Mediators of the nervous system. Mediators and receptors of the central nervous system Inhibitory mediators of the nervous system are

Classification of CNS synapses is carried out according to several criteria. According to the type of connected cells, the following synapses are distinguished: interneuronal localized in the central nervous system and autonomic ganglia ; neuroeffector(neuromuscular and neurosecretory), connecting efferent neurons of the somatic and autonomic nervous system with executive cells (striated and smooth muscle fibers, secretory cells); neuroreceptor(contacts in secondary receptors between the receptor cell and the dendrite of the afferent neuron0.

According to the morphological organization, there are: axosomatic, axodendritic, axoaxonal, dendrosomatic, dendrodendritic.

According to the method of signaling - chemical synapses, in which the mediator (mediator) of transmission is a chemical; electrical, in which signals are transmitted by electric current; mixed synapses - electrochemical.

In terms of functional effect - excitatory and inhibitory.

2.2.1 Chemical synapses and neurotransmitters.

According to the nature of the mediator, chemical synapses are divided into cholinergic (mediator - acetylcholine), adrenergic (naradrenaline), dopaminergic (dopamine), GABA - ergic (gamma - aminobutyric acid), etc.

The structural elements of a chemical synapse include: presynaptic and postsynaptic membranes, synaptic cleft (Fig. 24).

The presynaptic ending contains synaptic vesicles (vesicles) up to 200 nm in diameter. They are formed in the body of the neuron and, with the help of fast axon transport, are delivered to the presynaptic ending, where they are filled with a neurotransmitter, or mediator (transmitter). The presynaptic terminal contains mitochondria, which provide energy for synaptic transmission processes. The endoplasmic reticulum contains deposited Ca++. Microtubules and microfilaments are involved in the movement of vesicles. Binding of Ca++ to vesicle envelope proteins leads to mediator exocytosis into the synaptic cleft.

The synaptic cleft has a width of 20 to 50 nm, contains intercellular fluid and mucopolysaccharide dense substance to provide connections between the pre- and postsynaptic membranes, as well as enzymes.

The postsynaptic membrane of the synapse contains chemoreceptors capable of binding neurotransmitter molecules. There are two types of receptors on the postsynaptic membrane - ion receptors, which contain an ion channel that opens when the mediator molecules bind to a certain place (recognizing center) on the receptor molecule; metabotropic receptors, opening the ion channel indirectly through a chain of biochemical reactions, in particular, by activating the synthesis of special molecules, the so-called second messengers (mesengers). Substances such as c.GTP, c.AMP, calcium ions can play the role of secondary mediators. They trigger many biochemical reactions in the cell associated with protein synthesis, enzyme activation, etc.

Rice. 24. Central synapses

In the central nervous system, the mediator function is performed not by one substance, but by a heterogeneous group of substances.

There are several criteria according to which a particular substance can be classified as a mediator for a given type of synapse.

1. This substance must be present in sufficient quantities in the presynaptic nerve endings, where there must also be an enzymatic system for its synthesis. The synthesizing system can be localized elsewhere, but the substance must be delivered to the site of action.

2. When stimulating presynaptic neurons or nerves, this substance must be released from the endings in sufficient quantities.

3. With artificial administration, the activating or inhibitory effect of this substance on the postsynaptic cell should be identical with the effect of stimulation of the presynaptic nerve

4. In the area of ​​the synaptic cleft, there must be an enzymatic system that inactivates the given substance after its action has been carried out and, thus, makes it possible to quickly return the postsynaptic membrane to a state of readiness.

5. On the postsynaptic membrane there should be receptors with high affinity for this substance.

Acetylcholine is a fairly widespread excitatory mediator in the CNS. It was discovered in the 30s by the Austrian scientist O. Levy. By chemical nature, acetylcholine is the acetate ester of choline and is formed by acetylation of choline with the participation of the enzyme acetylcholine transferase. After release from presynaptic terminals, acetylcholine is rapidly degraded by the enzyme acetylcholinesterase.

Cholinergic neurons include the alpha motor neurons of the spinal cord. With the help of acetylcholine, alpha motor neurons transmit an excitatory effect to Renshaw's inhibitory cells through the collaterals of their axons.

