Nerve mediator. Picks

Synapse

How is excitation transmitted from one neuron to another or from a neuron, for example, to a muscle fiber? This problem is of interest not only to professional neurobiologists, but also to doctors, especially pharmacologists. Knowledge of biological mechanisms is necessary for the treatment of certain diseases, as well as for the creation of new drugs and drugs. The fact is that one of the main places where these substances affect the human body are the places where excitation is transferred from one neuron to another (or to another cell, for example, a cell of the heart muscle, vascular walls, etc.). The process of a neuron axon goes to another neuron and forms a contact on it, which is called synapse(translated from Greek - contact; see Fig. 2.3). It is the synapse that holds many of the secrets of the brain. Violation of this contact, for example, by substances that block its work, leads to severe consequences for a person. This is the site of drug action. Examples will be given below, but now let's look at how the synapse is arranged and how it works.

The difficulties of this study are determined by the fact that the synapse itself is very small (its diameter is not more than 1 micron). One neuron receives such contacts, as a rule, from several thousand (3-10 thousand) other neurons. Each synapse is securely closed by special glia cells, so it is very difficult to study it. On fig. 2.12 shows a diagram of a synapse, as modern science imagines. Despite its diminutiveness, it is very complex. One of its main components are bubbles, that are inside the synapse. These vesicles contain a biologically very active substance called neurotransmitter or mediator(transmitter).

Recall that a nerve impulse (excitation) moves along the fiber with great speed and approaches the synapse. This action potential causes depolarization of the synapse membrane (Fig. 2.13), but this does not lead to the generation of a new excitation (action potential), but causes the opening of special ion channels with which we are not yet familiar. These channels allow calcium ions to enter the synapse. Calcium ions play a very important role in the activity of the body. A special gland of internal secretion - parathyroid (it is located on top of the thyroid gland) regulates the calcium content in the body. Many diseases are associated with impaired calcium metabolism in the body. For example, its deficiency leads to rickets in young children.

How is calcium involved in synapse function? Once in the cytoplasm of the synaptic ending, calcium enters into contact with the proteins that form the shell of the vesicles in which the mediator is stored. Ultimately, the membranes of the synaptic vesicles contract, pushing their contents into the synaptic cleft. This process is very similar to the contraction of a muscle fiber in a muscle, in any case, these two processes have the same mechanism at the molecular level. Thus, calcium binding by the vesicle envelope proteins leads to its contraction, and the content of the vesicle is injected (exocytosis) into the gap that separates the membrane of one neuron from the membrane of another. This gap is called synoptic gap. From the description it should be clear that the excitation (electrical action potential) of a neuron at the synapse is converted from an electrical impulse into a chemical impulse. In other words, each excitation of a neuron is accompanied by the release of a portion of a biologically active substance, a mediator, at the end of its axon. Further, the mediator molecules bind to special protein molecules that are located on the membrane of another neuron. These molecules are called receptors. The receptors are unique and bind only one type of molecule. Some descriptions indicate that they fit like a "key to a lock" (a key only fits its own lock).

The receptor consists of two parts. One can be called a "recognizing center", the other - an "ion channel". If the mediator molecules have taken certain places (recognizing center) on the receptor molecule, then the ion channel opens and ions begin to enter the cell (sodium ions) or leave the cell (potassium ions) from the cell. In other words, an ion current flows through the membrane, which causes a change in potential across the membrane. This potential is called postsynaptic potential(Fig. 2.13). A very important property of the described ion channels is that the number of open channels is determined by the number of bound mediator molecules, and not by the membrane potential, as is the case with the electrically excitable nerve fiber membrane. Thus, postsynaptic potentials have the property of gradation: the amplitude of the potential is determined by the number of molecules of the mediator bound by receptors. Due to this dependence, the amplitude of the potential on the neuron membrane develops in proportion to the number of open channels.

On the membrane of one neuron, two types of synapses can simultaneously be located: brake and excitatory. Everything is determined by the arrangement of the ion channel of the membrane. The membrane of excitatory synapses allows both sodium and potassium ions to pass through. In this case, the neuron membrane depolarizes. The membrane of inhibitory synapses allows only chloride ions to pass through and becomes hyperpolarized. Obviously, if the neuron is inhibited, the membrane potential increases (hyperpolarization). Thus, due to the action through the corresponding synapses, the neuron can be excited or stop excitation, slow down. All these events take place on the soma and numerous processes of the neuron's dendrite; on the latter, there are up to several thousand inhibitory and excitatory synapses.

As an example, let's analyze how the mediator, which is called acetylcholine. This mediator is widely distributed in the brain and in the peripheral endings of nerve fibers. For example, motor impulses, which, along the corresponding nerves, lead to the contraction of the muscles of our body, operate with acetylcholine. Acetylcholine was discovered in the 30s by the Austrian scientist O. Levy. The experiment was very simple: they isolated the heart of a frog with the vagus nerve coming to it. It was known that electrical stimulation of the vagus nerve leads to a slowdown in heart contractions up to its complete stop. O. Levy stimulated the vagus nerve, got the effect of cardiac arrest and took some blood from the heart. It turned out that if this blood is added to the ventricle of a working heart, then it slows down its contractions. It was concluded that when the vagus nerve is stimulated, a substance is released that stops the heart. It was acetylcholine. Later, an enzyme was discovered that split acetylcholine into choline (fat) and acetic acid, as a result of which the action of the mediator ceased. This study was the first to establish the exact chemical formula of the neurotransmitter and the sequence of events in a typical chemical synapse. This sequence of events boils down to the following.

The action potential that came along the presynaptic fiber to the synapse causes depolarization, which turns on the calcium pump, and calcium ions enter the synapse; calcium ions are bound by proteins of the membrane of synaptic vesicles, which leads to active emptying (exocytosis) of the vesicles into the synaptic cleft. The mediator molecules bind (recognizing center) to the corresponding receptors of the postsynaptic membrane, and the ion channel opens. An ion current begins to flow through the membrane, which leads to the appearance of a postsynaptic potential on it. Depending on the nature of the open ion channels, an excitatory (channels for sodium and potassium ions open) or inhibitory (channels for chloride ions open) postsynaptic potential arises.

Acetylcholine is very widely distributed in wildlife. For example, it is found in the stinging capsules of nettles, in the stinging cells of intestinal animals (for example, freshwater hydra, jellyfish), etc. In our body, acetylcholine is released at the endings of the motor nerves that control muscles, from the endings of the vagus nerve, which controls the activity of the heart and other internal organs. A person has long been familiar with the antagonist of acetylcholine - it is poison curare, which was used by the Indians of South America when hunting animals. It turned out that curare, getting into the bloodstream, causes immobilization of the animal, and it actually dies from suffocation, but curare does not stop the heart. Studies have shown that there are two types of acetylcholine receptors in the body: one successfully binds nicotinic acid, and the other is muscarine (a substance that is isolated from a fungus of the genus Muscaris). The muscles of our body have nicotinic-type receptors for acetylcholine, while the heart muscle and brain neurons have muscarinic-type acetylcholine receptors.

