Glutamic acid receptors. Very nervous excitement. Dysfunction of the glutamatergic system

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Many people want to improve their brain function and for this they resort to the use of nootropics. Familiarize yourself with the properties and rules for the use of glutamate.

The human body is a complex mechanism. Surely you have noticed how some people are able to think quickly, while others can “slow down”. This is influenced by a lot of factors, but there are two that can be influenced. We are now talking about the neurotransmitters GABA (slowing down) and glutamate (exciting). Although their effect on the body is the opposite, for the synthesis of these substances is used glutamic acid.

Glutamate is now actively used in Food Industry. Surely in the composition of any products you have come across the name "monosodium glutamate". This substance deceives the brain, telling it that the food is delicious.

Mechanism of glutamate

If we talk about the mechanism of the substance in a few words, then glutamate accelerates the process of information transfer between the cells of the nervous system. As a result, a person is able to act and make decisions faster. There are millions of chains of nerve cells in the brain and they are constantly exchanging information. It should be noted that each of these chains is responsible for some process.

For example, you saw something and based on this you make an appropriate decision. The first to react to the situation is the retina with the optic nerve. Then the signals are transmitted to the cerebral cortex and further along the chain to the motor organs. Glutamate can be compared to a magnet that depolarizes the cells of the nervous system. The more actively their polarity changes, the faster the signal is transmitted.

Glutamate acts on cell structures using one of two pathways - metabotropic or ionotropic. The first is slower, but the impact lasts longer.

You probably know that neurotransmitters are synthesized by a neuron and then act on the corresponding receptors of the second one. Receptors can be compared to doors that open the way for a neurotransmitter to a second neuron. Glutamate is able to interact with the following types of receptors:

• NMDA - at rest, the receptors are "closed" with the help of a magnesium ion. As soon as a glutamate molecule enters the synaptic cleft, the “door” opens and ions depolarize. As a result, sodium enters the neuron, and potassium and calcium leave it. This process largely determines the level of human intelligence.
• AMPA - today scientists are actively working on the creation of nootropics that can actively interact with these receptors.
• Cocaine - scientists have not yet revealed all the secrets of this type of receptor. It is well established that their number is less than the two described above. However, in terms of their ability to pass potassium and sodium ions, cocaine receptors are similar to AMPA. Thus, these receptors are able to speed up the process of data transfer. But at the same time, the rate of depolarization of the postsynaptic neuron is low.

We have now considered the ionotropic pathway of the neurotransmitter. To activate metabotropic glutamate, it acts on mGlu receptors. As we said above, they have a different mechanism of work and have a longer potential.

Positive and negative properties of glutamate

Among the positive properties of the neurotransmitter, it should be noted an increase in the speed of thinking, a person remembers information faster, and also has time to do more in a short period of time. Among the negative points, it is necessary to remember the increase in impulsivity, the appearance of a feeling of anxiety, as well as excitotoxicity.

How to increase the concentration of glutamate?

Since it is synthesized from glutamic acid, it is first necessary to increase the amount of this raw material in the body. Food items include meat, fish and cheese. However, you remember that the same glutamic acid is also used for the synthesis of GABA, and what exactly needs to be synthesized at a particular point in time is decided by the body itself. So far, scientists are sure of only one natural way to increase the concentration of glutamate - stress and cramming.

07 October 2016

Glutamate

Physiologist Vyacheslav Dubynin on sensory transmission, NMDA receptors and the properties of glutamic acid.

At the heart of the brain is the interaction of nerve cells, and they talk to each other with the help of substances called mediators. There are quite a lot of mediators, for example, acetylcholine, norepinephrine. One of the most important mediators, and perhaps the most important, is called glutamic acid, or glutamate. If you look at the structure of our brain and what substances different nerve cells use, then glutamate is secreted by about 40% of neurons, that is, this is a very large proportion of nerve cells.

With the help of glutamate release in our brain, brain and spinal cord, the main information flows are transmitted: everything related to sensory (vision and hearing), memory, movement, until it reaches the muscles - all this is transmitted through the release of glutamic acid. Therefore, of course, this mediator deserves special attention and is being actively studied.

