Glutamic acid is a neurotransmitter. Neurotransmitters and the most important ways to treat mental illness. Gamk: the main inhibitory neurotransmitter
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Glutamate is the most abundant excitatory neurotransmitter in nervous system vertebrates. 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 entry of a large amount of calcium ions into the cell through the channels of NMDA receptors, which in turn causes damage and even death of the cell - 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 of 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.
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 release of glutamate 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 studied very actively.
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 mediator, 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 work algorithm. 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 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 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 found in various foods, 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 chemical substances from the blood to the 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 occurs quite often if a person uses glutamate in large quantities as a dietary supplement.
The point is that our taste system 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 the chemical analysis of food, singled out glutamate as a sign of protein food, that is, we must eat protein, because protein is the main building material of our body. Similarly, our taste system has learned to detect glucose very well, because glucose and similar monosaccharides are the main source of 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. There is a structure in our brain 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 the most necessary 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 various 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.
Historically, the first open mediators were acetylcholine and monoamines. This is due to their wide distribution in the peripheral nervous system (at least in the case of acetylcholine and norepinephrine). However, they are far from being the most common CNS mediators. More than 80% of the nerve cells of the brain and spinal cord use amino acid substances as mediators, which carry the bulk of sensory, motor and other signals through neural networks (excitatory amino acids), and also control such transfer (inhibitory amino acids). It can be said that amino acids implement a fast information transfer, and monoamines and acetylcholine create a general motivational and emotional background and "watch" the level of wakefulness. There are even "slower" levels of regulation of brain activity - these are systems of neuropeptides and hormonal effects on the central nervous system.
Compared with the formation of monoamines, the synthesis of amino acid mediators is a simpler process for the cell, and all of them are simple in chemical composition. The mediators of this group are characterized by a greater specificity of synaptic effects - either a particular compound has excitatory properties (glutamic and aspartic acids) or inhibitory properties (glycine and gamma-aminobutyric acid - GABA). Amino acid agonists and antagonists cause more predictable effects in the CNS than acetylcholine and monoamine agonists and antagonists. On the other hand, the impact on glutamate or GABAergic systems often leads to too "broad" changes in the entire CNS, which creates its own difficulties.
The main excitatory neurotransmitter of the CNS is glutamic acid. In the nervous tissue, the mutual transformations of glutamic acid and its precursor glutamine are as follows:
As a non-essential dietary amino acid, it is widely distributed in a wide variety of proteins, and its daily intake is at least 5-10 g. However, food-derived glutamic acid normally penetrates the blood-brain barrier very poorly, which protects us from serious disruptions in brain activity. Almost all glutamate required by the central nervous system is synthesized directly in the nervous tissue, but the situation is complicated by the fact that this substance is also an intermediate stage in the processes of intracellular amino acid metabolism. Therefore, nerve cells contain a lot of glutamic acid, only a small part of which performs mediator functions. The synthesis of such glutamate occurs in presynaptic endings; the main precursor source is the amino acid glutamine.
Being released into the synaptic cleft, the neurotransmitter acts on the corresponding receptors. The diversity of receptors for glutamic acid is extremely large. Currently, there are three types of ionotropic and up to eight types of metabotropic receptors. The latter are less common and less studied. Their effects can be realized both by suppressing the activity of acenylate cyclase and by enhancing the formation of diacylglycerol and inositol triphosphate.
Ionotropic glutamic acid receptors are named after specific agonists: NMDA receptors (N-methyl-D-aspartate agonist), AMPA receptors (alpha-amiacid agonist), and kainate receptors (kainic acid agonist). Today, most attention is paid to the first of them. NMDA receptors are widely distributed in the CNS from the spinal cord to the cerebral cortex, most of them in the hippocampus. The receptor (Fig. 3.36) consists of four subunit proteins with two active centers for binding glutamic acid 1 and two active sites for glycine binding 2. These proteins form ion channel, which can be blocked by the magnesium ion 3 and channel blockers 4.
The proverb applies to the fate of the mediator who fulfilled his role in transmitting the signal: the Moor has done his job - the Moor must leave. If the neurotransmitter remains on the postsynaptic membrane, it will interfere with the transmission of new signals. There are several mechanisms to eliminate used mediator molecules: diffusion, enzymatic cleavage, and reuse.