Currently, synthetic analogues of curare are widely used in medicine to immobilize patients during complex operations on internal organs. The use of these drugs leads to complete paralysis of the motor muscles (binding to nicotinic-type receptors), but does not affect the functioning of internal organs, including the heart (muscarinic-type receptors). Brain neurons, excited through muscarinic acetylcholine receptors, play an important role in the manifestation of certain mental functions. It is now known that the death of such neurons leads to senile dementia (Alzheimer's disease). Another example, which should show the importance of the nicotinic-type receptors on the muscle for acetylcholine, is a disease called miastenia grevis (muscle weakness). This is a genetically inherited disease, i.e. its origin is associated with "breakdowns" of the genetic apparatus, which are inherited. The disease manifests itself at the age closer to puberty and begins with muscle weakness, which gradually intensifies and captures more and more extensive muscle groups. The cause of this disease turned out to be that the patient's body produces protein molecules that are perfectly bound by nicotinic-type acetylcholine receptors. Occupying these receptors, they prevent the binding of acetylcholine molecules ejected from the synaptic endings of the motor nerves to them. This leads to blocking of synaptic conduction to the muscles and, consequently, to their paralysis.

The type of synaptic transmission described by the example of acetylcholine is not the only one in the CNS. The second type of synaptic transmission is also widespread, for example, in synapses, in which biogenic amines (dopamine, serotonin, adrenaline, etc.) are mediators. In this type of synapses, the following sequence of events takes place. After the complex "mediator molecule - receptor protein" is formed, a special membrane protein (G-protein) is activated. One molecule of the mediator, when bound to the receptor, can activate many G-protein molecules, and this enhances the effect of the mediator. Each activated G-protein molecule in some neurons can open an ion channel, while in others it can activate the synthesis of special molecules inside the cell, the so-called secondary intermediaries. Secondary messengers can trigger many biochemical reactions in the cell associated with the synthesis of, for example, a protein, in which case an electric potential does not occur on the neuron membrane.

There are other mediators as well. In the brain, a whole group of substances “works” as mediators, which are combined under the name biogenic amines. In the middle of the last century, the English doctor Parkinson described a disease that manifested itself as trembling paralysis. This severe suffering is caused by the destruction in the patient's brain of neurons, which in their synapses (endings) secrete dopamine - substance from the group of biogenic amines. The bodies of these neurons are located in the midbrain, forming a cluster there, which is called black substance. Recent studies have shown that dopamine in the mammalian brain also has several types of receptors (six types are currently known). Another substance from the group of biogenic amines - serotonin (another name for 5-hydroxytryptamine) - was first known as a means of leading to an increase in blood pressure (vasoconstrictor). Please note that this is reflected in its name. However, it turned out that the depletion of serotonin in the brain leads to chronic insomnia. In experiments on animals, it was found that the destruction in the brain stem (posterior parts of the brain) of special nuclei, which are known in anatomy as seam core, leads to chronic insomnia and further death of these animals. A biochemical study has established that the neurons of the raphe nuclei contain serotonin. In patients suffering from chronic insomnia, a decrease in the concentration of serotonin in the brain was also found.

Biogenic amines also include epinephrine and noradrenaline, which are contained in the synapses of neurons of the autonomic nervous system. During stress, under the influence of a special hormone - adrenocorticotropic (for more details, see below), adrenaline and noradrenaline are also released from the cells of the adrenal cortex into the blood.

From the foregoing, it is clear what role mediators play in the functions of the nervous system. In response to the arrival of a nerve impulse to the synapse, a neurotransmitter is released; mediator molecules are connected (complementary - like a "key to the lock") with receptors of the postsynaptic membrane, which leads to the opening of the ion channel or to the activation of intracellular reactions. The examples of synaptic transmission discussed above are fully consistent with this scheme. However, thanks to research in recent decades, this rather simple scheme of chemical synaptic transmission has become much more complicated. The advent of immunochemical methods made it possible to show that several groups of mediators can coexist in one synapse, and not just one, as previously assumed. For example, synaptic vesicles containing acetylcholine and norepinephrine can be simultaneously located in one synaptic ending, which are quite easily identified in electronic photographs (acetylcholine is contained in transparent vesicles with a diameter of about 50 nm, and norepinephrine is contained in electron-dense vesicles up to 200 nm in diameter). In addition to classical mediators, one or more neuropeptides may be present in the synaptic ending. The number of substances contained in the synapse can reach up to 5-6 (a kind of cocktail). Moreover, the mediator specificity of a synapse may change during ontogeny. For example, neurons in the sympathetic ganglia that innervate the sweat glands in mammals are initially noradrenergic but become cholinergic in adult animals.

Currently, when classifying mediator substances, it is customary to distinguish: primary mediators, concomitant mediators, mediator-modulators and allosteric mediators. Primary mediators are considered to be those that act directly on the receptors of the postsynaptic membrane. Associated mediators and mediator-modulators can trigger a cascade of enzymatic reactions that, for example, phosphorylate the receptor for the primary mediator. Allosteric mediators can participate in cooperative processes of interaction with the receptors of the primary mediator.

For a long time, a synaptic transmission to an anatomical address was taken as a sample (the “point-to-point” principle). The discoveries of recent decades, especially the mediator function of neuropeptides, have shown that the principle of transmission to a chemical address is also possible in the nervous system. In other words, a mediator released from a given ending can act not only on “its own” postsynaptic membrane, but also outside this synapse, on the membranes of other neurons that have the corresponding receptors. Thus, the physiological response is provided not by exact anatomical contact, but by the presence of the corresponding receptor on the target cell. Actually, this principle has long been known in endocrinology, and recent studies have found it more widely used.

All known types of chemoreceptors on the postsynaptic membrane are divided into two groups. One group includes receptors, which include an ion channel that opens when the mediator molecules bind to the "recognizing" center. Receptors of the second group (metabotropic receptors) open the ion channel indirectly (through a chain of biochemical reactions), in particular, through the activation of special intracellular proteins.

One of the most common are mediators belonging to the group of biogenic amines. This group of mediators is quite reliably identified by microhistological methods. Two groups of biogenic amines are known: catecholamines (dopamine, norepinephrine and adrenaline) and indolamine (serotonin). The functions of biogenic amines in the body are very diverse: mediator, hormonal, regulation of embryogenesis.