In terms of its chemical structure, glutamate is a fairly simple molecule. It is an amino acid, and a food amino acid, that is, we get similar molecules simply as part of the proteins that we eat. But I must say that food glutamate (from milk, bread or meat) practically does not pass into the brain. Nerve cells synthesize this substance right at the endings of axons, right in those structures that are part of the synapses, "in place" and further isolated in order to transmit information.

Making glutamate is very easy. The starting material is α-ketoglutaric acid. This is a very common molecule, it is obtained during the oxidation of glucose, in all cells, in all mitochondria there is a lot of it. And further on this α-ketoglutaric acid, it is enough to transplant any amino group taken from any amino acid, and now we get glutamate, glutamic acid. Glutamic acid can also be synthesized from glutamine. This is also a food amino acid, glutamate and glutamine are very easily converted into each other. For example, when glutamate has completed its function in the synapse and transmitted a signal, it is further destroyed to form glutamine.

Glutamate is an excitatory neurotransmitter, that is, it is always in our nervous system, in synapses, causing nervous excitation and further signal transmission. In this, glutamate differs, for example, from acetylcholine or norepinephrine, because acetylcholine and norepinephrine can cause excitation in some synapses, inhibition in others, they have a more complex algorithm of work. And glutamate in this sense is simpler and more understandable, although you won’t find such simplicity at all, since there are about 10 types of receptors for glutamate, that is, sensitive proteins that this molecule acts on, and different receptors conduct at different speeds and with different parameters glutamate signal.

Plant evolution has found a number of toxins that act on glutamate receptors. For what it is for plants, in general, is quite clear. Plants, as a rule, are against being eaten by animals, so evolution comes up with some kind of protective toxic constructs that stop herbivores. The most powerful plant toxins are associated with algae, and it is algae toxins that can very powerfully affect the glutamate receptors in the brain and cause total excitement and convulsions. It turns out that the superactivation of glutamate synapses is a very powerful excitation of the brain, a convulsive state. Probably the most famous molecule in this series is called domoic acid, it is synthesized by unicellular algae - there are such algae, they live in the western part of Pacific Ocean, on the coast, for example, Canada, California, Mexico. Toxin poisoning of these algae is very, very dangerous. And this poisoning sometimes happens, because zooplankton feeds on unicellular algae, all kinds of small crustaceans or, for example, bivalve mollusks, when they filter water, draw in these algal cells, and then in some mussel or oyster there is too high a concentration of domoic acid, and can be seriously poisoned.

Even human deaths have been recorded. True, they are single, but nevertheless this speaks of the power of this toxin. And very characteristic is domoic acid poisoning in the case of birds. If some seabirds, which again eat small fish that feed on zooplankton, get too much domoic acid, then a characteristic psychosis occurs: some gulls or pelicans stop being afraid of large objects and, on the contrary, attack them, that is, they become aggressive . There was a whole epidemic of such poisonings sometime in the early 1960s, and newspaper reports of this epidemic of "bird psychosis" inspired Daphne Du Maurier to write the novel The Birds, and then Alfred Hitchcock directed the classic thriller The Birds, where you see thousands of very aggressive seagulls that torment the main characters of the film. Naturally, in reality there were no such global poisonings, but nevertheless, domoic acid causes very characteristic effects, and it and molecules like it, of course, are very dangerous for the brain.

We eat glutamic acid and similar glutamate in large quantities simply with dietary proteins. Our proteins, which are part of various food products, contain 20 amino acids. Glutamate and glutamic acid are part of this twenty. Moreover, they are the most common amino acids, if you look at the structure of proteins totally. As a result, in a day with regular food, we eat from 5 to 10 grams of glutamate and glutamine. At one time, it was very difficult to believe that glutamate functions as a mediator in the brain, because it turns out that the substance that we literally consume in horse doses performs such subtle functions in the brain. There was such a logical inconsistency. But then they realized that, in fact, food glutamate practically does not pass into the brain. For this we must thank the structure called the blood-brain barrier, that is, special cells surround all the capillaries, all the small vessels that penetrate the brain, and quite tightly control the movement of chemicals from the blood into nervous system. If not for this, then some eaten cutlet or bun would cause convulsions in us, and, of course, no one needs this. Therefore, food glutamate almost does not pass into the brain and, indeed, is synthesized in order to perform mediator functions directly in synapses. However, if you eat a lot of glutamate at once, then a small amount still penetrates the brain. Then there may be a slight excitement, the effect of which is comparable to a cup of strong coffee. This effect of high doses of dietary glutamate is known, and it occurs quite often if a person uses glutamate in large quantities as a food supplement.