Two types of receptors sensitive to acetylcholine have been found: muscarinic (M - receptors) and nicotinic receptors (H - receptors). On the muscles of our body are nicotinic-type receptors for acetylcholine. Poison is a nicotinic receptor blocker curare, d - tubocurarine, diplacin, fluxedil(acetylcholine antagonists). Curare poison was used by the Indians when hunting animals. Currently, synthetic analogs of curare are widely used to immobilize patients during abdominal operations under artificial respiration. Receptors for acetylcholine in the heart muscle are of the muscarinic type and curare does not stop the heart.

Nicotinic receptors are also found in some structures of the brain (reticular formation of the brain stem, hypothalamus).

The effect of acetylcholine can be both activating and inactivating through the excitation of inhibitory interneurons. Acetylcholine has an inhibitory effect with the help of M-cholinergic receptors in the deep layers of the cerebral cortex, the brain stem, and the caudate nucleus.

Brain neurons, excited through muscarinic acetylcholine receptors, play an important role in the manifestation of certain mental functions. It is known that the death of such neurons leads to senile dementia (Alzheimer's disease).

Biogenic amines include two groups of mediators: catecholamines(norepinephrine, epinephrine, dopamine) and indolamine(serotonin).

Catecholamines are derivatives of tyrosine and perform a mediator function in peripheral and central synapses. The action of catecholamines as metabolic regulators is mediated through alpha and beta receptors and a system of secondary messengers.

Noradrenergic neurons are concentrated mainly in the midbrain (locus coeruleus). 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.

Norepinephrine is an inhibitory mediator of Purkinje cells of the cerebellum, excitatory - in the hypothalamus, epithalamic nuclei.

Noradrenergic neurons are found in large numbers in the peripheral nervous system.

Norepinephrine regulates mood, emotional reactions, ensures the maintenance of wakefulness, participates in the mechanisms of formation of certain phases of sleep and dreams

Dopaminergic neurons are located predominantly in the midbrain, as well as in the hypothalamic region. The dopamine system of the black substance of the midbrain has been well studied. This system contains 2/3 of the dopamine in the brain. The processes of neurons of the substantia nigra are projected into the striatum, which play an important role in the regulation of tonic movements. The degeneration of the neuron in the substantia nigra leads to Parkinson's disease.

Dopamine is involved in the formation of a sense of pleasure, the regulation of emotional reactions, and the maintenance of wakefulness.

Currently, two subtypes of dopamine receptors (D1 and D2 subtypes) have been identified. D1 and D2 receptors are found on striatal neurons. D2 receptors were found in the pituitary gland, under the action of dopamine on them, the synthesis and secretion of prolactin, oxytocin, melanostimulating hormone, endorphin is inhibited.

Serotonin (5-hydroxytryptamine) along with catecholamines belongs to aminergic mediators. It is formed by hydroxylation of the amino acid tryptophan followed by decarboxylation. The chemical structure of serotonin was deciphered in 1952. 90% of serotonin is formed in the body by enterochromaffin cells of the mucous membrane of the entire digestive tract. Most of the serotonin binds to platelets and is carried throughout the body through the bloodstream. Intracellular serotonin is inactivated by monoamine oxidase (MAO) contained in mitochondria. Part of serotonin 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, mainly in the structures of autonomic functions. In humans, it is found in various parts of the brain (brain stem, pons, raphe nuclei). With the help of serotonin, excitatory and inhibitory influences are transmitted in the neurons of the brain stem. The highest concentration of serotonin is found in the pineal gland. Here, serotonin is converted to melatonin, which is involved in skin pigmentation and affects the activity of female gonads.

Serotonin realizes its influence with the help of ionotropic and metabotropic receptors. There are several types of serotonin receptors located on both the presynaptic and postsynaptic membranes. The serotonin receptor antagonist is lysergic acid diethylamide (LSD), which is a powerful hallucinogen

The physiological effects of serotonin are associated with its participation in the learning process, the formation of pain sensations, and the regulation of sleep. Serotonin plays an important role in downstream control of spinal cord activity and hypothalamic control of body temperature. Violations of the function of serotonergic synapses are observed in schizophrenia and other mental disorders.

Nerve cells control body functions with the help of signaling chemicals, neurotransmitters, and neurohormones. neurotransmitters- short-lived substances of local action; they are released into the synaptic cleft and transmit a signal to neighboring cells (produced by neurons and stored in synapses; when a nerve impulse arrives, they are released into the synaptic cleft, selectively bind to specific receptor on the postsynaptic membrane of another neuron or muscle cell, stimulating these cells to perform their specific functions). The substance from which the mediator is synthesized (the precursor of the mediator) enters the neuron or its ending from the blood or cerebrospinal fluid (fluid circulating in the brain and spinal cord) and, as a result of biochemical reactions under the influence of enzymes, turns into the corresponding mediator, and then is transported to the synaptic cleft in the form of bubbles (vesicles). Mediators are also synthesized in presynaptic endings.