The main source of noradrenergic axons are the neurons of the locus coeruleus and adjacent areas of the midbrain (Fig. 2.14). The axons of these neurons are widely distributed in the brain stem, cerebellum, and in the cerebral hemispheres. In the medulla oblongata, a large cluster of noradrenergic neurons is located in the ventrolateral nucleus of the reticular formation. In the diencephalon (hypothalamus), noradrenergic neurons, along with dopaminergic neurons, are part of the hypothalamic-pituitary system. Noradrenergic neurons are found in large numbers in the nervous peripheral system. Their bodies lie in the sympathetic chain and in some intramural ganglia.

Dopaminergic neurons in mammals are located mainly in the midbrain (the so-called nigro-neostriatal system), as well as in the hypothalamic region. The dopamine circuits of the mammalian brain are well studied. Three main circuits are known, all of them consist of a single-neuron circuit. The bodies of neurons are in the brainstem and send axons to other areas of the brain (Fig. 2.15).

One circuit is very simple. The body of the neuron is located in the hypothalamus and sends a short axon to the pituitary gland. This pathway is part of the hypothalamic-pituitary system and controls the endocrine gland system.

The second dopamine system is also well studied. This is a black substance, many cells of which contain dopamine. The axons of these neurons project into the striatum. This system contains approximately 3/4 of the dopamine in the brain. It is crucial in the regulation of tonic movements. A lack of dopamine in this system leads to Parkinson's disease. It is known that with this disease, the death of neurons of the substantia nigra occurs. The introduction of L-DOPA (a precursor of dopamine) relieves some of the symptoms of the disease in patients.

The third dopaminergic system is involved in the manifestation of schizophrenia and some other mental illnesses. The functions of this system have not yet been sufficiently studied, although the pathways themselves are well known. The bodies of neurons lie in the midbrain next to the substantia nigra. They project axons to the overlying structures of the brain, the cerebral cortex, and the limbic system, especially to the frontal cortex, the septal region, and the entorhinal cortex. The entorhinal cortex, in turn, is the main source of projections to the hippocampus.

According to the dopamine hypothesis of schizophrenia, the third dopaminergic system is overactive in this disease. These ideas arose after the discovery of substances that relieve some of the symptoms of the disease. For example, chlorpromazine and haloperidol have different chemical nature, but they equally suppress the activity of the dopaminergic system of the brain and the manifestation of some symptoms of schizophrenia. Schizophrenic patients who have been treated with these drugs for a year develop movement disorders called tardive dyskinesia (repetitive bizarre movements of the facial muscles, including the muscles of the mouth, which the patient cannot control).

Serotonin was discovered almost simultaneously as a serum vasoconstrictor factor (1948) and enteramine secreted by enterochromaffin cells of the intestinal mucosa. In 1951, the chemical structure of serotonin was deciphered and it received a new name - 5-hydroxytryptamine. In mammals, it is formed by hydroxylation of the amino acid tryptophan followed by decarboxylation. 90% of serotonin is formed in the body by enterochromaffin cells of the mucous membrane of the entire digestive tract. Intracellular serotonin is inactivated by monoamine oxidase contained in mitochondria. Serotonin in the extracellular space is oxidized by peruloplasmin. Most of the serotonin produced binds to platelets and is carried throughout the body through the bloodstream. The other part acts as a local hormone, contributing to the autoregulation of intestinal motility, as well as modulating epithelial secretion and absorption in the intestinal tract.

Serotonergic neurons are widely distributed in the central nervous system (Fig. 2.16). They are found in the dorsal and medial nuclei of the suture of the medulla oblongata, as well as in the midbrain and pons. Serotonergic neurons innervate vast areas of the brain, including the cerebral cortex, hippocampus, globus pallidus, amygdala, and hypothalamus. Interest in serotonin was attracted in connection with the problem of sleep. When the nuclei of the suture were destroyed, the animals suffered from insomnia. Substances that deplete the storage of serotonin in the brain had a similar effect.

The highest concentration of serotonin is found in the pineal gland. Serotonin in the pineal gland is converted to melatonin, which is involved in skin pigmentation, and also affects the activity of the female gonads in many animals. The content of both serotonin and melatonin in the pineal gland is controlled by the light-dark cycle through the sympathetic nervous system.

Another group of CNS mediators are amino acids. It has long been known that nervous tissue, with its high metabolic rate, contains significant concentrations of a whole range of amino acids (listed in descending order): glutamic acid, glutamine, aspartic acid, gamma-aminobutyric acid (GABA).

Glutamate in the nervous tissue is formed mainly from glucose. In mammals, glutamate is highest in the telencephalon and cerebellum, where its concentration is about 2 times higher than in the brain stem and spinal cord. In the spinal cord, glutamate is unevenly distributed: in the posterior horns it is in greater concentration than in the anterior ones. Glutamate is one of the most abundant neurotransmitters in the CNS.

Postsynaptic glutamate receptors are classified according to affinity (affinity) for three exogenous agonists - quisgulate, kainate and N-methyl-D-aspartate (NMDA). Ion channels activated by quisgulate and kainate are similar to channels controlled by nicotinic receptors - they allow a mixture of cations to pass through (Na + and. K+). Stimulation of NMDA receptors has a complex activation pattern: the ion current, which is carried not only by Na + and K + , but also by Ca ++ when the receptor ion channel opens, depends on the membrane potential. The voltage-dependent nature of this channel is determined by the different degree of its blocking by Mg ++ ions, taking into account the level of the membrane potential. At a resting potential of the order of - 75 mV, Mg ++ ions, which are predominantly located in the intercellular environment, compete with Ca ++ and Na + ions for the corresponding membrane channels (Fig. 2.17). Due to the fact that the Mg ++ ion cannot pass through the pore, the channel is blocked every time a Mg ++ ion enters there. This leads to a decrease in the open channel time and membrane conductivity. If the neuron membrane is depolarized, then the number of Mg ++ ions that close the ion channel decreases and Ca ++ , Na + and ions can freely pass through the channel. K + . With rare stimulations (the resting potential changes little), the glutamatergic receptor EPSP occurs mainly due to the activation of quisgulate and kainate receptors; the contribution of NMDA receptors is insignificant. With prolonged membrane depolarization (rhythmic stimulation), the magnesium block is removed, and NMDA channels begin to conduct Ca ++, Na + and ions. K + . Ca++ ions can potentiate (enhance) minPSP through second messengers, which can lead, for example, to a long-term increase in synaptic conductance, which lasts for hours and even days.