By diffusion, some part of the mediator molecules always leaves the synaptic cleft, and in some synapses this mechanism is the main one. Enzymatic cleavage is the main way to remove acetylcholine at the neuromuscular junction: this is done by cholinesterase attached at the edges of the end plate folds. The resulting acetate and choline are returned to the presynaptic ending by a special capture mechanism.
Two enzymes are known that cleave biogenic amines: monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT). Cleavage of neurotransmitters of a protein nature can occur under the action of extracellular peptidases, although such mediators usually disappear from the synapse more slowly than low molecular weight ones, and often leave the synapse by diffusion.
The reuse of mediators is based on the mechanisms of uptake of their molecules by both neurons themselves and glial cells, which are specific for different neurotransmitters; special transport molecules are involved in this process. Specific reuse mechanisms are known for norepinephrine, dopamine, serotonin, glutamate, GABA, glycine, and choline (but not acetylcholine). Some psychopharmacological substances block the reuse of a mediator (for example, biogenic amines or GABA) and thereby prolong their action.
Separate mediator systems
The chemical structure of the most important neurotransmitters is shown in Figure 6.1.
Acetylcholine
It is formed using the enzyme acetyltransferase from acetylcoenzyme A and choline, which neurons do not synthesize, but are captured from the synaptic cleft or from the blood. It is the only mediator of all motor neurons of the spinal cord and autonomic ganglia; in these synapses, its action is mediated by H-cholinergic receptors, and the channel control is direct, ionotropic. Acetylcholine is also released by the postganglionic endings of the parasympathetic division of the autonomic nervous system: here it binds to M-cholinergic receptors, i.e. acts metabotropically. In the brain, it is used as a neurotransmitter by numerous pyramidal cortical cells that act on the basal ganglia, for example, approximately 40% of the total amount of acetylcholine formed in the brain is released in the caudate nucleus. With the help of acetylcholine, the tonsils of the brain excite the cells of the cerebral cortex.
M-cholinergic receptors are found in all parts of the brain (cortex, structures of the limbic system, thalamus, trunk), they are especially numerous in the reticular formation. With the help of cholinergic fibers, the midbrain is connected with other neurons of the upper brainstem, the optic tubercles, and the cortex. Perhaps the activation of these particular pathways is essential for the transition from sleep to wakefulness, in any case, the characteristic changes in the electroencephalogram after taking cholinesterase inhibitors confirm this version.
In progressive dementia, known as Alzheimer's disease, a decrease in acetyltransferase activity was found in the neurons of the Meinert nuclei located in the basal forebrain, directly under the striatum. In this regard, cholinergic transmission is disrupted, which is considered as an important link in the development of the disease.
Acetylcholine antagonists, as shown in animal experiments, hinder the formation of conditioned reflexes and reduce the efficiency of mental activity. Cholinesterase inhibitors lead to the accumulation of acetylcholine, which is accompanied by an improvement in short-term memory, accelerated formation of conditioned reflexes and better retention of memory traces.
The notion that the cholinergic systems of the brain are extremely necessary for the implementation of its intellectual activity and for providing the informational component of emotions is quite popular.
Biogenic amines
As already mentioned, biogenic amines are synthesized from tyrosine, and each stage of the synthesis is controlled by a special enzyme. If the cell has a complete set of such enzymes, then it will secrete adrenaline and, in a smaller amount, its precursors - norepinephrine and dopamine. For example, the so-called. chromaffin cells of the adrenal medulla secrete adrenaline (80% secretion), norepinephrine (18%) and dopamine (2%). If there is no enzyme for the formation of adrenaline, then the cell can only release norepinephrine and dopamine, and if there is no enzyme required for the synthesis of norepinephrine, then dopamine will be the only released mediator, the precursor of which, L-DOPA, is not used as a mediator.
Dopamine, norepinephrine, and epinephrine are often referred to as catecholamines. They control metabotropic adrenoreceptors, which are present not only in the nervous, but also in other tissues of the body. Adrenoreceptors are divided into alpha-1 and alpha-2, beta-1 and beta-2: the physiological effects caused by the addition of catecholamines to different receptors differ significantly. The ratio of different receptors is not the same in different effector cells. Along with the adrenoreceptors common to all catecholamines, there are specific receptors for dopamine that are found in the central nervous system and in other tissues, for example, in the smooth muscles of blood vessels and in the heart muscle.