Mechanism of action. Mediators and modulators bind to receptors on the postsynaptic membrane of neighboring cells. Most neurotransmitters stimulate the opening of ion channels, and only a few - the closure. The nature of the change in the membrane potential of the postsynaptic cell depends on the type of channel. A change in the membrane potential from -60 to +30 mV due to the opening of Na + channels leads to the emergence of a postsynaptic action potential. A change in the membrane potential from -60 mV to -90 mV due to the opening of Cl - channels inhibits the action potential (hyperpolarization), as a result of which excitation is not transmitted (inhibitory synapse). According to their chemical structure, mediators can be divided into several groups, the main of which are amines, amino acids, and polypeptides. A fairly widespread mediator in the synapses of the central nervous system is acetylcholine.

Acetylcholine occurs in various parts of the central nervous system (cerebral cortex, spinal cord). Known mainly as exciting mediator. In particular, it is a mediator of alpha motor neurons of the spinal cord that innervates skeletal muscles. These neurons transmit an excitatory effect on Renshaw's inhibitory cells. In the reticular formation of the brain stem, in the hypothalamus, M- and H-cholinergic receptors were found. Acetylcholine also activates inhibitory neurons, which determines its effect.

Amines ( histamine, dopamine, norepinephrine, serotonin) are mostly contained in significant amounts in the neurons of the brain stem, in smaller quantities are detected in other parts of the central nervous system. Amines provide the occurrence of excitatory and inhibitory processes, for example, in the diencephalon, substantia nigra, limbic system, and striatum.

Norepinephrine. Noradrenergic neurons are concentrated mainly in the locus coeruleus (midbrain), where there are only a few hundred of them, but their axonal branches are found throughout the CNS. Norepinephrine is an inhibitory mediator of the Purkinje cells of the cerebellum and an excitatory one in the hypothalamus, epithalamic nuclei. Alpha and beta-adrenergic receptors were found in the reticular formation of the brain stem and hypothalamus. Norepinephrine regulates mood, emotional reactions, maintains wakefulness, participates in the mechanisms of formation of certain phases of sleep and dreams.

Dopamine. Dopamine receptors are divided into D1 and D2 subtypes. D1 receptors are localized in the cells of the striatum, act through dopamine-sensitive adenylate cyclase, like D2 receptors. D2 receptors are found in the pituitary gland, under the action of dopamine on them, the synthesis and secretion of prolactin, oxytocin, melanostimulating hormone, endorphin are inhibited. . Dopamine is involved in the formation of a sense of pleasure, the regulation of emotional reactions, and the maintenance of wakefulness. Striatal dopamine regulates complex muscle movements.

Serotonin. With the help of serotonin, excitatory and inhibitory influences are transmitted in the neurons of the brain stem, and inhibitory influences are transmitted in the cerebral cortex. There are several types of serotonin receptors. Serotonin realizes its influence with the help of ionotropic and metabotropic receptors that affect biochemical processes with the help of second messengers - cAMP and IF 3 / DAG. Contained mainly in structures related to the regulation of autonomic functions . Serotonin accelerates the learning process, the formation of pain, sensory perception, falling asleep; angiothesin increases blood pressure (BP), inhibits the synthesis of catecholamines, stimulates the secretion of hormones; informs the central nervous system about the osmotic pressure of the blood.

Histamine in a fairly high concentration found in the pituitary gland and the median eminence of the hypothalamus - it is here that the main number of histaminergic neurons is concentrated. In other parts of the central nervous system, the level of histamine is very low. Its mediator role has been little studied. Allocate H 1 -, H 2 - and H 3 -histamine receptors.

Amino acids.Acidic amino acids(glycine, gamma-aminobutyric acid) are inhibitory mediators in the synapses of the central nervous system and act on the corresponding receptors. Glycine- in the spinal cord GABA- in the cerebral cortex, cerebellum, brain stem and spinal cord. Neutral amino acids(alpha-glutamate, alpha-aspartate) transmit excitatory influences and act on the corresponding excitatory receptors. Glutamate is thought to be an afferent mediator in the spinal cord. Receptors for glutamine and aspartic amino acids are present on the cells of the spinal cord, cerebellum, thalamus, hippocampus, and cerebral cortex . Glutamate is the main excitatory mediator of the CNS (75%). Glutamate receptors are ionotropic (K + , Ca 2+ , Na +) and metabotropic (cAMP and IP 3 /DAG). Polypeptides also perform a mediator function in the synapses of the central nervous system. In particular, substance P is a mediator of neurons that transmit pain signals. This polepiptide is especially abundant in the dorsal roots of the spinal cord. This suggested that substance P could be a mediator of sensitive nerve cells in the area of ​​their switching to interneurons.

