SEROTONIN

From Big Medical Encyclopedia

SEROTONIN (Serotoninum, synonym: 5-oksitriptamin, 5-OT, Enteraminum) — biologically active agent from group of indolylalkylamines. In the chemical relation represents 3 (beta aminoethyl) - 5 hydroxyindole; With 10 H 12 N 2 O:

Page it is eurysynusic in the nature. It is found in many edible and inedible plants, including in poisonous for the person, and also in a number of mollusks and other invertebrates, in poison of nek-ry insects, in tissues of all vertebrata. At mammals and the person to 90% of serotonin contains in enterokhromaffinny cells of intestines (0,9 — 8,6 mkg is 1 g fresher than fabric) in this connection S. was called Enteraminum in the beginning. Many S. contains also in thrombocytes of the person and hematothermal animals (2,4 ± 0,5 µmol on 1 g of protein). S.'s concentration in whole blood fluctuates from 0,05 to 0,2 mg/l. In significant amounts of S. of a spleen, kidneys, the pechena collects in mast cells of skin, in tissue of lungs. S.'s maintenance in different departments of c. N of page it is unequal. In the greatest numbers it is found in the field of a hypothalamus and a mesencephalon. Rather less S. contains in a thalamus, a hippocampus, a cerebellum and gray matter of a spinal cord. Large numbers of S. are found in an epiphysis (in the person to 22,8 mkg/g), and the maximum maintenance of S. in this gland is noted in the afternoon, minimum — in night. The cells capable to synthesize and accumulate S. carry to APUD-system, or the APUD system (Amine precursor uptake and decarboxylation), t. e. to system of the cells which are carrying out taking of predecessors of amines and decarboxylation of the last (see. APUD-system ).

Physical and chemical properties and methods of definition. In the form of the free basis of S. represents inodorous white powder, a little soluble in methyl and 95% alcohol. It is insoluble in absolute ethyl alcohol, pyridine, chloroform, ethylacetone, ether, gasoline; t°pl 209 — 212 °; pier. weight (weight) 176,2. At pH 5,4 water solution of serotonin has maxima of absorption at 275 and 293 microns. At pH 4,0 radiation of solutions of serotonin an ultraviolet light with the wavelength of 295 microns causes fluorescence with a maximum in the field of 550 microns.

Because in the form of the free basis of S. it is unstable, it is allocated in the form of various salts (e.g., picric, adipinic, salicylic, etc.) or in a look creatinine - a sulfate complex. The last represents crystal powder of inodorous light yellow color. Let's dissolve in water, butanol, heptane, acetone, ice acetic to - those; t°pl 207 — 216 °; pier. weight (weight) 405.

For S.'s definition in fabrics use hl. obr. histochemical methods of a research (see), based on recovery of ammoniac silver, reaction with diazonium salts or chromaffin reaction, and also on excitement fluorescence (see): bluish in unstable cuts or zolotistozhelty in the cuts fixed by formalin. In biol. liquids C. define by biological, chemical, hromatografichesky and flyuorimetrichesky methods (see. Flyuorimetriya , Chromatography ). In a wedge, practice, napr, at diagnosis of a carcinoid syndrome (see. Carcinoid ), the level of biosynthesis of S. in an organism estimate usually by determination of the sum of 5 oxyindoles or contents 5 oxyindolyl acetic to - you in urine.

Exchange of serotonin. In S.'s organism it is formed from tryptophane (see), to-ry under the influence of a triptofangidroksila-za with education 5 oxytryptophanes (the limiting stage) are hydroxylated in the beginning. Then under the influence of a decarboxylase 5 oxytryptophane are decarboxylized and turns into the Village. Normal for S.'s education it is spent apprx. 1 — 3% of the tryptophane coming to an organism with food, at carcinoid — to 60% that causes a hyperserotoninemia and signs of a carcinoid syndrome. The synthesized S. collects in cellular depots in the form of granules (to 75%) and in a free form (to 25%).