Adrenaline is the main hormone of the adrenal medulla, beta receptors are especially sensitive to it. There is information about the use of adrenaline by some brain cells as a mediator. Norepinephrine is secreted by postganglionic neurons of the sympathetic division of the autonomic nervous system, and in the central nervous system by individual neurons of the spinal cord, cerebellum, and cerebral cortex. The largest accumulation of noradrenergic neurons are blue spots - the nuclei of the brain stem.
It is believed that the onset of REM sleep is associated with the activity of these noradrenergic neurons, but their function is not limited to this alone. Rostral to the blue spots, there are also noradrenergic neurons, the excessive activity of which plays a leading role in the development of the so-called. panic syndrome, accompanied by a feeling of insurmountable horror.
Dopamine is synthesized by neurons in the midbrain and diencephalic region, which form the three dopaminergic systems of the brain. This is, firstly, the nigrostriatal system: it is represented by neurons in the substantia nigra of the midbrain, the axons of which end in the caudate nuclei and putamen. Secondly, this is the mesolimbic system, formed by the neurons of the ventral tegmentum of the pons, their axons innervate the septum, tonsils, part of the frontal cortex, i.e. structures of the limbic system of the brain. And, thirdly, the mesocortical system: its neurons are in the midbrain, and their axons terminate in the anterior cingulate gyrus, deep layers of the frontal cortex, entorhinal and piriform (pear-shaped) cortex. The highest concentration of dopamine is found in the frontal cortex.
Dopaminergic structures play a prominent role in the formation of motivations and emotions, in the mechanisms of retention of attention and the selection of the most significant signals entering the central nervous system from the periphery. The degeneration of the substantia nigra neurons leads to a set of movement disorders known as Parkinson's disease. For the treatment of this disease, the precursor of dopamine, L-DOPA, is used, which, unlike dopamine itself, is able to overcome the blood-brain barrier. In some cases, attempts are being made to treat Parkinson's disease by injecting fetal adrenal medulla tissue into the cerebral ventricle. The injected cells can last up to a year and still produce significant amounts of dopamine.
In schizophrenia, an increased activity of the mesolimbic and mesocortical systems is found, which is considered by many as one of the main mechanisms of brain damage. In contrast, with the so-called. major depression has to use drugs that increase the concentration of catecholamines in the synapses of the central nervous system. Antidepressants help many patients, but, unfortunately, they are not able to make healthy people happy, just experiencing an unhappy time in their lives.
Serotonin
This low molecular weight neurotransmitter is formed from the amino acid tryptophan with the help of two enzymes involved in the synthesis. Significant accumulations of serotonergic neurons are found in the nuclei of the raphe, a thin band along the midline of the caudal reticular formation. The function of these neurons is related to the regulation of the level of attention and the regulation of the sleep-wake cycle. Serotonergic neurons interact with cholinergic structures of the tegmentum pons and noradrenergic neurons in the locus coeruleus. One of the blockers of serotonergic receptors is LSD, the consequence of taking this psychotropic substance is the unhindered passage into consciousness of such sensory signals, which are normally delayed.
Histamine
This substance from the group of biogenic amines is synthesized from the amino acid histidine and is found in the largest quantities in mast cells and basophilic granulocytes of the blood: there, histamine is involved in the regulation of various processes, including the formation of immediate allergic reactions. In invertebrates, it is a fairly common mediator; in humans, it is used as a neurotransmitter in the hypothalamus, where it is involved in the regulation of endocrine functions.
Glutamate
The most common excitatory neurotransmitter in the brain. It is secreted by the axons of most sensory neurons, pyramidal cells of the visual cortex, neurons of the associative cortex, which form projections onto the striatum.
Receptors for this mediator are divided into ionotropic and metabotropic. Ionotropic glutamate receptors are divided into two types, depending on their agonists and antagonists: NMDA (N-methyl-D-aspartate) and non-NMDA. NMDA receptors are associated with cation channels through which the flow of sodium, potassium and calcium ions is possible, and the channels of non-NMDA receptors do not allow calcium ions to pass through. Calcium entering through the channels of NMDA receptors activates a cascade of reactions of calcium-dependent second messengers. This mechanism is believed to play a very important role in the formation of memory traces. Channels associated with NMDA receptors open slowly and only in the presence of glycine: they are blocked by magnesium ions and the narcotic hallucinogen phencyclidine (which is called "angel dust" in English literature).