Enkephalins and endorphins - mediators of neurons that block pain impulses. They realize their influence through the corresponding opiate receptors, which are especially densely located on the cells of the limbic system; many of them are also on the cells of the substantia nigra, the nuclei of the diencephalon and the soletary tract, they are on the cells of the blue spot of the spinal cord. Endorphins, enkephalins, a peptide that causes beta sleep, give anti-pain reactions, increase resistance to stress, sleep. Angiotensin participates in the transmission of information about the body's need for water, luliberin - in sexual activity. Oligopeptides - mediators of mood, sexual behavior, transmission of nociceptive excitation from the periphery to the central nervous system, the formation of pain.

Chemicals circulating in the blood(some hormones, prostaglandins, have a modulating effect on the activity of synapses. Prostaglandins (unsaturated hydroxycarboxylic acids), released from cells, affect many parts of the synaptic process, for example, mediator secretion, the work of adenylate cyclases. They have high physiological activity, but are quickly inactivated and therefore operate locally.

hypothalamic neurohormones, regulating the function of the pituitary gland, also act as a mediator.

Dale principle. According to this principle, each neuron synthesizes and uses the same mediator or the same mediators in all branches of its axon (one neuron - one mediator), but, as it turned out, other accompanying mediators can be released at the axon endings ( comedians), playing a modulating role and acting more slowly. In the spinal cord, two fast-acting mediators were found in one inhibitory neuron - GABA and glycine, as well as one inhibitory (GABA) and one excitatory (ATP). Therefore, Dale's principle in the new edition sounds like this: "one neuron - one fast synaptic effect." The effect of the mediator depends mainly on the properties of the ion channels of the postsynaptic membrane and second messengers. This phenomenon is especially clearly demonstrated when comparing the effects of individual mediators in the central nervous system and peripheral synapses of the body. Acetylcholine, for example, in the cerebral cortex with microapplications to different neurons can cause excitation and inhibition, in the synapses of the heart - inhibition, in the synapses of the smooth muscles of the gastrointestinal tract - excitation. Catecholamines stimulate cardiac activity, but inhibit contractions of the stomach and intestines.

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, the so-called secondary 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 metabotropic 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. The most important are derivatives of glutamic acid (glutamate), substance R. 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.

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 a 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 simultaneously be 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, the mediator released from this ending can act not only on “its” 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 it. 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 (strengthen) 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 from the synaptic cleft into the cytoplasm of the neuron by a special mechanism). 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 actually form 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.

According to the chemical structure, mediators are a heterogeneous group. It includes choline ester (acetylcholine); a group of monoamines, including catecholamines (dopamine, norepinephrine and epinephrine); indoles (serotonin) and imidazoles (histamine); acidic (glutamate and aspartate) and basic (GABA and glycine) amino acids; purines (adenosine, ATP) and peptides (enkephalins, endorphins, substance P). This group also includes substances that cannot be classified as true neurotransmitters - steroids, eicosanoids and a number of ROS, primarily NO.

A number of criteria are used to decide on the neurotransmitter nature of a compound. The main ones are listed below.

1. The substance must accumulate in presynaptic endings and be released in response to an incoming impulse. The presynaptic region must contain the system for the synthesis of this substance, and the postsynaptic zone must detect a specific receptor for this compound.
2. When the presynaptic region is stimulated, Ca-dependent release (by exocytosis) of this compound into the intersynaptic cleft, proportional to the strength of the stimulus, should occur.
3. Mandatory identity of the effects of the endogenous neurotransmitter and the putative mediator when it is applied to the target cell and the possibility of pharmacological blocking of the effects of the putative mediator.
4. The presence of a reuptake system of the putative mediator into presynaptic terminals and/or into neighboring astroglial cells. There are cases when not the mediator itself, but the product of its cleavage is subjected to reuptake (for example, choline after the cleavage of acetylcholine by the enzyme acetylcholinesterase).