Of the inhibitory neurotransmitters, GABA is the most abundant in the CNS. It is synthesized from L-glutamic acid in one step by the enzyme decarboxylase, the presence of which is the limiting factor of this mediator. There are two types of GABA receptors on the postsynaptic membrane: GABA (opens channels for chloride ions) and GABA (opens channels for K + or Ca ++ depending on the type of cell). On fig. 2.18 shows a diagram of a GABA receptor. It is interesting that it contains a benzodiazepine receptor, the presence of which explains the action of the so-called small (daytime) tranquilizers (seduxen, tazepam, etc.). The termination of the action of the mediator in GABA synapses occurs according to the principle of reabsorption (mediator molecules are absorbed by a special mechanism from the synaptic cleft into the cytoplasm of the neuron). Of the GABA antagonists, bicuculin is well known. It passes well through the blood-brain barrier, has a strong effect on the body, even in small doses, causing convulsions and death. GABA is found in a number of neurons in the cerebellum (Purkinje cells, Golgi cells, basket cells), hippocampus (basket cells), olfactory bulb, and substantia nigra.

The identification of brain GABA circuits is difficult, since GABA is a common participant in metabolism in a number of body tissues. Metabolic GABA is not used as a mediator, although their molecules are chemically the same. GABA is determined by the decarboxylase enzyme. The method is based on obtaining antibodies to decarboxylase in animals (antibodies are extracted, labeled and injected into the brain, where they bind to decarboxylase).

Another known inhibitory mediator is glycine. Glycinergic neurons are found mainly in the spinal cord and medulla oblongata. It is believed that these cells act as inhibitory interneurons.

Acetylcholine is one of the first mediators studied. It is extremely widespread in the nervous peripheral system. An example is the motor neurons of the spinal cord and the neurons of the nuclei of the cranial nerves. Typically, cholinergic circuits in the brain are determined by the presence of the enzyme cholinesterase. In the brain, the bodies of cholinergic neurons are located in the nucleus of the septum, the nucleus of the diagonal bundle (Broca), and the basal nuclei. Neuroanatomists believe that these groups of neurons form, in fact, one population of cholinergic neurons: the nucleus of the pedic brain, nucleus basalis (it is located in the basal part of the forebrain) (Fig. 2.19). The axons of the corresponding neurons project to the structures of the forebrain, especially the neocortex and the hippocampus. Both types of acetylcholine receptors (muscarinic and nicotinic) occur here, although muscarinic receptors are thought to dominate in the more rostrally located brain structures. According to recent data, it seems that the acetylcholine system plays an important role in the processes associated with higher integrative functions that require the participation of memory. For example, it has been shown that in the brains of patients who died of Alzheimer's disease, there is a massive loss of cholinergic neurons in the nucleus basalis.

Postsynaptic glutamate receptors are classified according to affinity (affinity) for three exogenous agonists - quisgulate, kainate and N-methyl-D-aspartate (NMDA). Ion channels activated by quisgulate and kainate are similar to channels controlled by nicotinic receptors - they allow a mixture of cations to pass through (Na + and. K+). Stimulation of NMDA receptors has a complex activation pattern: the ion current, which is carried not only by Na + and K + , but also by Ca ++ when the receptor ion channel opens, depends on the membrane potential. The voltage-dependent nature of this channel is determined by the different degree of its blocking by Mg ++ ions, taking into account the level of the membrane potential. At a resting potential of the order of - 75 mV, Mg ++ ions, which are predominantly located in the intercellular environment, compete with Ca ++ and Na + ions for the corresponding membrane channels (Fig. 2.17). Due to the fact that the Mg ++ ion cannot pass through the pore, the channel is blocked every time a Mg ++ ion enters there. This leads to a decrease in the open channel time and membrane conductivity. If the neuron membrane is depolarized, then the number of Mg ++ ions that close the ion channel decreases and Ca ++ , Na + and ions can freely pass through the channel. K + . With rare stimulations (the resting potential changes little), the glutamatergic receptor EPSP occurs mainly due to the activation of quisgulate and kainate receptors; the contribution of NMDA receptors is insignificant. With prolonged membrane depolarization (rhythmic stimulation), the magnesium block is removed, and NMDA channels begin to conduct Ca ++, Na + and ions. K + . Ca++ ions can potentiate (enhance) minPSP through second messengers, which can lead, for example, to a long-term increase in synaptic conductance, which lasts for hours and even days.

Another known inhibitory mediator is glycine. Glycinergic neurons are found mainly in the spinal cord and medulla oblongata. It is believed that these cells act as inhibitory interneurons.

Mediators (from lat. mediator - mediator) - substances through which the transfer of excitation from the nerve to the organs and from one neuron to another is carried out.

Systematic studies of chemical mediators of nerve influence (nerve impulses) began with the classical experiments of Levi (O. Loewi).

Subsequent studies confirmed the results of Levi's experiments on the heart and showed that not only in the heart, but also in other organs, the parasympathetic nerves exercise their influence through the mediator acetylcholine (see), and the sympathetic nerves - the mediator norepinephrine. It was further established that the somatic nervous system transmits its impulses to the skeletal muscles with the participation of the mediator acetylcholine.

Through mediators, nerve impulses are also transmitted from one neuron to another in the peripheral ganglia and the central nervous system.
Dale (N. Dale), based on the chemical nature of the mediator, divides the nervous system into cholinergic (with the mediator acetylcholine) and adrenergic (with the mediator norepinephrine). Cholinergic include postganglionic parasympathetic nerves, preganglionic parasympathetic and sympathetic nerves, and motor nerves of skeletal muscles; to adrenergic - most of the postganglionic sympathetic nerves. The sympathetic vasodilating and sweat gland nerves appear to be cholinergic. Both cholinergic and adrenergic neurons were found in the CNS.

Questions continue to be intensively studied: is the nervous system limited in its activity to only two chemical mediators - acetylcholine and norepinephrine; what mediators determine the development of the inhibition process. With regard to the peripheral part of the sympathetic nervous system, there is evidence that the inhibitory effect on the activity of organs is carried out through adrenaline (see), and the stimulating effect is norepinephrine. Flory (E. Florey) extracted from the CNS of mammals an inhibitory substance, which he called factor J, which possibly contains an inhibitory mediator. Factor J is found in the gray matter of the brain, in the centers associated with the correlation and integration of motor functions. It is identical to aminohydroxybutyric acid. When factor J is applied to the spinal cord, inhibition of reflex reactions develops, especially tendon reflexes are blocked.

In some synapses in invertebrates, gamma-aminobutyric acid plays the role of an inhibitory mediator.

Some authors seek to attribute the mediator function to serotonin. The concentration of serotonin is high in the hypothalamus, midbrain and gray matter of the spinal cord, lower in the cerebral hemispheres, cerebellum, dorsal and ventral roots. The distribution of serotonin in the nervous system coincides with the distribution of norepinephrine and adrenaline.

However, the presence of serotonin in parts of the nervous system devoid of nerve cells suggests that this substance is not related to mediator function.