The activation of NMDA receptors in the hippocampus is associated with the emergence of a very interesting phenomenon - long-term potentiation, a special form of neuronal activity necessary for the formation of long-term memory (See Chapter 17). It is also interesting to note the fact that an excessively high concentration of glutamate is toxic to neurons - this circumstance has to be taken into account in certain brain lesions (hemorrhages, epileptic seizures, degenerative diseases, for example, Huntington's chorea).
GABA and glycine
Two amino acid neurotransmitters are the most important inhibitory neurotransmitters. Glycine inhibits the activity of interneurons and motor neurons of the spinal cord. A high concentration of GABA was found in the gray matter of the cerebral cortex, especially in the frontal lobes, in the subcortical nuclei (caudate nucleus and globus pallidus), in the thalamus, hippocampus, hypothalamus, and reticular formation. Some neurons of the spinal cord, olfactory tract, retina, and cerebellum are used as an inhibitory mediator of GABA.
A number of GABA-derived compounds (piracetam, aminolone, sodium oxybutyrate or GHB - gamma-hydroxybutyric acid) stimulate the maturation of brain structures and the formation of stable connections between neuron populations. This contributes to the formation of memory, which was the reason for the use of these compounds in clinical practice to accelerate recovery processes after various brain lesions.
It is assumed that the psychotropic activity of GABA is determined by its selective effect on the integrative functions of the brain, which consists in optimizing the balance of activity of interacting brain structures. So, for example, in states of fear, phobias, patients are helped by special anti-insurance drugs - benzodiazepines, the effect of which is to increase the sensitivity of GABAergic receptors.
Neuropeptides
Currently, about 50 peptides are considered as possible neurotransmitters, some of them were previously known as neurohormones released by neurons, but acting outside the brain: vasopressin, oxytocin. Other neuropeptides were studied for the first time as local hormones of the digestive tract, for example, gastrin, cholecystokinin, etc., as well as hormones produced in other tissues: angiotensin, bradykinin, etc.
Their existence in their former capacity is still not in doubt, but when it is possible to establish that a particular peptide is secreted by a nerve ending and acts on a neighboring neuron, it is rightly referred to as a neurotransmitter. In the brain, a significant number of neuropeptides are used in the hypothalamic-pituitary system, although the function of peptides in the transmission of pain sensitivity in the dorsal horns of the spinal cord is no less well known, for example.
All peptides originate from large precursor molecules that are synthesized in the cell body, modified in the cytoplasmic reticulum, converted in the Golgi apparatus, and delivered to the nerve ending by fast axonal transport in secretory vesicles. Neuropeptides can act as both excitatory and inhibitory mediators. Often they behave like neuromodulators, ie. do not themselves transmit a signal, but, depending on the need, increase or decrease the sensitivity of individual neurons or their populations to the action of excitatory or inhibitory neurotransmitters.
By identical sections of the amino acid chain, one can detect similarities between individual neuropeptides. For example, all endogenous opiate peptides at one end of the chain have the same amino acid sequence: tyrosine-glycine-glycine-phenylalanine. It is this site that is the active center of the peptide molecule. Often, the discovery of such a similarity between individual peptides indicates their genetic relationship. In accordance with this relationship, several main families of neuroactive peptides have been identified:
1.Opiate peptides: leucine-enkephalin, methionine-enkephalin, alpha-endorphin, gamma-endorphin, beta-endorphin, dynorphin, alpha-neoendorphin.
2. Peptides of the neurohypophysis: vasopressin, oxytocin, neurophysin.
3. Tachykinins: substance P, bombesin, fizalemin, cassinin, uperolein, eledoisin, substance K.
4. Secretins: secretin, glucagon, VIP (vasoactive intestinal peptide), somatotropin releasing factor.
5. Insulins: insulin, insulin-like growth factors I and II.
6. Somatostatins: somatostatin, a pancreatic polypeptide.
7. Gastrins: gastrin, cholecystokinin.
Some neurons can simultaneously release peptide and small molecule mediators, such as acetylcholine and VIP, with both acting on the same target as synergists. But it can be different, as, for example, in the hypothalamus, where glutamate and dynorphin secreted by one neuron act on the same postsynaptic target, but glutamate excites, and the opioid peptide inhibits. Most likely, peptides in such cases act as neuromodulators. Sometimes, along with the neurotransmitter, ATP is also released, which in some synapses is also considered as a mediator, unless, of course, it is possible to prove the presence of receptors for it on the postsynaptic membrane.