The main way of destruction of S. — oxidizing deamination under the influence of MAO (see. Monoamine oxidase ). 5 oxyindolylacetic aldehyde which is formed at the same time are oxidized under influence aldehyde dehydrogenase in 5-oksipndoliluksusny to - that, edges is removed by kidneys (it is normal on average 5,0 ± of 0,65 mg a day). Activity of MAO is highest in the cells containing Page. Small part C. is exposed to N-acetylation. In an epiphysis N-atsetilserotonin turning under the influence of oxyindole-0-methyl-transferase of hl at first is formed of S. obr. in N-acetyl - 5-metoksi-triptamin — melatonin (see), to-ry is considered as hormone of an epiphysis. Besides, in an epiphysis also other indoles, e.g. 5-oksitriptofol, a 5-metoksitripto-foul are formed. Activation N-atsetiliruyushche-go enzymes is mediated by R-adreno-retseptorami.

Ethanol and Reserpinum can strengthen the process of recovery proceeding with participation of an aldegidreduktaza 5 oxyindolylacetic aldehydes in 5-oksitriptofol. However 5 oxyindolylacetic aldehydes are exposed to recovery only apprx. 1%. In nek-ry fabrics C. in small amounts it can be metabolized by N-methylation with participation of the enzyme of indolamine-N-methyltransferase found in tissue of lungs and a brain of the person therefore in an organism it is formed bufotenin (N, N-dimetiltriptamin) having gallyutsionogenny properties. Besides, S.'s metabolites from number 5-of oxyindoles can be exposed to further transformations under the influence of detsikliziruyushchy enzyme and to interamination (see. Transaminirovaniye ), therefore the painted products of exchange S.

Odnim from biol are formed. mechanisms of maintenance in an organism of optimum level of physiologically active S. is serotoninopeksiya (see).

Interaction of serotonin with serotonergic receptors

According to modern representations of S. exerts impact on functions of various bodies and fabrics by interaction with specific se-rotoninergichesky receptors, sensitive to it, to-rye, apparently, are among chemoceptors of membrane type. With the help pharmakol. methods of a research (use of antagonists of S.) three types of cellular receptors, sensitive to S., are allocated. They received the designation D-, M - and T-serotoninergicheskikh receptors.

D-serotoninergicheskiye receptors, to-rye are blocked by diethyl amide lysergic acid (see) and dibenzylother, are localized generally in smooth muscles of internals. S.'s interaction with these receptors is followed by reductions of unstriated muscles. M-serotoninergicheskiye receptors are blocked by morphine and nek-ry other substances. They are located hl. obr. in vegetative gangliya. Influencing these receptors, S. causes gangliostimuliruyushchy effect. T-serotoninergicheskiye receptors (are blocked tipindoly) are found in a cardiopulmonary reflexogenic zone. Affecting them, S. causes a coronary and pulmonary chemoreflex. In a brain are found as D-, so M-seroto-ninergicheskiye receptors. Assume that in c. N of page are available as well T-serotoninergicheskiye receptors. S.'s interaction with specific receptors is followed by activation of adenylatecyclase that leads to increase in intracellular formation of cyclic adenosinemonophosphate. In nek-ry bodies (e.g., in unstriated muscles of intestines) under the influence of S. formation of a cyclic guanozinmonofosfat increases.

A role of serotonin in activity of a nervous system. In c. the N of page serotonin plays a role of a mediator of synoptic transfer of nervous impulses (see. Mediators ). Idea of mediator function C. was stated for the first time Brody and Blinders (V. V. of Brodie, P. A. Shore, 1957) on the basis of data on existence in a brain of animals and the person of specific system of the neurons synthesizing S. Obrazuyushchiysya in these neurons of S. moves ahead on axons, reaches their term leu and, being released from the last, interacts with serotonergic receptors of other neurons.

