GABA (NEUROTRANSMITTER): RECEPTORS, FUNCTIONS AND ALTERATIONS - GEOGRAFÍA - 2025

The GABA or gamma aminobutyric acid is the most important inhibitory neurotransmitter in the nervous system. It is the most abundant inhibitory neurotransmitter, and it is distributed throughout the brain and spinal cord.

In fact, between 30 and 40% of the neurons in our brain exchange the neurotransmitter GABA. These neurons are called GABAergic. This substance is essential on the sensitive, cognitive and motor plane. It also plays an important role in the stress response.

Neurons are interconnected in our brain and exchange excitatory and inhibitory neurotransmitters to send each other messages.

Too much excitement would cause instability in our brain activity. The neurons would transmit excitatory synapses to other neurons which, in turn, would excite their neighbors. The excitation would spread until it reached the neurons where the activation originated, causing all the neurons in the brain to discharge uncontrollably.

This is what happens in epileptic seizures or seizures. In fact, some scientists claim that one of the causes of epilepsy is an alteration of the neurons that secrete GABA or its receptors.

On the other hand, too much excitement can cause irritability, nervousness, insomnia, motor disorders, etc.

This is why the activity of inhibitory neurons, such as those that secrete gamma aminobutyric acid, is so important. This substance allows you to balance brain activation, so that optimal levels of arousal are maintained at all times.

To do this, the GABA receptors located in neurons receive chemical messages that make them inhibit or decrease nerve impulses. In this way, GABA acts as a brake after periods of intense stress; produces relaxation and induces sleep. In fact, some drugs used to treat anxiety, such as benzodiazepines, stimulate GABA receptors.

Altered levels of gamma aminobutyric acid are associated with psychiatric and neurological disorders. Low levels of this substance or a decrease in its function are linked to anxiety, depression, schizophrenia, sleep disorders, insomnia…

Brief history of GABA

GABA chemical structure

Gamma aminobutyric acid was first synthesized in 1883, but its effects were not known. It was only known that it was a product that acted on the metabolism of plants and microbes.

Around 1950, researchers realized that it was also found in the nervous system of mammals.

Biosynthesis

Gamma aminobutyric acid comes from glutamic acid (glutamate), the main excitatory neurotransmitter. This is converted to GABA through an enzyme called glutamic acid decarboxylase (GAD) and a cofactor called pyridoxal phosphate, which is the active form of vitamin B6. To create GABA, a carboxyl group is removed from glutamate.

For the effect of GABA to be interrupted, this substance must be received through glial cells. Neurons also recapture it thanks to special transporters. The goal is to remove the GABA from the brain's extracellular fluid so that it is not absorbed by GABAergic neurons.

Receivers

Two important receptors that capture GABA are:

GABA A receptor

It is a receptor that controls a chlorine channel. This is complex, as it has more than 5 different junction sites. They have a site that captures GABA, where muscimol, which mimics its effects (agonist), can also bind. In addition, it can capture bicuculin, a substance that blocks the effects of GABA (antagonist).

While, in the second place of the GABA A receptor, anxiolytic drugs called benzodiazepines (such as Valium and Líbrium) bind. They serve to reduce anxiety, relax muscles, induce sleep, reduce epilepsy, etc. Possibly in this same place alcohol binds to exert its effects.

A third place allows the binding of barbiturates, other older and less safe anxiolytic drugs. At low doses, they have a relaxing effect. However, higher doses cause problems with speaking and walking, loss of consciousness, coma, and even death.

A fourth site receives various steroids, such as some used for general anesthesia. In addition, there are hormones that the body produces, such as progesterone, that binds here. This hormone is released in pregnancy and produces mild sedation.

While in the last place picrotoxin binds, a poison present in a bush from India. This substance has the opposite effects to those of anxiolytics. That is, it blocks the activity of the GABA A receptor by functioning as an antagonist. That is why in high doses it can cause seizures.

Both benzodiazepines and barbiturates activate the GABA A receptor, which is why they are called agonists.

There are more complex binding sites than others, such as that of benzodiazepines. All of this is known from research, but there is much to know. Our brain can naturally produce substances that bind to these receptors, exerting agonistic or antagonistic effects. However, these compounds have not yet been identified.

GABA B receptor

This receptor regulates a potassium channel and is metabotropic. That is, it is a receptor coupled to a G protein. When activated, a series of biochemical events take place that can cause the opening of other ion channels.