Opiate peptides
The family of opiate peptides includes over a dozen substances, the molecules of which include from 5 to 31 amino acids. These substances have common biochemical features, although the ways of their synthesis may differ. For example, the synthesis of beta-endorphin is associated with the formation of adrenocorticotropic hormone (ACTH) from a common large precursor protein molecule, proopiomelanocortin, while enkephalins are formed from another precursor, and dynorphin from a third.
The search for opiate peptides began after the discovery in the brain of opiate receptors that bind opium alkaloids (morphine, heroin, etc.). Since it is difficult to imagine the appearance of such receptors for binding only foreign substances, they began to look inside the body. In 1975, Nature reported the discovery of two small peptides that consisted of five amino acids, bound to opiate receptors, and were more potent than morphine. The authors of this report (Hughes J., Smith T.W., Kosterlitz H.W. et al.) called the detected substances enkephalins (i.e. in the head). After a short time, three more peptides were isolated from the hypothalamic-pituitary extract, which were called endorphins, i.e. endogenous morphines, then dynorphin was discovered, etc.
All opiate peptides are sometimes referred to as endorphins. They bind to opiate receptors better than morphine and are 20 to 700 times more potent than morphine. Five functional types of opiate receptors have been described; together with the peptides themselves, they form a very complex system. Attachment of the peptide to the receptor leads to the formation of second messengers related to the cAMP system.
The highest content of opioid peptides is found in the pituitary gland, but they are synthesized mainly in the hypothalamus. A significant amount of beta-endorphin is found in the limbic system of the brain, it is also found in the blood. The concentration of enkephalins is especially high in the posterior horns of the spinal cord, where signals from pain endings are transmitted: there, enkephalins reduce the release of substance P, a mediator for transmitting information about pain.
Anesthesia can be induced in experimental animals by microinjection of beta-endorphin into the cerebral ventricle. Another method of pain relief is electrical stimulation of neurons located around the ventricle: this increases the concentration of endorphins and enkephalins in the cerebrospinal fluid. To the same result, i.e. to anesthesia, both the introduction of b-endorphins and stimulation of the periventricular (periventricular) region in cancer patients led. It is interesting that the level of opiate peptides in the cerebrospinal fluid increases both during anesthesia with the help of acupuncture and during the placebo effect (when the patient takes the medicine, not knowing that it does not contain an active active ingredient).
In addition to analgesic, i.e. analgesic effect, opioid peptides affect the formation of long-term memory, the learning process, regulate appetite, sexual functions and sexual behavior, they are an important link in the stress response and adaptation process, they provide a link between the nervous, endocrine and immune systems (opiate receptors are found in lymphocytes and blood monocytes).
Summary
In the central nervous system, both low molecular weight and peptide neurotransmitters are used to transfer information between cells. Different populations of neurons use different mediators, this choice is genetically determined and provided with a certain set of enzymes necessary for synthesis. For the same mediator, different cells have different types of postsynaptic receptors, with ionotropic or metabotropic control. Metabotropic control is carried out with the participation of transforming proteins and various systems secondary intermediaries. Some neurons simultaneously release a peptide mediator along with a low molecular weight one. Neurons that differ in the secreted mediator are concentrated in a certain order in different brain structures.
Questions for self-control
81. Which of the following is not a criterion for classifying a substance as a neurotransmitter?
A. Synthesized in a neuron; B. Accumulates in the presynaptic ending; B. Has a specific effect on the effector; G. It is released into the blood; D. With artificial administration, an effect is observed similar to what happens with natural release.
A. Prevents the release of the mediator from the presynaptic ending; B. Acts like a mediator; B. Acts differently than a mediator; G. Blocks postsynaptic receptors; D. Does not bind to postsynaptic receptors.
83. Which of the following is typical for peptide neurotransmitters?
A. They are formed during the enzymatic oxidation of amino acids; B. Formed as a result of decarboxylation of amino acids; B. Can be synthesized in the presynaptic ending; D. Delivered to the presynaptic ending by slow axoplasmic transport; D. Formed in the cell body of a neuron.
84. What causes the current of calcium ions to the presynaptic ending during the transmission of information through the synapse?
