellular spaces to influence other neurons in a different manner.
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 in a reverse mechanism. The following are the most clearly understood and most common types of neurotransmitters:
Acetylcholine is an excitatory neurotransmitter occurring throughout the nervous system and is the most well understood and studied. It was the first neurotransmitter to be discovered and was isolated in 1921 by a German biologist named Otto Loewi, who later won a Nobel Prize for his work. Acetylcholine has many functions ranging from the stimulation of muscles, including the muscles of the gastrointestinal system to vital organs. 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, the plant poisons, curare, and hemlock cause paralysis of muscles by blocking the acetylcholine receptor sites of myocytes. The well-known poison botulin works by preventing the vesicles in the axon ending from releasing acetylcholine, thus leading to paralysis of the effector muscle.
Norepinephrine, also known as noradrenaline, is an excitatory neurotransmitter secreted by the adrenal glands. It acts to increase the alertness of the nervous system as well as to stimulate the processes in the body. For example, it is very important in the endogenous production of epinephrine. It was first identified by a Swedish biologist called Ulf von Euler in 1946. Norepinephrine has been implicated in mood disorders such as anxiety, in which case its concentration in the body is abnormally high. Alternatively, an abnormally low concentration of it may lead to an impaired sleep cycle.
Also known as adrenaline, epinephrine is an excitatory neurotransmitter produced by the adrenal glands and released into the bloodstream. It prepares the body for the fight or flight reaction. That means that when a person is highly stimulated (fear, anger etc), extra amounts of epinephrine are released into the bloodstream. This release of epinephrine, increases the heart rate, the blood pressure and the glucose production from the liver (glycogenolysis). In this way, the nervous and the endocrine system prepare the body for dangerous and extreme situations.
Dopamine is considered a special type of neurotransmitter because its effects are both excitatory and inhibitory. It was discovered in the 1950s by another Swede, Arvid Carlsson. It is strongly associated with the reward mechanisms in the brain, and drugs such as cocaine, opium, heroin, and alcohol can temporarily increase its levels in the blood, leading to abnormal firing of nerve cells, which may sometimes manifest as intoxication, or several manners of consciousness/focus issues (such as not remembering where we put our keys, or forgetting what a paragraph said when we have just finished reading it, or simply daydreaming and not being able to stay on task). 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 an inhibitory neurotransmitter isolated in 1950 by Eugene Roberts and J. Awapara. An abnormally low secretion of GABA may cause conditions like anxiety. Because it is an inhibitory neurotransmitter, GABA acts as a brake to the excitatory neurotransmitters, and 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 is another neurotransmitter with an excitatory effect and usually ensures homeostasis with the effects of GABA. It is the most common neurotransmitter in the central nervous system; however, excessive levels of it can be toxic to the nerve cells and may lead to conditions like stroke.
Serotonin is an inhibitory neurotransmitter that has been found to be intimately involved in emotion and mood. It was discovered by Vittorio Erspamer in the 1930s but was first found in blood serum in 1948 by Irvine Page who named it serotonin (meaning “serum-tonic”). Adequate amounts of serotonin are necessary for a stable mood, and also to balance any excessive excitatory neurotransmitter effects in the brain. Like norepinephrine, serotonin also regulates many processes in the body, such as carbohydrate cravings, the sleep cycle, pain control, and the digestion of food. 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 basophils and is found in high concentrations in the blood. It is involved primarily in the inflammatory responses, 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. It also plays a role in the wake/sleep cycle, by increasing wakefulness.
In addition to the above classification, neurotransmitters can also be classified based on their molecular types. Dopamine, adrenaline, noradrenaline, and 5-hydroxytryptamine (the indoleamine serotonin) are classified as monoamines. Glycine, glutamate, and GABA are classed under amino acids.
Disorders associated with Neurotransmitters
Generally, several neurotransmitters have been linked to many different disorders. For example, Alzheimer’s disease, characterized by learning and memory impairments, is associated with a lack of glutamate and acetylcholine in certain regions of the brain. Schizophrenia, which is a severe mental illness, has been shown to involve excessive amounts of dopamine in the frontal lobes, and drugs that block dopamine are used to help schizophrenic conditions. On the other hand, too little dopamine in the motor areas of the brain is responsible for the loss of control or uncontrollable muscle tremors seen in patients suffering from Parkinson's disease. It was the same Arvid Carlsson mentioned above who figured out that the precursor to dopamine (called L-dopa) could alleviate some of the symptoms of Parkinson's disease.
A chronic reduction of GABA in the brain can lead to epilepsy and Huntington’s disease. Similarly, an imbalance in serotonin can lead to depression, suicidal ideation, impulsive behavior, and aggressiveness, while other mood disorders such as manic depression have been linked to a deficiency in noradrenaline. Furthermore, myasthenia gravis is a rare chronic autoimmune disease characterized by impairment of synaptic transmission of neurotransmitters, particularly acetylcholine, at a neuromuscular junction 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, inhibiting the excitatory effects of acetylcholine on nicotinic receptors at the neuromuscular junctions. Also, in a much rarer form, muscle weakness may result from a genetic defect in some part of the neuromuscular junction that is inherited, as opposed to developing through passive transmission from the mother's immune system at birth or through autoimmunity later in life.