The fact is that our taste system is very sensitive to glutamate. Again, this is due to the fact that there is a lot of glutamate in proteins. It turns out that the evolution of the taste system, tuning in to chemical analysis food, it was glutamate that she singled out as a sign of protein food, that is, we must eat protein, because protein is the main construction material our body. Similarly, our taste system has become very good at detecting glucose, because glucose and similar monosaccharides are main source energy, and protein is the main building material. Therefore, the taste system has tuned in to identify glutamate as a signal of protein food, and along with sour, sweet, salty, bitter tastes, we have sensitive cells in the tongue that react specifically to glutamate. And glutamate is also a well-known so-called flavor additive. Calling it a flavor enhancer is not entirely correct, because glutamate has its own taste, which is as great in importance as bitter, sour, sweet and salty.

I must say that the existence of glutamate taste has been known for more than a hundred years. Japanese physiologists discovered this effect due to the fact that glutamate (in the form of soy sauce or a sauce made from seaweed) has been used in Japanese and Chinese cuisine for a very long time. Accordingly, the question arose: why are they so tasty and why does this taste so different from standard tastes? Further, glutamate receptors were discovered, and then glutamate was already used almost in its pure form (E620, E621 - monosodium glutamate), in order to be added to a variety of foods. Sometimes it happens that glutamate is blamed for all mortal sins, they call it “another white death”: salt, sugar and glutamate are white death. This, of course, is greatly exaggerated, because I repeat once again: during the day we eat from 5 to 10 grams of glutamate and glutamic acid with ordinary food. So if you add a little glutamate to your food to bring out that meaty taste, there is nothing wrong with that, although, of course, excess is not healthy.

Indeed, there are many receptors for glutamate (about 10 types of receptors), which conduct glutamate signals at different rates. And these receptors are studied primarily from the point of view of the analysis of memory mechanisms. When in our brain and cortex hemispheres memory arises, this really means that synapses begin to work more actively between nerve cells that transmit some kind of information flow. The main mechanism for activating the work of synapses is an increase in the efficiency of glutamate receptors. Analyzing different glutamate receptors, we see that different receptors change their effectiveness in different ways. Probably the most studied are the so-called NMDA receptors. This is an abbreviation, it stands for N-methyl-D-aspartate. This receptor responds to glutamate and NMDA. The NMDA receptor is characterized by the fact that it is able to be blocked by a magnesium ion, and if a magnesium ion is attached to the receptor, then this receptor does not function. That is, you get a synapse in which there are receptors, but these receptors are turned off. If some strong, significant signal has passed through the neural network, then magnesium ions (they are also called magnesium plugs) break away from the NMDA receptor, and the synapse literally instantly starts to work many times more efficiently. At the level of information transfer, this just means recording a certain trace of memory. In our brain there is a structure called the hippocampus, there are just a lot of such synapses with NMDA receptors, and the hippocampus is perhaps the most studied structure in terms of memory mechanisms.

But NMDA receptors, the appearance and departure of the magnesium plug is the mechanism of short-term memory, because the plug can leave and then return - then we will forget something. If a long-term memory is formed, everything is much more complicated there, and other types of glutamate receptors work there, which are capable of transmitting a signal from the membrane of a nerve cell directly to nuclear DNA. And having received this signal, nuclear DNA triggers the synthesis of additional receptors in glutamic acid, and these receptors are embedded in synaptic membranes, and the synapse begins to work more efficiently. But this does not happen instantly, as in the case of knocking out a magnesium plug, but it takes several hours, requires repetition. But if this happened, then seriously and for a long time, and this is the basis of our long-term memory.

Of course, pharmacologists use glutamate receptors to influence various brain functions, mainly to reduce the excitation of the nervous system. A very famous drug is called ketamine. It works like an anesthetic. Ketamine, in addition, is known as a molecule with a narcotic effect, because hallucinations often occur when you come out of anesthesia, so ketamine is also referred to as a hallucinogenic, psychedelic drug, it is very difficult to deal with it. But in pharmacology, this often happens: a substance that is an essential drug has some side effects, which ultimately lead to the fact that the distribution and use of this substance must be very tightly controlled.