A. Action potential; B. Resting potential; B. Exocytosis; D. Connection of synaptic vesicles with the cytoskeleton; D. The emergence of postsynaptic potential.
85. What converts the excitation of the presynaptic ending into non-electrical activity (release of a neurotransmitter)?
A. Exocytosis; B. Incoming current of calcium ions; B. Entry of sodium ions upon excitation of the ending; D. Exit of potassium ions during repolarization; E. Increasing the activity of enzymes necessary for the synthesis of the mediator.
86. What causes post-tetanic potentiation?
A. The summation of mediator quanta; B. Increasing the diffusion rate of the mediator; B. An increase in the concentration of calcium ions in the presynaptic ending; D. Increased activity of enzymes for the synthesis of the mediator; D. High density channels for calcium in the region of the active zones.
87. Which of the following events leads to the activation of G-proteins?
A. Converting GDP to GTP; B. Conversion of ATP to cAMP; B. Activation of adenylate cyclase; D. Activation of protein kinase; D. Formation of postsynaptic potential.
88. Which of the indicated events should occur earlier than others during metabotropic control?
A. Formation of cAMP; B. Activation of protein kinase; B. Activation of adenylate cyclase; D. G-protein activation; D. Opening of the ion channel.
89. What is the function of presynaptic membrane autoreceptors?
A. Implementation of the reverse transport of neurotransmitters; B. Regulation of the amount of mediator in the synaptic cleft; B. Switching on the mechanisms of mediator splitting; D. Ionotropic control of presynaptic membrane channels; E. Binding of the mediator released from the postsynaptic neuron.
90. Which of the following mechanisms is not used to remove neurotransmitters from the synaptic cleft?
A. Enzymatic cleavage; B. Capture of mediator molecules by glial cells; C. Capture of mediator molecules by a postsynaptic neuron; D. Transport of mediator molecules to the end of the presynaptic neuron; D. diffusion.
91. With progressive dementia (Alzheimer's disease), the synthesis of one of the neurotransmitters is impaired. This:
A. Acetylcholine; B. Glutamate; B. Dopamine; G. Norepinephrine; D. GABA.
92. What neurotransmitter is secreted by the neurons of the blue spot?
A. Dopamine; B. Glycine; B. Glutamate; G. Norepinephrine; D. Adrenaline.
93. What mediator is synthesized in the neurons of the substantia nigra of the midbrain?
A. Dopamine; B. Norepinephrine; B. Acetylcholine; G. b-Endorphin; D. Glutamate.
94. In which of the following brain structures is the highest concentration of dopamine found?
BUT. Reticular formation; B. Occipital cortex; B. Frontal cortex; G. Cerebellum; D. Thalamus.
95. What neurotransmitter is secreted by the neurons of the raphe nuclei?
A. Dopamine; B. Norepinephrine; B. Serotonin; G. Histamine; D. Glycine.
96. What mediator acts on NMDA receptors?
A. Acetylcholine; B. Glutamate; B. Glycine; G. Enkefalin; D. Adrenaline.
97. Derivatives of one of the neurotransmitters are used to speed up recovery processes and improve memory after brain damage. Specify it.
A. GABA; B. Glycine; B. Acetylcholine; G. Glutamate; D. Dopamine.
98. Which of the following substances is not a peptide neurotransmitter?
A. Endorphin; B. Glycine; B. Substance P; G. Somatostatin; D. Enkephalin.
99. What mediator is synthesized by some neurons of the brain and affects the transmission of information about pain stimuli in the spinal cord?
A. Endorphin; B. Enkephalin; C. Substance R. G. Oxytocin; D. Vasopressin.
100. In what area of the brain are peptide neurotransmitters most often used as mediators?
A. Cerebellum; B. Reticular formation; B. Hypothalamus and pituitary gland; G. Frontal cortex; D. Subcortical nuclei.
The sixth (and last) article in the series on neurotransmitters will be devoted to glutamate. This substance is more familiar to us as a flavor enhancer in foods, but it plays an important role in our nervous system. Glutamate is the most abundant excitatory neurotransmitter in the nervous system of mammals in general and humans in particular.