The main amount of the neurons synthesizing S. is in the kernels of a seam (nuclei raphe) located in the central part of an average and a myelencephalon. Existence in these kernels of S., their localization and bonds with other departments of c. the N of page were established by the Swedish scientists by Dalstr and Fuchs (A. Dahlstrom, To. Fuxe, 1964) by means of histochemical methods of a research. They offered also classification of the kernels containing serotoninsinteziruyu-shchy neurons, according to a cut in a brain there are 9 such kernels. The specified kernels designate a Latin letter B with the corresponding digital indexes. Most caudally located pale (B1) and dark (B2) of a kernel are in a myelencephalon. They give rise to the axons descending to a spinal cord, the terminations to-rykh are distributed segmentarno on all its extent. Most rostralno located dorsal (B7) and median (B8) of a kernel of a seam are on average a brain and give rise to the ascending serotonergic ways going to an intermediate and end brain. Neurons of other kernels have the short axons terminating in structures of a brainstem and a cerebellum. Neurons of the listed kernels, the axons departing from them and their bombway are considered as the specific serotonergic system of a brain anatomically connected with other its departments.

Two main serotonin-ergichesky ways are described: mesolimbic (from a kernel of B8 to a hippocampus, a hypothalamus, a partition and limbic bark) and mezostriatny (from a kernel of B7 to a striatum, a thalamus, a hypothalamus and a neocortex). Bombways of these ways in the specified structures are distributed unevenly. So, in a neocortex increase of their density from sublayers to upper and dominance of aksoden-dritichesky contacts over aksosoma-tichesky is observed that is characteristic of nonspecific structures of a brain.

By means of an electronic mikrosko-picheskogo of a method it is established that these contacts are presented by the varicosity of amyelinic fibers containing granules of Page. In this regard assume that S. which is released from them can exert distantny impact on the next educations. Such organization of contacts of serotoninergi-chesky bombways creates a possibility of the modulating influence of serotonergic structures of a brain on activity of cortical neurons and character of their answers to the signals arriving on specific afferent ways, the going sg of sense bodys than and participation of these structures in processes of perception, processing and fixing of information is defined. Existence of the specified influences is confirmed with the help elektrofiziol. methods of a research. It is established, e.g., that S. exerts impact on the potentials of a brain caused by touch incentives. Features of the organization of se-rotoninergichesky system of a brain and its broad bonds with other departments of c. N of page cause participation of this system in regulation of many functions of an organism and irregular shapes of behavior. At the same time the large role is played by interrelation of serotoninergi-chesky system of a brain with neurosecretory kernels hypothalamus (see), having the next anatomo-funk-tsionalnoye relation to pituitary and adrenal system.

The Serotoninergichesky system of a brain participates in regulation of the general level of activity of c. N of page, cycles of a dream — wakefulness, the general physical activity, different forms of an affective behavior, processes of memory and training. At the same time interaction of serotonergic system of a brain with other its neuromediator systems, including with a hole drenergichesky is very important. So, the modulating influences of serotonergic and noradrenergichesky systems of a brain amplifying at increase in emotional pressure have essential value for information processing. S.'s allocation from bombways strengthens circulation of excitement in the neural systems connected with perception and fixing of information and promotes transition of a neurodynamic phase of fixing of traces of memory to a phase of structural and metabolic changes, i.e. transformation of a short-term memory to long-term, Taking part in regulation of an emotional state, S. plays a large role in formation of emotional memories (see).

The interfaced influences of serotonergic and noradrenergichesky systems of a brain considerably define phase structure dream (see), i.e. ratio of medlennovolnovy and paradoxical phases of a dream. At the same time the serotonergic system has preferential relation to the organization of a medlennovolnovy phase of a dream. At animals increase in fiziol. limits of activity of seroto-ninergichesky structures of a brain is followed by decrease in the general level of motor and approximate and consecutive performance. At people at reception of tryptophane (the main source of S.) deepening of a dream and decrease in a physical activity is noted.