Another molecule very well known in connection with glutamate is memantine, a substance that can quite gently block NMDA receptors and, as a result, reduce the activity of the cerebral cortex in a variety of areas. Memantine is used in a fairly wide range of situations. Its pharmacy name is Akatinol. It is used to lower the overall level of arousal in order to reduce the likelihood of epileptic seizures, and perhaps the most active use of memantine is in situations of neurodegeneration and Alzheimer's disease.

· Natural content of glutamate · Applications · Notes · Related articles · Official site ·

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. In chemical synapses, glutamate is stored in presynaptic vesicles (vesicles). The nerve impulse triggers the release of glutamate from the presynaptic neuron. On a postsynaptic neuron, glutamate binds to and activates postsynaptic receptors such as NMDA receptors. Due to the involvement of the latter in synaptic plasticity, glutamate is involved in such cognitive functions as learning and memory. One form of synaptic plasticity, called long-term potentiation, occurs at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain. Glutamate is involved not only in classical conduction nerve impulse from neuron to neuron, but also in bulk neurotransmission, when the signal is transmitted to neighboring synapses by the summation of glutamate released in neighboring synapses (the so-called extrasynaptic or bulk neurotransmission))) In addition, glutamate plays a decisive role in the regulation of growth cones and synaptogenesis during the development of the brain, as described by Mark Matson.

Glutamate transporters have been found on neuronal and neuroglial membranes. They rapidly remove glutamate from the extracellular space. In brain damage or disease, they can work in the opposite direction, whereby glutamate can accumulate on the outside of the cell. This process leads to the a large number calcium ions into the cell through NMDA receptor channels, which in turn causes damage and even cell death - which is called excitotoxicity. Cell death mechanisms also include:

• damage to mitochondria by excessively high intracellular calcium,
• Glu/Ca2±mediated promotion of transcription factors of pro-apoptotic genes or reduced transcription of anti-apoptotic genes.

Excitotoxicity due to increased release of glutamate or its reduced reuptake occurs in the ischemic cascade and is associated with stroke, and is also observed in diseases such as amyotrophic lateral sclerosis, lathyrism, autism, some forms mental retardation, Alzheimer's disease. In contrast, a decrease in the release of glutamate is observed in classical phenylketonuria, which leads to impaired expression of glutamate receptors. Glutamic acid is involved in the realization of an epileptic seizure. Microinjection of glutamic acid into neurons causes spontaneous depolarization and this pattern is reminiscent of paroxysmal depolarization during seizures. These changes in the epileptic focus lead to the opening of voltage-dependent calcium channels, which again stimulates the release of glutamate and further depolarization. The role of the glutamate system today is given a large place in the pathogenesis of such mental disorders as schizophrenia and depression. One of the most rapidly studied theories of the etiopathogenesis of schizophrenia today is the hypothesis of NMDA receptor hypofunction: when using NMDA receptor antagonists, such as phencycline, symptoms of schizophrenia appear in healthy volunteers in the experiment. In this regard, it is assumed that the hypofunction of NMDA receptors is one of the causes of disturbances in dopaminergic transmission in patients with schizophrenia. Data have also been obtained that damage to NMDA receptors by an immune-inflammatory mechanism (“anti-NMDA receptor encephalitis”) has a clinical picture of acute schizophrenia. In the etiopathogenesis of endogenous depression, it is believed that excessive glutamatergic neurotransmission plays a role, as evidenced by the effectiveness of the dissociative anesthetic ketamine with a single use in treatment-resistant depression in the experiment.

Glutamate receptors

There are ionotropic and metabotropic (mGLuR 1-8) glutamate receptors.

Ionotropic receptors are NMDA receptors, AMPA receptors, and kainate receptors.

Endogenous glutamate receptor ligands are glutamic acid and aspartic acid. Glycine is also required to activate NMDA receptors. NMDA receptor blockers are PCP, ketamine, and others. AMPA receptors are also blocked by CNQX, NBQX. Kainic acid is an activator of kainate receptors.