Mediators are synthesized mainly in the neuron body, although many authors recognize the possibility of additional synthesis of mediators in axonal endings. The mediator synthesized in the body of the nerve cell is transported along the axon to its endings, where the mediator performs its main function of transmitting excitation to the effector organ. Together with the mediator, enzymes that ensure its synthesis are also transported along the axon (for example, choline acetylase, which synthesizes acetylcholine). Released in the presynaptic nerve endings, the mediator diffuses through the synaptic space to the postsynaptic membrane, on the surface of which it connects to a specific chemoreceptor substance, which has either an excitatory (depolarizing) or inhibitory (hyperpolarizing) effect on the membrane of the postsynaptic cell (see Synapse). Here, the mediator is destroyed under the influence of the corresponding enzymes. Acetylcholine is cleaved by cholinesterase, norepinephrine and adrenaline - mainly by monoamine oxidase.

Thus, these enzymes regulate the duration of the action of the mediator and the extent to which it spreads to neighboring structures.

See also Excitation, Neurohumoral regulation.

The main function of the central nervous system is the processing of external and internal information flows aimed at meeting the needs of the body. Only with a clear understanding of the integrative function of the brain is it possible to effectively treat nervous and mental diseases. Clinical experience, in turn, contributes to the clarification of brain functions: the failure of treatment or unexpected side effects of drugs often serve as a reason to search for previously unknown molecular and cellular mechanisms. One of the most exciting problems of modern neuropharmacology is the relationship between the processes occurring at the neuron level, on the one hand, and behavior and pathological disorders of nervous activity, on the other. The general approach to this problem is based on the following principle: drugs that act on behavior and are effective in nervous and mental diseases either facilitate or impede synaptic transmission to the CNS.

CNS studies include different levels: molecular, cellular, systemic and behavioral. In neuropharmacology, studies at the molecular level remain leading. These studies make it possible to elucidate the key mechanisms of synaptic transmission that drugs act on. Targets for these funds can be:

1) ion channels that provide a neuron's response to a mediator - excitation or inhibition, 2) mediator receptors, 3) intramembrane and intracellular molecules that convert and transmit a signal from the receptor to intracellular effector systems for rapid short-term excitation or inhibition of the neuron or for a long-term change its state - due, for example, to changes in gene expression (Neyroz et al., 1993; Gudermann et al., 1997), 4) carrier proteins that ensure the reuptake of the mediator by nerve endings, and then by synaptic vesicles (Blakely et al. , 1994; Amara and Sonders, 1998; Fairman and Amara, 1999); these two processes involve different carrier proteins, see Liu and Edwards (1997).

Research at the molecular level provides new methodological possibilities (in particular, pharmacological analysis) for studying processes at the cellular, systemic and behavioral levels and their genetic basis. To date, the molecular mechanisms of most of the processes occurring in the neuron are known. As is known, the electrical activity of a neuron is determined by a change in the permeability of its numerous ion channels. Now many molecular mechanisms have become known, on which the selective current of the main cations - Na *, K +, Ca and the SG anion depends. Ion channels are divided into voltage-dependent (Fig. 12.2) and chemosensitive (Fig. 12.3). Potential-dependent channels provide a rapid change in ion currents necessary for the emergence and propagation of a nerve impulse, as well as for the release of a neurotransmitter in response to excitation of the presynaptic ending (Catterall, 1988, 1993). Molecular genetic methods revealed similarities in the structure of the main cation channels (Fig. 12.2, A). The main subunit of the fast sodium and slow calcium channels consists of four homologous transmembrane domains, each of which includes six transmembrane segments. Potassium channels are more diverse, which is confirmed by X-ray diffraction analysis (Doyle et al., 1998). The main subunit of a number of voltage-gated potassium channels consists of a single domain, which includes 6 transmembrane segments (Fig. 12.2, B). Abnormally rectifying potassium channels (Kir) are also formed by a single domain, but it contains only the fifth and sixth transmembrane segments - between them there is an intramembrane loop that extends to the outer surface of the membrane and forms the outer mouth of the channel. These two structural forms form different heterooligomers, which creates additional opportunities for controlling potassium channels in response to a change in the membrane potential, the action of a mediator, as well as through a system of intracellular proteins or due to post-translational modifications (Krapivinsky et al., 1995). The study of various structural forms of potassium channels (Jan et al., 1997; Doyle et al., 1998) makes it possible to find out how drugs, toxins or electrical stimulation act on the electrical activity of a neuron, giving it, for example, spontaneous activity or causing its death due to constant stay open potassium channels (Adams and Swanson, 1994).

Different variants of potassium channels (delayed rectifier potassium channels, calcium-dependent potassium channels, and hyperpolarizing current potassium channels), which are regulated by the second messenger system, provide complex modulatory effects in CNS synapses (Nicoll et al., 1.99c-Malenka and Nicoll, 1999).

Research at the cellular level allows us to find out which neurons and which of their closest synaptic contacts are relevant to the behavioral effects of the drug. Such studies establish the nature of the interaction of neurons - excitation, inhibition, or more complex forms of synaptic effects (Aston-Jones et al., 1999; Brown et al., 1999).

The system level combines data on the structure and function of mediator systems, that is, it establishes a connection between the neurons that synthesize and release the mediator and the behavioral effect that this mediator causes. Quite a lot of “transmitter-behavior” connections have been found, although in none of these cases it can be argued that only those neurons that produce the corresponding mediator are responsible for this type of behavior.

Figure 12.2. The structure of voltage-gated ion channels. A. The alpha subunit of the fast sodium and slow calcium channels consists of four homologous domains, each of which includes six transmembrane segments; between the fifth and sixth transmembrane fragments there is an intramembrane loop. B. The composition of the slow calcium channel also includes small additional subunits a2, P, y, and 6. Subunits a2 and 8 are connected by a disulfide bond (not shown in the figure). The structure of the sodium channel also contains additional regulatory subunits. B. The main subunit of the voltage-gated delayed-rectifier potassium channel consists of a single transmembrane domain—similar to the corresponding domains of the sodium and calcium channels. The proposed structure of potassium channels of abnormal K|r straightening includes a subunit consisting of a domain in which only the 5th and 6th transmembrane segments are present. Additional p-subunits modulate the activity of voltage-gated potassium channels (Kv). These two types of structures can form various heterooligomers. Krapivinsky et al., 1995.

Figure 12.3. The structure of receptors associated with ion channels. Such receptors are composed of four or five subunits surrounding an ion channel pore (right). Each subunit includes 4 transmembrane domains. It is assumed that N-cholinergic receptors, 5-HT3 receptors, GABAd receptors, and glycine receptors have such a structure. Glutamate receptors have a slightly different structure.

Studies at the behavioral level make it possible to understand integrative processes - that is, to attribute one or another group of neurons to specialized neural circuits, neural ensembles or distributed systems responsible for the implementation of behavior in general - from elementary reflexes to complex forms of voluntary activity. The modeling of mental illness in animals is based on the following principle: the state of an animal and the state of a person can be considered similar if they correspond to similar changes in physiological parameters: heart rate, respiration, motor reactions, etc. (Kandel, 1998).