The Serotoninergichesky system of a brain participates in regulation of sexual behavior. It is established that increase in level C. in a brain is followed by oppression of sexual activity, and decrease in content of serotonin in c. the N of page leads to its increase. In an experiment on animals it is established also that the serotonergic system of a brain takes part in regulation of aggressive states. The fact that decrease in its activity by local destructions of srednemozgovy kernels of a seam or with the help pharmakol demonstrates to it. means, oppressing S.'s biosynthesis, is followed by strengthening of aggression, and increase in level C. in a brain — its easing.

The Serotoninergichesky system of a brain, obviously, takes part in regulation of perception pains (see) since painful sensitivity at animals goes down at increase in content of serotonin in c. the N of page, and at oppression of biosynthesis of S. in a brain (e.g., after introduction p-hlorfe-nilalanina) increases. From the content of serotonin in c. the N of page depends also degree of manifestation of soothing effect of morphine and other narcotic analgetics. It is established, e.g., that against the background of increase in maintenance of S. in a brain the analgetic effect of morphine amplifies and extended. At oppression of biosynthesis of serotonin in c. the N of page soothing effect of morphine is weakened. On the basis of these facts assume that S. along with endogenous opioid peptides (see. Opiates endogenous ) participates in regulation of functions of the so-called anti-nociceptive system of a brain weakening perception of pain. Besides, are available this, testimonial of influence of serotonergic system of a brain on excitability of the vasculomotor and temperature-controlled centers, and also the emetic center. S.'s influence on functions of nek-ry closed glands is caused, apparently, not only its direct action, but also the central mechanisms since in under-bugornoy areas of a brain bombways of serotonergic neurons are found, stimulation to-rykh is followed by strengthening of allocation of a kortikoliberin (see. Hypothalamic neurohormones ), prolactin (see) and somatotropic hormone (see).

S.'s role in regulation of functions of a peripheral nervous system is a little studied. It is known only that S. strengthens transfer of nervous impulses in vegetative gangliya, and also increases their reactions to electric irritation of preganglionic fibers and administration of the ganglio-stimulating substances, napr, acetylcholine. The described effects are caused by S.'s interaction with M-serotoninergicheskimi the receptors which are localized in vegetative gangliya (see. Autonomic nervous system ).

Influence of serotonin on functions of other systems of an organism

According to experimental data S.'s influence on cardiovascular system is characterized by hl. obr. changes of a cordial rhythm and ABP. At the same time depending on experimental conditions and a type of animal change of the ABP can have phase character since the hypotension arising after S.'s introduction can be replaced by hypertensia, after a cut sometimes hypotension develops again. This results from the fact that renders both direct, and reflex influence on a tone of vessels of S. Affecting reflexogenic zones of heart and lungs, S. causes bradycardia and hypotension, and its direct impact on smooth muscles leads to a vasospasm and increase in the ABP. It is not excluded that nek-ry other factors, napr, allocation of a histamine and catecholamines under the influence of S., its gangliostimulpruyushchy action, etc. also can participate in mechanisms of action of S. on cardiovascular system.

S.'s influence on went. - kish. the path is shown generally by increase in a pepsinia and mucin a mucous membrane of a stomach and strengthening of a vermicular movement of intestines.

The page is important in mechanisms of a hemostasis since release of S. deposited in thrombocytes is followed by their aggregation and a spasm of the damaged vessel. Besides, S. increases trombo-plasticheskugo activity, and also activity II, V and VI blood-coagulation factors. In this regard S. use in a wedge, practice as a hemostatic.

On function of nek-ry closed glands (bark of adrenal glands, a thyroid gland, ovaries, etc.) The page renders both the direct, and mediated stimulating influence, a cut is shown at S.'s introduction in high doses.

Value of disturbances of exchange of serotonin in pathology. S.'s participation in regulation of various functions of an organism defines need of studying of a role of disturbances of exchange of S. for pathology, and in particular in psychopathology.