"Circulation" of glutamate

In the presence of glucose in the mitochondria of nerve endings, deamination of glutamine to glutamate occurs with the help of the enzyme glutaminase. Also, during aerobic oxidation of glucose, glutamate is reversibly synthesized from alpha-ketoglutarate (formed in the Krebs cycle) using aminotransferase.

The glutamate synthesized by the neuron is pumped into the vesicles. This process is proton-coupled transport. H + ions are pumped into the vesicle with the help of proton-dependent ATPase. When protons exit along the gradient, glutamate molecules enter the vesicle using the vesicular glutamate transporter (VGLUTs).

Glutamate is excreted into the synaptic cleft, from where it enters astrocytes, where it is transaminated to glutamine. Glutamine is released back into the synaptic cleft and only then is taken up by the neuron. According to some reports, glutamate is not directly returned by reuptake.

The role of glutamate in acid-base balance

Deamination of glutamine to glutamate by the enzyme glutaminase leads to the formation of ammonia, which, in turn, binds to a free proton and is excreted into the lumen of the renal tubule, leading to a decrease in acidosis. The conversion of glutamate to -ketoglutarate also occurs with the formation of ammonia. Further, ketoglutarate breaks down into water and carbon dioxide. The latter, with the help of carbonic anhydrase through carbonic acid, are converted into a free proton and hydrocarbonate. The proton is excreted into the lumen of the renal tubule by cotransport with the sodium ion, and the bicarbonate enters the plasma.

Glutamatergic system

There are about 10 6 glutamatergic neurons in the CNS. The bodies of neurons lie in the cerebral cortex, olfactory bulb, hippocampus, substantia nigra, cerebellum. In the spinal cord - in the primary afferents of the dorsal roots.

In GABAergic neurons, glutamate is the precursor of the inhibitory neurotransmitter, gamma-aminobutyric acid, produced by the enzyme glutamate decarboxylase.

In brain tissue, glutamate is found in high concentrations than dopamine and serotonin. Glutamate is found in almost 40% of synapse terminals of brain neurons, including all cortical pyramidal neurons and neurons, while its main part is not considered to be a neurotransmitter. However, glutamate is at the same time the main mediator that regulates and activates excitation processes in mammals.

In pyramidal neurons, glutamate is initially formed from glutamine by the phosphate-activated enzyme glutaminase.

Most of the glutamate released by neurons is taken up glial cells and turns here into glutamine, which then returns to neurons again, turning into glutamate.

Glutamic acid regulates the plasticity of synapses, the growth and development of neurons, takes part in the processes of memorization, learning and regulation of movements.

Projections of the glutamatergic system are found in the basal ganglia and the limbic system.

Glutamate-sensitive receptors are divided into two types: ionotropic and metabotropic.

Glutamate receptors

Ionotropic receptors

• NMDA receptors
• PCP receptors
• AMPA receptors

Metabotropic receptors

• Group I receptors facilitating release of glutamate from presynaptic terminals and postsynaptic NMDA neurotransmission
• II - a group of receptors that limits the transmission of glutamate
• III - a group of receptors that limits the transmission of glutamate

Ionotropic receptors are differentiated based on their sensitivity to the synthetic glutamate derivative NMDA, AMPA (alpha-amino 3-hydroxy-5-methyl-4-isoxisolepropionic acid) and kainate.

Metabotropic receptors (G-protein) are involved in the regulation of the neuromodulatory effect of glutamate.

One of the main glutamate receptors, representing its central component of the glutamatergic system, is considered NMDA-receptor.

According to contemporary view, the NMDA receptor is involved in the mechanism of the hallucinatory effect provoked by phencyclidine intoxication.

Dysfunction of the glutamatergic system

1. Cognitive impairment
2. Negative symptoms
3. Disorder of motor regulation
4. psychomotor agitation

The glutamatergic system providesinhibitory effect on the dopaminergic system and complex more often activating, effect on the activity of serotonergic neurons, in particular, acting as an excitatory mediator of the limbic cortex. In turn, the dopaminergic system affects the activity of the glutamatergic system in the striatum and cortex. Recall that the dopaminergic system is activated by the glutamatergic system and inhibited through intermediate compounds of the GABAergic system.