Definition of central mediators

To understand the functions of central mediators, it is important to determine which substances belong to them. The criteria to be met by CNS mediators are, in principle, the same as for the autonomic nervous system.

The mediator must be present in the presynaptic neuron and its ending. A more rigorous formulation of this condition requires evidence that the presynaptic neuron synthesizes the mediator, and does not accumulate it from the extracellular space. Compliance with this criterion is checked by immunocytochemistry, fluorescent in situ hybridization, using biochemical analysis of brain tissue or subcellular fractions.

In animal experiments, these methods make it possible to test whether a putative neurotransmitter has disappeared from the synaptic region after surgical or chemical destruction of presynaptic neurons. Compliance with the criterion confirms the presence in postsynaptic neurons of mRNA encoding the receptors of this mediator.

The mediator must be released upon excitation of the presynaptic neuron. Compliance with this criterion is checked in experiments in vivo: during electrical stimulation of the presynaptic fiber, the putative mediator should appear in the synapse region. Previously, periodic determination of the composition of the perfusate washing the synapse for a long time was used for this, but today microdialysis and microelectrode polarography methods have appeared that allow capturing the presence of amines and amino acids in a limited volume and in a short time with high accuracy. The appearance of a mediator in response to iontophoretic or electrical stimulation can be traced in vitro - on brain slices or subcellular fractions of presynaptic endings. The mechanism of release of all mediators, including the supposed release of mediators from dendrites (Morris et al., 1998), is triggered by a change in the membrane potential and requires calcium ions to enter the presynaptic terminal. Sodium ions do not play any role in this process, since neither the extracellular concentration of sodium nor tetrodotoxin (a blocker of fast sodium channels) affects the release of mediators.

The application of the mediator to the target cells should cause the same effect as the stimulation of the presynaptic fiber. The putative mediator and stimulation of the presynaptic fiber should act on the target cell in the same way: either inhibit or excite it. For a more rigorous proof, it is required to show that both stimulation of the presynaptic neuron and application of the putative mediator cause the same ion currents in the postsynaptic neuron. Compliance with this criterion can also be verified pharmacologically: the effect of stimulation of the presynaptic neuron and the effect of application of the putative mediator must be eliminated by the same dose of the same blocker. At the same time, this blocker should not suppress the response of the target cell to stimulation of other presynaptic fibers and to the application of other putative mediators. Finally, the effect of the putative mediator must match that of its synthetic agonist.

Numerous studies, especially those devoted to peptides, show that central synapses may contain not one, but several mediators (Hokfelt et al., 2000). Although there is no strong evidence yet, it is suggested that co-localized mediators are released together and act together on the postsynaptic membrane (Derrick and Martinez, 1994; Jin and Chavkin, 1999). If signals are transmitted by more than one mediator, then a single agonist cannot accurately reproduce the effect of synapse activation, and a single blocker cannot completely eliminate this effect.

Discovery of central mediators

The first candidates for the role of central mediators were acetylcholine and norepinephrine - as well-known mediators of the autonomic and somatic nervous system. In the 1960s there was an assumption that serotonin, adrenaline and dopamine can be CNS mediators. Histochemical, biochemical and pharmacological studies generally confirmed their mediator role, although they did not fully meet all the criteria for determining a mediator. In the early 1970s mediators were recognized as GABA, glycine and glutamate - due to the emergence of selective, highly active blockers. The studies of hormones of the hypothalamic-pituitary system that were taking place at the same time were accompanied by the improvement of methods for isolating, purifying, determining the amino acid sequence, and synthesizing more and more new neuropeptides (Hokfelt et al., 2000). Immunohistochemical studies have shown that the peptides can act as CNS mediators. Adaptation of biological assays previously used in studies of pituitary hormones to other models (eg, smooth muscle contraction) and then the introduction of immunochemical methods led to the discovery of endogenous peptides that act on opiate receptors (chapter 23). A search was then made for endogenous compounds capable of binding to benzodiazepine receptors (Costa and Guidotti, 1991). Relatively recently, endogenous ligands of cannabinoid receptors, fatty acid amides, have been identified (Piomelli et al., 1998).

Study of receptors

Until recently, the properties of central receptors were judged by the binding of labeled ligands, as well as by electrical or biochemical processes caused by their activation in vivo and in vitro. The study of labeled ligand binding makes it possible to estimate the number of receptors in a particular section of the CNS, to trace their appearance in phylogenesis and ontogenesis, and also to find out how various physiological and pharmacological interventions affect the number of receptors and their affinity for ligands (Dumont et al., 1998; Redrobe et al., 1999).

Electrophysiological methods evaluate the response of a neuron to a mediator. For example, a change in the electrical activity of a neuron is recorded in response to an iontophoretic application of a mediator. The method of local fixation (patch-clamp) allows you to trace the response to the mediator of individual ion channels. Electrophysiological methods make it possible not only to describe, but also to measure the effects of a putative mediator (Jardemarketal., 1998). Biochemical methods study receptors, the activation of which causes an enzymatic reaction, for example, the synthesis of a second mediator.

Modern methods of molecular biology have made it possible to isolate mRNAs that encode receptors for almost all known mediators. The introduction of such mRNA into foreign cells (frog oocytes or mammalian cells) causes the expression of receptors in them, the properties of which are assessed by the effects of ligands or the synthesis of second mediators. Molecular genetic methods have established two main types of receptors, different in structure and function. Receptors coupled to ion channels (ionotropic receptors, receptor channels, chemosensitive channels) are formed by several subunits. Each subunit includes 4 transmembrane hydrophobic domains of 20-25 amino acids (Fig. 12.3). In addition, these receptors have sites for reversible phosphorylation, as well as sites that respond to changes in the membrane potential. These receptors include N-cholinergic receptors (Ch. 2 and 7), receptors for amino acids and GABA, glycine, glutamate and aspartate, as well as 5-HT3 receptors (Ch. 11).

The second main type of receptors are G-protein coupled receptors (Ch. 2). They consist of a single subunit with seven transmembrane domains connected by three extracellular and three intracellular loops of various lengths (Fig. 12.4). Stimulation of such receptors leads to the activation of G proteins (heterotrimeric GTP-binding proteins), which in turn causes the activation or inhibition of intracellular effector enzymes (for example, adenylate cyclase or phospholipase C) or changes in the functioning of ion channels (for example, slow calcium channels or chemosensitive potassium channels). In addition, these receptors themselves can be phosphorylated at several sites. The mechanisms of all these processes have been studied in detail using molecular genetic methods. Such receptors include M-cholinergic receptors, GABA receptors, some glutamate receptors, and some amine and neuropeptide receptors. Transfection of cells to express mRNA encoding unknown types of receptors has led to the discovery of new neuropeptides (Reinscheid et al., 1995). In the CNS, there are also receptors of another type - receptors with their own enzymatic activity, for example, guanylate cyclase (Ch. 2).