Baclofen is known to be an agonist of this receptor, causing muscle relaxation. While the compound CGP 335348, works as an antagonist.

In addition, when GABA B receptors are activated, potassium channels open, producing inhibitory potentials in neurons.

GABA C receptor

On the other hand, a GABA C receptor is also being studied. These are not modulated by benzodiazepines, barbiturates or steroids.

It appears to be predominantly found in the retina, although it may be elsewhere in the central nervous system. It is involved in cells that regulate vision, and its main agonists are TACA, GABA, and muscimol. Meanwhile, picrotoxin exerts antagonistic effects.

For now, no diseases have been found that are associated with mutations in this receptor. However, it appears that GABA C receptor antagonists are associated with prevention of myopia-induced form of deprivation, and further research is required to see what their role is in ocular disorders.

GABA functions

GABA A receptor cell. Source: Bruce Blaus via Wikimedia Commons)

It is not surprising that GABA performs a multitude of functions due to its wide distribution and quantity throughout the central nervous system. Many of its exact functions are not known today. Much of the current discoveries are due to research with drugs that potentiate, mimic or inhibit the effects of GABA.

In summary, gamma aminobutyric acid is known to be an inhibitory substance that helps maintain balanced brain activity. Participate in:

Relaxation

GABA inhibits the neural circuits that are activated by stress and anxiety, producing a state of relaxation and tranquility. Thus, glutamate would activate us while GABA would restore calm by reducing the excitation of neurons.

The dream

GABA increases progressively when we are sleepy. When we are asleep, it reaches very high levels, since it is the moment when we are most relaxed and calm.

In our brain there is a group of cells called the ventrolateral preoptic nucleus, also known as the "sleep switch." 80% of the cells in this area are GABAergic.

On the other hand, GABA participates in the maintenance of our internal clock or circadian rhythms. In fact, when animals hibernate, their amount of GABA increases markedly.

During sleep, accompanied by an increase in GABA, an increase in cytokines also occurs. They are proteins that protect the body from inflammation. That is why adequate rest is essential, since the body is kept healthy, repairing its damages.

The pain

GABA is known to have nociceptive (pain perception) effects. For example, if baclofen, a substance that binds to GABA B receptors, is administered, it produces an analgesic effect in humans. This substance works by decreasing the release of pain neurotransmitters in neurons in the dorsal horn of the spinal cord.

Thus, when areas of these receptors are altered, animals develop hyperalgesia (a very intense perception of pain). For this reason, GABA B receptors are thought to be involved in maintaining an adequate pain threshold.

Endocrine functions

It appears that after receiving high doses of GABA, there is a significant increase in growth hormone. This hormone allows the development and recovery of muscles, and also increases during deep sleep.

GABA also appears to play an important role in the regulation of female hormonal cycles.

GABA alterations

GABA metabolism, glial cell involvement. Source: Pancrat via Wikimedia Commons)

GABA levels or its activity can be altered by various conditions. For example, due to the consumption of alcohol, drugs or drugs.

On the other hand, certain psychiatric and neurological diseases are associated with alterations in the functioning of GABAergic neurons and their receptors.

Each of these situations is explained in more detail below.

Anxiety

Low GABA levels or inadequate activity of this neurotransmitter is associated with anxiety and stress.

This is why a large number of anxiolytic drugs act on GABA A receptors. Also, some relaxing activities (such as yoga) may act in part on GABA levels. Specifically, it significantly increases its amount in the brain.

Depression

Excessive levels of GABA can translate into depression, as too much relaxation can turn into indifference or apathy.

Hallucinations

An association between low levels of GABA in the brain and olfactory and taste hallucinations has been discovered. These are positive symptoms of schizophrenia, a condition that is also associated with changes in GABA.

Furthermore, these hallucinations were found to cease with a treatment that increased GABA in the central nervous system.

Movement disorders

Some neurological movement disorders such as Parkinson's disease, Tourette syndrome, or tardive dyskinesia seem to be related to GABA.

Baclofen, a synthetic analog of GABA, appears to be effective in treating Tourette syndrome in children.

While GABA agonists like gabapentin and zolpidem help in the treatment of Parkinson's disease. On the other hand, vigabatrin benefits tardive dyskinesia and other motor problems.

All this suggests that the origin of these conditions may be a defective signaling of the GABAergic pathways.

Epilepsy

A failure or dysregulation in the transmission of gamma aminobutyric acid produces hyperexcitability. That is, neurons become overly activated, leading to epileptic activity.