These neurotransmitter systems interact with each other through complex mechanisms, while ensuring the optimal functioning of the neuronal networks of the frontotemporo-thalamic regions of the brain. A malfunction in the glutamatergic system, for example, due to regular use of cannabis, distorts the interaction of other neurotransmitter systems, in particular, manifesting itself as a syndrome of hyperactivity of the dopaminergic system, which is known to be characterized by productive psychotic symptoms.

According to some researchers, the “dopamine endophenotype of schizophrenia” is, as it were, secondarily capable of causing hypofunction of the NMDA system for a long time and impairing the transmission of this mediator. A continuous increase in the activity of the glutamatergic system leads to a decrease in the synthesis of synaptic proteins, thereby reducing the viability of neurons. At the same time, they do not die, but function as if in a weakened mode.

The specific transporter of inorganic phosphorus is localized selectively on the terminals of glutamatergic neurons.

The role of glutamic acid in the pathogenesis of schizophrenia became of interest to researchers after the discovery of glutamate antagonistic effects in certain drugs (phencyclidine, ketamine) (Chen G., Weston J., 1960). Interest in glutamate increased markedly after the elucidation of the role of the so-called "schizophrenia risk genes": dysbendin and neuregulin in the system that guards glutamate receptors.

Later, in schizophrenia, a significant weakening of the activity of the glutamatergic system in the area of ​​the frontal cortex was found, which, presumably, could lead to a decrease in the activity of glutamatergic transmission, disruption of the structure of NMDA receptors located on corticolimbic GABAergic neurons. It was assumed that the inhibitory side of glutamate, which regulates the activity of neurotransmitters, weakened and ultimately contributed to an increase in the release of dopamine.

Many researchers note that in schizophrenia, changes in the glutamate system affect the transport and metabolism of glutamate.

The level of glutamate is reduced in the cerebrospinal fluid of patients with schizophrenia.

Magnetic resonance spectroscopy revealed a decrease in glutamate activity in pyramidal neurons in the prefrontal cortex. Some changes found in the brain structures of patients with schizophrenia are reflected in peripheral blood platelets, which contain components of the glutamate system, in particular, enzymes of glutamate metabolism: a protein similar to glutamate synthetase and glutamate dehydrogenase.

In the study of G.Sh. Burbaeva. et al. (2007) found a significant positive correlation of glutamit synthetase-like protein with PANSS scores for negative symptoms, especially for symptoms such as poor communication skills, blunted affect, emotional withdrawal, and a negative correlation with arousal and severity. Scientists also found a positive correlation between the severity of emotional withdrawal and the amount of glutamate dehydrogenase. Based on the results of the study, it was concluded that the amount of a protein like glutamate synthetase in platelets makes it possible to predict the effectiveness of antipsychotic therapy in relation to negative symptoms.

Currently the theory of toxicosis is associated with a violation of the activity of receptors of the glutamate system.

M.Ya. Sereisky (1941), I.G. Ravkin (1956), S.G. Zhislin (1965), in his toxic-hypoxic theory of the pathogenesis of schizophrenia, attached importance to tissue hypoxia of the brain, insufficiency of its blood supply, especially characteristic of catatonia. In this theory, significant importance was given to the study of tissue hypoxia, oxidative processes in brain tissues, changes in carbohydrate-phosphorus metabolism, and disruption of general metabolism.

Previously, it was assumed that in schizophrenia there is a pathology on the part of nitrogen metabolism and a violation of enzymatic processes in the central nervous system. In his opinion, somatic diseases, infectious, endocrine disorders, skull injuries, hereditary diseases, and even psychogenic injuries can lead to the development of a toxic process and hypoxia.

Note that the metabolic processes in schizophrenia were also studied by domestic psychiatrists L.I. Lando, A.E. Kulkov and others.

The modern hypothesis of external toxicosis is one of the most popular theories of the pathogenesis of schizophrenia. According to this theory, under conditions of toxicosis, the normal process of transmission between neurons is disrupted. Instead of the usual excitation process, there is a situation of "deadly excited neurons" that cannot be controlled. Turning on the excitation mechanism, as it were, at the wrong time or without adequate control, leads to the fact that important synapses or even entire groups of neurons are destroyed, which is manifested by degeneration nervous tissue(Stahl S., 2001).