Figure 12.4. The structure of receptors coupled to G-proteins. Such receptors consist of a single subunit with seven transmembrane domains. The binding site for low molecular weight mediators is immersed in the membrane; the second and third intracellular loops interact with the G protein (Ch. 2).

In the central synapses, there are also carrier proteins that ensure the reuptake of the mediator - from the synaptic cleft to the axoplasm of the presynaptic ending, and from the axoplasm to the synaptic vesicles (Fig. 12.5). They are thought to include 12 transmembrane domains - as well as glucose transport proteins and mammalian adenylate cyclase (Tang and Gilman, 1992).

The response of a postsynaptic neuron to a neurotransmitter is determined by its excitability and the number of mediator receptors. Prolonged excess of the mediator (or its analogue) leads to a decrease in the number of receptors and, consequently, sensitivity to the mediator (desensitization). On the contrary, with a deficiency of the mediator, the number of receptors increases, and sensitivity to the mediator increases. These adaptive changes are especially important to take into account in the treatment of chronic diseases of the central nervous system: the effect of the drug with a single and long-term use can be very different. Similar changes operate at the presynaptic level, affecting the synthesis, storage, release, and reuptake of the neurotransmitter.

Mediators, neurohormones and neuromodulators

Picks

It follows from the above criteria that a mediator is a substance that a neuron synthesizes, releases and uses to transmit a signal to a postsynaptic target cell. The action of the mediator can be directed both directly to the electrical activity of the target cell and to the biochemical processes occurring in it, on which its response to other synaptic inputs depends. In addition, the effect of the mediator may depend on the state of the target cell, that is, not so much cause excitation or inhibition, but rather enhance these processes (Bourne and Nicoll, 1993). Thus, the effect of any mediator must be considered in the context of the neural system that includes the given synapse. If one neuron acts on several target cells, this action can be either different or the same - it all depends on the properties of postsynaptic receptors and the way in which the signal is transmitted from the receptor to the effector mechanisms of the cell.

Two classical electrophysiological effects of mediators are known: 1) excitation: opening of ion channels leads to the entry of cations and depolarization, while membrane resistance decreases, 2) inhibition: opening of ion channels leads to such ion currents, as a result of which hyperpolarization develops, membrane resistance also decreases. But there are other, "non-classical" options for the action of mediators. Both depolarization and hyperpolarization can be due, on the contrary, to the closing of ion channels; membrane resistance in this case increases (Shepherd, 1998). Some mediators (monoamines and some peptides) by themselves have little or no effect on ion currents and membrane potential, but at the same time they can enhance or suppress the response of the target cell to the classical - excitatory or inhibitory - mediator. Such an effect is called modulating; it is assumed that there are different variants of it (Nicoll et al., 1990; Foote and Aston-Jones, 1995). Whatever the mechanisms of the modulating action, it differs significantly from the above-described fast and precise excitatory and inhibitory influences - to which, as was previously believed, all variants of synaptic transmission are reduced. There was even a doubt that substances that have a modulating effect can be classified as mediators. Let us briefly consider some of these substances and their mechanisms of action.

Neurohormones

Some hypothalamic cells have been called neurosecretory because they are both neurons (receiving synaptic inputs from CNS neurons) and endocrine cells (releasing substances directly into the bloodstream). Substances secreted by such cells became known as neurohormones. An example is ADH, which is produced in the neurons of the hypothalamus, stored at the endings of their axons in the neurohypophysis, and from here secreted into the blood. At the same time, it became known that these neurons of the hypothalamus form synapses on other neurons (Hokfelt et al., 1995, 2000), and the role of a mediator in such synapses, as shown by cytochemical studies, is played by oxytocin and ADH. Thus, these and other substances produced by the hypothalamus can be called "neurohormones" only insofar as they are able to be released into the blood (for example, in the neurohypophysis), but this term does not in any way reflect all their functions.

neuromodulators

Florey (Florey, 1967) called neuromodulators compounds that act differently on neurons than typical neurotransmitters. Modulators are released outside the synapse, but nevertheless affect the excitability of nerve cells. Flory suggested that CO2 and ammonia, which are released from active neurons and glia, can play the role of neuromodulators. Currently, steroid hormones, neurosteroids (Baulieu, 1998), adenosine and other purines, prostaglandins and other derivatives of arachidonic acid, as well as NO (Gaily et al., 1990) are considered to have neuromodulatory effects. Second intermediaries. In some cases, the response of a postsynaptic neuron to a mediator is due to the formation of second mediators, the best known of which are cAMP, cGMP, and products of the phosphoinositide system (Ch. 6, 7,10,11). At the same time, it can be methodically difficult for brain neurons to prove that a change in the concentration of these substances immediately precedes the postsynaptic potential, and is also necessary and sufficient for its occurrence. It is possible that the second mediators only contribute to the emergence of the postsynaptic potential by activating the reaction of protein phosphorylation and thereby triggering a complex cascade of molecular events. As a result, the properties of the membrane and cytoplasmic proteins, on which neuron excitability depends, change (Greengard et al., 1999). It is these mechanisms that can be affected by drugs that enhance or weaken the effects of mediators (see below).

Neurotrophic factors

Neurons, astrocytes and microglia, as well as cells of the immune system that temporarily appear in the brain tissue (for example, during inflammation), synthesize substances that support the growth, survival and repair of neurons. This function is performed by various substances of a peptide nature, divided into 7 types (Black, 1999; McKay et al., 1999): 1) classical neurotrophins, for example, nerve growth factor, brain-derived neurotrophic factor, 2) neuropoietins (neuropoietic cytokines), which have an effect both neurons and myeloid cells, e.g. leukemia inhibitory factor, ciliary neurotrophic factor, some interleukins, 3) peptide growth factors, including epidermal growth factor, transforming growth factors a and β, glial neurotrophic factor, activin A, 4) fibroblast growth factor, 5) insulin-like growth factors, 6) platelet-derived growth factors, 7) axon growth directing factors, some of which are able to attract cells of the immune system (Song and Poo, 1999; Spriggs, 1999). Drugs that activate the synthesis and release of neurotrophins or mimic their action could be an effective tool for stimulating recovery processes.

Figure 12.5. The proposed structure of carrier proteins. The amine and amino acid transport proteins of both the presynaptic membrane and synaptic vesicles include 12 transmembrane domains (the exact orientation of the N-terminal residues is not known). Otherwise, the structure of these two types of carrier proteins is somewhat different.