Molecules and bonds
Glutamate (glutamic acid) is one of the 20 essential amino acids. In addition to participating in the synthesis of proteins, it can act as a neurotransmitter - a substance that transmits a signal from one nerve cell to another in the synaptic cleft. It should be borne in mind that glutamate, which is in food, does not penetrate the blood-brain barrier, that is, it does not have a direct effect on the brain. Glutamate is formed in the cells of our body from α-ketoglutarate by transamination. The amino group is transferred from alanine or aspartate, replacing the ketone radical of α-ketoglutarate (Fig. 1). As a result, we get glutamate and pyruvate or oxaloacetic acid (depending on the amino group donor). The last two substances are involved in many important processes: oxaloacetic acid, for example, is one of the metabolites in the great and terrible Krebs cycle. The destruction of glutamate occurs with the help of the enzyme glutamate dehydrogenase, and during the reaction, the already familiar α-ketoglutarate and ammonia are formed.
Figure 1. Synthesis of glutamate. Glutamate is formed from α-ketoglutarate by replacing the keto group with an amino group. When carrying out the reaction in cells, nicotinamide adenine dinucleotide phosphate (NADP, NADP) is spent. Figure from lecturer.ukdw.ac.id.
Glutamate, like most other mediators, has two types of receptors - ionotropic(which open the membrane pore to ions in response to ligand attachment) and metabotropic(which, when attached to the ligand, cause metabolic rearrangements in the cell). The group of ionotropic receptors is divided into three families: NMDA receptors, AMPA receptors, and kainic acid receptors. NMDA receptors so called because their selective agonist, a substance that selectively stimulates these receptors, is N-methyl-D-aspartate (NMDA). When AMPA receptors such an agonist would be α-aminomethylisoxazolepropionic acid, and kainate receptors selectively stimulated by kainic acid. This substance is found in red algae and is used in neuroscience research to model epilepsy and Alzheimer's disease. Recently, ionotropic receptors have also been supplemented with δ-receptors: They are located on Purkinje cells in the mammalian cerebellum. Stimulation of the "classic" - NMDA-, AMPA- and kainate - receptors leads to the fact that potassium begins to leave the cell, and calcium and sodium enter the cell. During these processes, excitation occurs in the neuron, and an action potential is triggered. Metabotropic the same receptors are associated with the G-protein system and are involved in the processes of neuroplasticity. Neuroplasticity refers to the ability of nerve cells to form new connections with each other or destroy them. The concept of neuroplasticity also includes the ability of synapses to change the amount of neurotransmitter released, depending on what behavioral acts and thought processes are taking place at the moment and with what frequency.
The glutamate system is nonspecific: almost the entire brain "works" on glutamic acid. Other neurotransmitter systems described in previous articles had more or less narrow specifics - for example, dopamine influenced our movements and motivation. In the case of glutamate, this does not happen - its influence on the processes inside the brain is too wide and indiscriminate. It is difficult to single out any specific function, except exciting. For this reason, one has to speak of the glutamate system as a combination of a large number of connections in the brain. Such a collection is called connectome. The human brain contains great amount neurons that form with each other large quantity connections. Compiling a human connectome is a task that science cannot do today. However, it has already been described by the worm's connection Caenorhabditis elegans(Fig. 2). Admirers of the idea of connectome argue that our identity is recorded in human connectomes: our personality and memory. In their opinion, our “I” is hidden in the totality of all connections. Also, the "communicators" believe that after describing all the neural connections, we will be able to understand the cause of many mental and neurological disorders, and therefore we will be able to successfully treat them.
Figure 2. Nematode connectome Caenorhabditis elegans Each neuron of the worm has its own name, and all connections between neurons are taken into account and plotted on the diagram. As a result, the scheme is more confusing than the map of the Tokyo subway. Drawing from connectomethebook.com.
It seems to me that this idea is promising. In a simplified form, the connections between neurons can be represented as wires, complex cables connecting one neuron to another. If these connections are damaged - the signal is distorted, the wires are broken - there may be a violation of the coordinated work of the brain. Such diseases that occur when there is a failure in neural communication channels are called connectopathies. The term is new, but pathological processes already known to scientists are hidden behind it. If you want to learn more about connectomes, I recommend reading Sebastian Seung's book " Connectome. How the brain makes us what we are» .
Network congestion
Figure 3. Structure of memantine. Memantine is a derivative of the hydrocarbon adamantane (not to be confused with adamant). Drawing from Wikipedia.