It is believed that the exotoxic process is triggered by a pathological process causing excessive glutamate activity. This leads to excessive opening of calcium channels with subsequent poisoning of the cell with excess calcium and the formation of free radicals. The latter attack the cell, negatively affecting its membrane and organelles, ultimately destroying it (Stahl S., 2001). The glutamate receptor subtype mediating degenerative exotoxic poisoning is considered to be the NMDA (H-methyl-D-aspartate) subtype.

Recently, American scientists at the University of Baltimore have proposed a new pathophysiological model of schizophrenia based on the effect of ketamine (an anesthetic widely used in dentistry) and phencyclidine on NMDA receptors. Phencyclidine and ketamine are antagonists of these receptors. They block ion channels (some researchers believe that calcium ions act as secondary intracellular messengers of glutamate action) and can cause perceptual alterations and cognitive impairments that resemble the symptoms of schizophrenia.

Using PET (positron emission tomography), it was found that ketamine increases the volume of regional cerebral blood flow in the anterior cingulate cortex and reduces blood flow in the hippocampus and cerebellum. It gives the impression that hypoglutamatergic state initially develops in the hippocampus. This inhibits the transmission of excitatory impulses to the region of the anterior cingulate gyrus and the temporal cortex. It is interesting to note that carriers of the schizophrenia risk haplotype, in particular neuregulin 1, tend to have a small hippocampus. According to F. Ebner et al., (2006), complications that develop during pregnancy and childbirth can also contribute to a decrease in the volume of the hippocampus, which increases the risk.

There is evidence of an increase in the number of NMDA in the brain of patients with schizophrenia. Changes found in some cortical formations, including the prefrontal cortex, may indicate a weakening of their innervation by glutamate. Perhaps this weakening is associated with both morphological and functional changes in this area of ​​the cerebral cortex.

Drugs that block electrically controlled calcium channels are effective in pathological excitation, but at the same time they practically do not affect the electrical activity of neurons.

From a therapeutic point of view, the effectiveness of glutamate receptor agonists (glycine, cycloserine, D-serine) is of interest, especially in relation to the negative symptoms observed in the process of these drugs (Deakin J., 2000; Tuominen H. et al., 2005; Carpenter W et al., 2005).

Recently, data have been obtained on the corrective effect of nifedipine in relation to cognitive impairment caused by taking haloperidol (Dzhuga N.P., 2006).

What are neurotransmitters?

Whatever our brain is busy with, whether it's working on scientific problem, trying to remember a phone number, or looking at a shop window while choosing a cake, the process is based on the timely release of neurotransmitters in the synapses of neurons and their binding to the corresponding receptors of other neurons. We can’t even hug someone without one biomolecule in our brain connecting with another, perfectly matching in shape, like pieces of a puzzle.

"Neurotransmitter" means "mediator between neurons." It is biologically active Chemical substance, through which the transmission of an electrochemical impulse from one nerve cell to another is carried out, therefore it is also called a "neurotransmitter".
Every millisecond, a remarkable chain of events unfolds in the human brain: billions of neurons send messages to each other in trillions of connections called synapses.
Each synapse consists of the endings of two neurons separated by a microscopic synaptic cleft, measured in nanometers, that is, billionths of a meter.
When a neuron receives new information, it generates an electrical impulse that causes the release of a neurotransmitter from a special vesicle called a vesicle. Next, the neurotransmitter molecule passes through the synaptic cleft and connects to a special receptor molecule at the end of the second neuron.

Each specific neurotransmitter has its own receptor, which perfectly matches its shape, as if it were a keyhole into which the key enters. The signal is transmitted through a network of neurons in the brain, as well as from neurons to muscle tissue or glandular cells, initiating the movement of parts of the body or some stage in the functioning of an organ.

These processes occur with great speed and precision, providing all the functions of the brain, and any failure in this finely tuned system leads to neurological and mental disorders, including autism, schizophrenia, Alzheimer's disease, epilepsy.

Even a disease such as botulism (severe food poisoning) is associated with a signal transmission problem in the synapse. Botulinum toxin is known to attack proteins that play an important role in the release of neurotransmitters, and this leads to muscle paralysis. Doctors, however, have learned to use this property of botulinum toxin to paralyze muscles in order to relieve pain from spasms in a neurological disease such as muscular dystonia.

Synapse function and neurotransmitter balance are extremely important for neurological and mental health and are one area of ​​intense research by microbiologists, biochemists, and pharmacologists.