Central mediators

Many drugs that act on the CNS interfere with neurotransmitter transmission. Thus, to understand the effects of these drugs, it is necessary to know the mechanisms of action of central mediators. According to the hypothesis of chemical specificity, or Dale's principle (Dale, 1935), one neuron synthesizes one mediator, which is released in all its presynaptic endings. However, more and more evidence suggests that a neuron may contain multiple mediators (Hokfelt et al., 1995, 2000). Thus, the Dale principle is modified as follows: the neuron synthesizes and releases the same set of mediators in all its presynaptic endings. But even such a reading can hardly be considered final. It is not clear, for example, whether only one identical peptide is excised from the precursor peptide, destined for all neuron endings. In table. 12.1 summarizes the properties of the most studied CNS mediators. Further mediators will be considered by chemical groups: amino acids, amines and peptides. Other compounds that are involved in synaptic transmission include purines such as adenosine and ATP (Edwards and Robertson, 1999; Moreau and Huber, 1999; Baraldi et al., 2000) as well as NO (Cork et al., 1998) and arachidonic acid derivatives (Mechoulam et al., 1996; Piomelli et al., 1998).

Amino acids

The CNS is characterized by a high concentration of certain amino acids - especially glutamate and GABA. These simple compounds are found in almost every structure of the brain, and they have an immediate, powerful and short-term effect on any neuron. True mediators are characterized by selectivity - both in distribution and in action. Therefore, the mediator role of amino acids was not immediately recognized. Monoamino dicarboxylic amino acids have a strong excitatory effect, monoamino monocarboxylic (GABA, glycine, β-alanine, taurine) have an equally strong, but inhibitory effect (Kelly and Beart, 1975). The advent of selective blockers has opened up the possibility of identifying amino acid receptors and discovering their subtypes. Subsequent mapping of receptors with labeled ligands conclusively confirmed that GABA, glycine, and glutamate are central mediators.

GABA

The presence of GABA in brain tissue was discovered in 1950 - but its inhibitory effect was not immediately recognized. When studying crustacean stretch receptors, the following facts were found: 1) GABA has an inhibitory effect on muscles, 2) it is found exclusively in inhibitory nerves, 3) an extract of these nerves has the same inhibitory effect, 4) no other inhibitory amino acid was found, 5) the release of GABA correlates with the frequency of stimulation of the inhibitory nerves, 6) the application of GABA and stimulation of the inhibitory nerves caused the same effect: an increase in chloride conductivity in the muscle fiber. These facts made it possible to classify GABA with full right as a mediator (for more on the history of the issue, see the review by Bloom, 1996).

It was soon found that GABA has similar physiological and pharmacological effects in the mammalian CNS. It turned out that GABA mediates the action of inhibitory neurons in local circuits of the brain, as well as presynaptic inhibition in the spinal cord. Inhibitory GABAergic synapses exist in many brain structures: they are formed by Purkinje cells of the cerebellar cortex on neurons of the Deiters nucleus; intercalary neurons on Purkinje cells, olfactory bulb, sphenoid nucleus of the medulla oblongata, hippocampus, lateral nucleus of the transparent septum; neurons of the vestibular nuclei on the motoneurons of the nucleus of the trochlear nerve. GABA provides inhibition in the cerebral cortex, as well as the inhibitory effect of the striatum on the substantia nigra. Thus, GABA is the main inhibitory mediator in the mammalian CNS. The localization of GABAergic neurons and the distribution of their nerve endings have been established by methods that make it possible to detect glutamate decarboxylase, an enzyme for the synthesis of GABA from glutamic acid. Immunocytochemical methods reveal the enzyme itself, fluorescent in situ hybridization - the mRNA encoding it. Many GABAergic neurons also contain one or more neuropeptides. For studies of GABAergic transmission, GABA receptor blockers, bicuculline and picrotoxin, are used. Many substances that provoke convulsive activity, such as penicillin and pentetrazole, have also been found to be selective GABA antagonists (Macdonald et al., 1992; Macdonald and Olsen, 1994). It is not yet clear whether GABA agonists - stimulators of GABA receptors (muscimol), inhibitors of its reuptake (2,4-diaminobutyric acid, nipecotic acid, guvacine) or substances that affect its metabolism (for example, aminooxyacetic acid) have a therapeutic effect. .

GABA receptors are divided into two types. The most common GABAd receptors are ionotropic: they are chemosensitive chloride channels, about

Mediators, or neurotransmitters, of CNS neurons are various biologically active substances. Depending on the chemical nature, they can be divided into 4 groups: 1) amines (acetylcholine, norepinephrine, dopamine, serotonin), 2) amino acids (glycine, glutamic, aspartic, gamma-aminobutyric - GABA), 3) purine and nucleotides (ATP) ; 4) neuropeptides (substance P, vasopressin, opioid peptides, etc.).
Previously, it was believed that in all endings of one neuron "one mediator is released (according to the Dale principle). In recent years, it has been found out that many neurons can contain 2 mediators or more.
According to their action, mediators can be divided into ionotropic and metabolotropic. Ionotropic mediators after interaction with the cytoreceptors of the postsynaptic membrane change the permeability of ion channels. Metabolotropic mediators exhibit a postsynaptic effect by activating specific membrane enzymes. As a result, so-called second messengers (second messengers) are activated in the membrane or (more often) in the cytoplasm of the cell, which in turn trigger cascades of intracellular processes, thereby affecting cell functions.
The main messengers of intracellular signaling systems include adenylate cyclase and polyphosphoinositide. The first is based on the adenylate cyclase mechanism. The central link of the second system is the calcium-mobilizing cascade of polyphosphoinositides, which is controlled by phospholipase C. The physiological effect of these systems is carried out by activating specific enzymes - protein phosphokinases, the end result of which is a wide range of effects on protein substrates that can undergo phosphorylation. As a result, the permeability of membranes for ions changes, mediators are synthesized and released, protein synthesis is regulated, energy metabolism is carried out, etc. Most neuropeptides have a metabolotropic effect. Metabolic changes occurring in a cell or on its membrane under the action of metabolicotropic mediators are longer than under the action of ionotropic mediators. They can even affect the genome of a cell.
According to their functional properties, the mediators of the central nervous system are divided into excitatory, inhibitory and modulating. Excitatory mediators can be various substances that cause depolarization of the postsynaptic membrane. Derivatives of glutamic acid (glutamate), substance P, are of paramount importance. Some central neurons have cholinergic receptors, i.e. contain receptors on the postsynaptic membrane that react with choline compounds, for example, acetylcholine in Renshaw cells .. monoamines (norepinephrine, dopamine, serotonin) can also be excitatory mediators. There is reason to believe that the type of mediator that is formed in the synapse is determined not only by the properties of the ending, but also by the general direction of biochemical processes in the entire neuron.
The nature of the inhibitory mediator has not been fully established. It is believed that in the synapses of various nerve structures, this function can be performed by amino acids - glycine and GABA.

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