The main epileptic foci where GABA fails are the neocortex and the hippocampus. However, epilepsy has a strong genetic component. There are people who are born with a greater predisposition than others to suffer epileptogenic activity or seizures.

Currently, it has been discovered that a failure in the expression of γ2, a part of the GABA A receptor, causes the appearance of epilepsy.

Alcohol consumption

Alcohol or ethanol is a widely used substance in today's society. It has a depressant action on the central nervous system.

Specifically, it blocks the excitation produced by NMDA receptors and enhances the inhibitory impulses of GABA A receptors.

At low levels, ethanol produces disinhibition and euphoria. Although in high levels in the blood, it can cause respiratory failure and even death.

Cognition

GABA A receptors have been found to possess a site of action for a substance called RO4938581. This drug is an inverse agonist, that is, it does the opposite effect of GABA.

It appears that this drug improves cognition. Specifically, it allows us to better consolidate spatial and temporal memories (where and when something happened).

Furthermore, when GABA receptors are inhibited or have mutations in the hippocampus, there are improvements in association learning.

Drug addiction

Baclofen, a drug mentioned earlier, appears to be helpful in treating addiction to drugs such as alcohol, cocaine, heroin, or nicotine. Although it has many side effects and other similar ones are used that also cause an inhibitory effect.

Drugs of abuse cause a release of dopamine in the nucleus of accumbens. This area of ​​the brain is essential in the sensation of reward and in reinforcement.

When baclofen is given, the desire to take drugs decreases. This occurs because the substance reduces the activation of dopaminergic neurons in that area. Ultimately, they feel that the drug does not have the expected effect and they no longer want to consume it.

Sleep disorders

Changes in GABA can cause various sleep problems. When there is less GABA than normal or neurons do not work properly, insomnia often occurs.

However, when the levels of this substance are very high, you can suffer from sleep paralysis. In this disorder, the person can wake up when their body is paralyzed by REM phase and cannot move.

On the other hand, narcolepsy has been linked to hyperactivity of GABAergic receptors.

Alzheimer's

In some investigations, elevated levels of GABA have been observed in patients with Alzheimer's disease. Senile plaque formation and increased GABA appear to progressively block neuronal activity in patients. Above all, those involved in learning and memory.

High GABA levels

Too much GABA can cause excessive drowsiness, as occurs with alcohol or Valium consumption.

However, very high GABA can produce the opposite effect in many people, and can cause anxiety or panic. It is accompanied by tingling, shortness of breath, and changes in blood pressure or heart rate.

GABA supplements

A microscopic image of stained neurons taken from an electron microscope. Source: Neuron Experts (Contract Research Organization)

Currently gamma aminobutyric acid is commercially available as a dietary supplement, both natural and synthetic. Natural GABA is created by a fermentation process that uses a bacteria called Lactobacillus hilgardii.

Many people consume it to sleep better and reduce anxiety. It is also famous in athletes, since it appears to contribute to fat loss and the development of muscle mass.

This is because it produces an intense increase in growth hormone, which is essential for muscle. In addition, it allows you to sleep better, something that those who do bodybuilding need.

However, the use of this supplement is subject to controversy. Many believe that scientific evidence on its benefits is lacking.

Furthermore, it appears that it is difficult for GABA in the blood to cross the blood-brain barrier to reach the brain. Therefore, it could not act on the neurons of our nervous system.

References

1. Alfaro Valverde, E. (2011). GABA receptors (GABA receptors). University of Costa Rica, National Psychiatric Hospital: 8-16.
2. Carlson, NR (2006). Physiology of behavior 8th Ed. Madrid: Pearson.
3. Cortes-Romero, C., Galindo, F., Galicia-Isasmendi, S., & Flores, A. (2011). GABA: functional duality? Transition during neurodevelopment. Rev Neurol, 52, 665-675.
4. Function of the GABA Neurotransmitter and Everything Else About It. (Sf). Retrieved on March 21, 2017, from Examined Existence: examinedexistence.com.
5. GABA. (sf). Retrieved on March 21, 2017, from Biopsicología: biopsicologia.net.
6. Gamma-Aminobutyric Acid (GABA) Monograph. (2007). Alternative Medicine Review, 12 (3): 274-279.
7. Konkel, L. (2015, October 16). What is GABA? Retrieved from Everyday health: everydayhealth.com.
8. What is GABA? - Function, Benefits & Side Effects. (sf). Retrieved on March 22, 2017, from Study: study.com.