A number of medications are aimed at correcting the imbalance of neurotransmitters in the brain in mental disorders. For example, in depression, serotonin reuptake inhibitors are often used, which block the uptake of this neurotransmitter by the emitting neuron, thereby increasing its content in the synaptic cleft and making it available to the receiving neuron.

But let's take a closer look at some of the most studied neurotransmitters. There are about fifty of them today.

Let's start with serotonin, which we already know.

Serotonin

This neurotransmitter helps control mood, appetite, pain, and sleep. Studies show that serotonin levels are lowered in depression, which is why pharmacists are developing drugs designed to increase them.

Surprising fact: 90% of serotonin is in the gastrointestinal tract, and only 10% is in the brain. Serotonin is involved in physiological processes such as digestion and the formation of blood clots. It belongs to inhibitory, that is, calming neurotransmitters, so its deficiency can lead to increased excitability and anxiety.

Gamma-amino-butyric acid (GABA)

Another inhibitory neurotransmitter is GABA. The release of GABA leads to calmness. Caffeine is a stimulant precisely because it inhibits the release of GABA, and many sedatives, sleeping pills, and tranquilizers work by helping release this neurotransmitter.

GABA plays an important role in vision and motor control. There is medications, which work to increase GABA levels in the brain, helping with seizures (epilepsy) and tremors (Huntingtog's disease).

GABA also controls other neurotransmitters such as norepinephrine, dopamine, and serotonin.

decline normal level GABA can lead to anxiety, impulsivity, inability to cope with stress, restlessness, and irritability.

Dopamine (dopamine)

This neurotransmitter plays a number of important roles in the brain depending on its location. In the frontal cortex, dopamine controls the flow of information to other areas of the brain. It is also involved in functions such as attention, memory, problem solving, and movement.

However, his most famous role is to be a mediator of pleasure. When you eat a piece of chocolate, dopamine is released in a certain area of ​​your brain, which motivates you to eat more. Dopamine plays an important role in the occurrence of addictions (alcohol, drugs, gambling addiction). Addictions most often occur when dopamine levels are low.

Decreased dopamine levels are not uncommon and manifest as reduced motivation, the ability to focus on tasks, and to remember information.

Violation of dopamine production can also lead to Parkinson's disease, which manifests itself in a decrease in the ability to voluntary movement, tremors, muscle numbness and other symptoms.

And here high level of this neurotransmitter, the so-called "dopamine storm" can lead to hallucinations, arousal, mania and psychosis. Such cases require immediate medical attention.

Acetylcholine (ACC)

This neurotransmitter plays a leading role in memory formation, verbal and logical thinking, and concentration. ACh is also involved in synaptogenesis, that is, the production of new healthy synapses in the brain. Acetylcholine itself is made from a substance called choline found in eggs, seafood, and nuts.

ACh plays a crucial role in the movement. When it is released into the synaptic cleft between the muscle fiber and the nerve cell, a series of mechanical and chemical reactions leading to muscle contraction. When the ACh level decreases, the reaction stops and the muscle relaxes.

Norepinephrine (norepinephrine)

It is another excitatory neurotransmitter that helps activate the sympathetic nervous system, which is responsible for the fight-or-flight response to an external stressor. Norepinephrine is important for concentration, emotions, sleep and dreams, and learning. When norepinephrine enters the bloodstream, it speeds up the heart rate, releases glucose, and increases blood flow to the muscles.

A decrease in the normal level of this neurotransmitter leads to chronic fatigue, inattention, problems with body weight. The increase results in sleep problems, anxiety and ADHD.

Glutamate

It is one of the main excitatory neurotransmitters. Its release increases the flow of electricity between neurons, which is necessary for the normal functioning of neural networks. Glutamate plays a critical role in early development brain, in memory and learning.

Lack of glutamate production leads to chronic fatigue and low brain activity. Elevated levels lead to the death of nerve cells. Glutamate imbalance has been linked to many neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and Tourette's syndrome.

Scientists believe that there are several hundred neurotransmitters that have yet to be discovered and studied. This is one of the most important avenues for finding effective therapies for neurodegenerative and psychiatric diseases, so any discovery in this area is a big step forward in the path of medical progress.