Influence of drugs on various stages of mediator function in synaptic transmission

	Modifying Influence	Result impact
Synthesis mediator	Precursor addition Reuptake blockade Blockade of synthesis enzymes	↓ ↓
Accumulation	Inhibition of uptake in vesicles Inhibition of binding in vesicles
Selection (exocytosis)	Stimulation of inhibitory autoreceptors Blockade of autoreceptors Violation of the mechanisms of exocytosis	↓ ↓
Action	Effects of agonists on receptors
on receptors	Blockade of postsynaptic receptors
Destruction mediator	Reuptake blockade by neurons and/or glia Inhibition of destruction in neurons
	Inhibition of destruction in the synaptic cleft

The use of various methods for testing the mediator function, including the most modern ones (immunohistochemical, recombinant DNA, etc.), is difficult due to the limited availability of most individual synapses, as well as due to the limited set of targeted pharmacological agents.

An attempt to define the concept of "mediators" encounters a number of difficulties, since in recent decades the list of substances that perform the same signaling function in the nervous system as classical mediators, but differ from them in chemical nature, synthesis pathways, receptors, has significantly expanded. First of all, the above applies to a large group of neuropeptides, as well as to ROS, and primarily to nitric oxide (nitroxide, NO), for which the mediator properties are well described. In contrast to the "classical" mediators, neuropeptides, as a rule, are larger, synthesized at a low rate, accumulate in low concentrations, and bind to receptors with low specific affinity; in addition, they do not have presynaptic terminal reuptake mechanisms. The duration of the effect of neuropeptides and mediators also varies significantly. As for nitroxide, despite its participation in intercellular interaction, according to a number of criteria, it can be attributed not to mediators, but to secondary messengers.

Initially, it was thought that a nerve ending could contain only one neurotransmitter. To date, the possibility of the presence in the terminal of several mediators released jointly in response to an impulse and acting on one target cell - concomitant (coexisting) mediators (commediators, cotransmitters) has been shown. In this case, the accumulation of different mediators occurs in the same presynaptic region, but in different vesicles. Examples of mediators are classical neurotransmitters and neuropeptides, which differ in the place of synthesis and, as a rule, are localized in one end. The release of cotransmitters occurs in response to a series of excitatory potentials of a certain frequency.

In modern neurochemistry, in addition to neurotransmitters, substances are isolated that modulate their effects - neuromodulators. Their action is tonic in nature and longer in time than the action of mediators. These substances can have not only neuronal (synaptic) but also glial origin and are not necessarily mediated by nerve impulses. Unlike a neurotransmitter, a modulator acts not only on the postsynaptic membrane, but also on other parts of the neuron, including intracellularly.

There are pre- and postsynaptic modulation. The concept of "neuromodulator" is broader than the concept of "neurotransmitter". In some cases, the mediator may also be a modulator. For example, norepinephrine, released from the sympathetic nerve ending, acts as a neurotransmitter on a1 receptors, but as a neuromodulator on a2 adrenergic receptors; in the latter case, it mediates inhibition of the subsequent secretion of norepinephrine.

Substances that perform mediator functions differ not only in their chemical structure, but also in which compartments of the nerve cell they are synthesized. Classical small molecule mediators are synthesized in the axon terminal and are incorporated into small synaptic vesicles (50 nm in diameter) for storage and release. NO is also synthesized in the terminal, but since it cannot be packaged in vesicles, it immediately diffuses out of the nerve ending and affects the target. Peptide neurotransmitters are synthesized in the central part of the neuron (perikaryon), packed into large vesicles with a dense center (100-200 nm in diameter) and transported by axonal current to the nerve endings.

Acetylcholine and catecholamines are synthesized from circulating precursors, while amino acid mediators and peptides are ultimately formed from glucose. As is known, neurons (like other cells of higher animals and humans) cannot synthesize tryptophan. Therefore, the first step leading to the beginning of the synthesis of serotonin is the facilitated transport of tryptophan from the blood to the brain. This amino acid, like other neutral amino acids (phenylalanine, leucine and methionine), is transported from the blood to the brain by special carriers belonging to the family of monocarboxylic acid carriers. Thus, one of the important factors determining the level of serotonin in serotonergic neurons is the relative amount of tryptophan in food compared to other neutral amino acids. For example, volunteers who were fed a low-protein diet for one day and then given a tryptophan-free amino acid mixture showed aggressive behavior and a change in the sleep-wake cycle, which is associated with a decrease in serotonin levels in the brain.