In a normally functioning brain, signals from neurons are evenly distributed to all other cells. Neurotransmitters are released in the required amount, and there are no damaged cells. However, after a stroke (acute lesion) or during dementia (a long-term process), glutamate begins to be released from neurons into the surrounding space. It stimulates the NMDA receptors of other neurons, and calcium enters these neurons. The influx of calcium triggers a number of pathological mechanisms, which ultimately leads to the death of the neuron. The process of cell damage due to the release of a large amount of endogenous toxin (in this case, glutamate) is called excitotoxicity.
Figure 4. Action of memantine in Alzheimer's dementia. Memantine reduces the intensity of excitatory signals that come from cortical neurons to Meinert's nucleus. The acetylcholine neurons that make up this structure regulate attention and a number of other cognitive functions. Reducing the excess activation of the Meinert nucleus leads to a decrease in the symptoms of dementia. Drawing from .
In order to prevent the development of excitotoxicity or reduce its effect on the course of the disease, you can prescribe memantine. Memantine is a very beautiful NMDA receptor antagonist molecule (Fig. 3). The drug is most commonly prescribed for vascular dementia and dementia in Alzheimer's disease. Normally, NMDA receptors are blocked by magnesium ions, but when stimulated with glutamate, these ions are released from the receptor, and calcium begins to enter the cell. Memantine blocks the receptor and prevents the passage of calcium ions into the neuron - the drug exerts its neuroprotective effect by reducing the overall electrical "noise" in the cell's signals. In Alzheimer's dementia, in addition to glutamate-mediated problems, the level of acetylcholine, a neurotransmitter involved in such processes as memory, learning, and attention, is reduced. In connection with this feature of Alzheimer's disease, psychiatrists and neurologists use to treat acetylcholinesterase inhibitors, an enzyme that breaks down acetylcholine in the synaptic cleft. The use of this group of drugs increases the content of acetylcholine in the brain and normalizes the patient's condition. Experts recommend co-administration of memantine and acetylcholinesterase inhibitors to more effectively combat dementia in Alzheimer's disease. With the combined use of these drugs, there is an effect on two mechanisms of the development of the disease at once (Fig. 4).
Dementia is a long-term brain lesion in which the death of neurons occurs slowly. And there are diseases that lead to a rapid and large-scale damage to the nervous tissue. Excitotoxicity is an important component of nerve cell damage in stroke. For this reason, the use of memantine in cerebrovascular disorders may be justified, but research on this topic is just beginning. Currently, there is work done on mice, which shows that the administration of memantine at a dose of 0.2 mg/kg per day reduces the amount of brain damage and improves the prognosis of stroke. Perhaps further work on this topic will improve the treatment of stroke in humans.
Voices in my head
The most common hallucinations in patients with schizophrenia are auditory: the patient hears "voices" in his head. The voice can scold, comment on what is happening around, including the actions of the patient. One of my patients had "voices" read the signs of the shops on the street where she was walking; another heard a voice say, "Get your pension and let's go to a cafe." Currently, there is a theory explaining the emergence of such voices. Imagine that the patient is walking down the street. He sees the sign, and the brain automatically "reads" it. With increased activity in the temporal lobe, which is responsible for auditory perception, the patient has auditory sensations. They could be suppressed due to the normal functioning of areas of the frontal cortex, but this does not happen due to a decrease in their activity (Fig. 5). Excessive activity of the auditory cortex can be caused by hyperfunction of the glutamate (excitatory) system or a defect in GABAergic structures responsible for normal inhibition in the human brain. Most likely, insufficient activity of the frontal lobe in the case of schizophrenia is also associated with a violation of the neurotransmitter balance. The mismatch of actions leads to the fact that a person begins to hear "voices" that clearly correlate with the environment or convey his thoughts. Very often we “pronounce” our thoughts in our head, which can also be a source of “voices” in the brain of a person with schizophrenia.
Figure 5. Occurrence of auditory hallucinations in the brain of a patient with schizophrenia. The primary sensation from automatic "reading" of signs or when thoughts arise, localized in the temporal cortex (1), is not suppressed by the frontal cortex (2). The parietal cortex (3) captures the emerging pattern of activity in the brain and shifts the focus of activity to it. As a result, a person begins to hear a “voice”. Drawing from .
This concludes our journey into the world of neurotransmitters. We met the motivating dopamine, the calming γ-aminobutyric acid, and four other heroes of our brain. Be interested in your brain - because, as the title of Dick Swaab's book says, . Neurotox. Res. 24 , 358–369;