Assume that disturbances of exchange of S. matter in a pathogeny of depressions, schizophrenia and epilepsy. Ideas of value of deficit of serotonin in c. the N of page in development of depressions is confirmed by results of a postmortal-ny research (in a brain of patients with a depression find the lowered S.'s maintenance), and also data on antidepressive effect of predecessors of S. (e.g., tryptophane) and the medicinal substances promoting accumulation of serotonin in c. N of page (e.g., MAO inhibitors and nek-ry other antidepressants). At the same time it is known that blockers of serotoninovy receptors pizotifen and mianserin also render to lay down. effect at depressions. However this hypothesis, creating idea of S.'s participation in genesis only of monopolars-nykh of depressions, does not allow to judge its role in development of other forms of depressions, at to-rykh a certain role along with S. can play changes of balance of other amines, napr, noradrenaline.

Assume also that the perversion of exchange of S. plays the known role in a pathogeny of psychotic frustration at schizophrenia. It is confirmed by the maintenance of metabolites of S. (e.g., a bufotenina) having hallucinogenic properties given about increase at patients with schizophrenia with the expressed psychotic symptomatology. In the absence of such symptomatology at patients with schizophrenia the specified changes of metabolism

of S. O of a role of disturbances of exchange of S. at epilepsy are not revealed state the contradictory points of view. The opinion that exhaustion of reserves of serotonin in c is conventional. the N of page is followed by reduction of the threshold of convulsive activity.

Functional insufficiency of serotonergic system of a brain, obviously, serves as the major pathogenetic factor in development of a post-anoxic reflex myoclonia and nek-ry other its forms (see. Hyperkinesias ). Proceeding from these representations, for treatment of a myoclonus use the drugs increasing S.'s maintenance in the central nervous system, napr, clonazepam and also combinations of the predecessor of serotonin of alpha tryptophane with MAO inhibitors.

S.'s role in a pathogeny of cardiovascular diseases is a little studied. Disturbances of exchange of S., apparently, matter in a pathogeny migraines (see) since during an attack of migraine in blood and a brain S.'s maintenance falls, and after the termination of an attack raises. However at migraine to lay down. the effect is rendered not only by the drugs promoting S.'s accumulation (e.g., MAO inhibitors), but also nek-ry blockers of D-serotoninergicheskikh of receptors, napr, metisergid and cyproheptadine.

Existence of communication between development of endomyocardial fibrosis and S.'s accumulation in an organism, napr, owing to excess arrival of S. with food is undoubted (bananas, pineapples, etc.) that is most often noted at residents of the nek-ry districts of Africa. Development of this pathology is possible also at a carcinoid syndrome owing to the raised S.'s education in an organism. Explain with S.'s accumulation in blood also many other manifestations of a carcinoid syndrome — a bronchospasm, diarrhea, abdominal pains, etc. (see Carcinoid). From enterokhromaffinny cells of intestines connect also main signs of a dumping syndrome with increase in allocation of S. (see. Postgastrorezektsionny complications ). About S.'s role in a pathogeny of a peptic ulcer of a stomach there are mutually exclusive points of view.

In a pathogeny of inflammatory reactions of S. has smaller value, than such mediators of an inflammation as prostaglandins (see) and kinipa (see). According to experimental data, S. together with histamine (see) can cause nek-ry initial manifestations of an acute inflammation (see), napr, increase in vascular permeability, exudation in the center of an inflammation. However on nek-ry models of an inflammation (e.g., at a thermal burn) it is not established a little zakhmetny participation of G. in development of inflammatory reaction of fabrics. About S.'s role as mediator of allergic reactions — see Mediators of allergic reactions.

Agonists and antagonists of serotonin

Substances, to-rye at interaction with serotoninovy receptors cause inherent S. effects, are considered as its agonists, and вещества^ S. interfering action and its agonists on the corresponding receptors — as S.

Agonistami S. antagonists are tripta-min., 4-oksitryptamin, the petroltruck - new and petrolthiofoehn analogs of a triptamin, kvipazin. Like S. they cause reduction of unstriated muscles, braking or strengthening of pulse activity of neurons of c. N of page, excitement of neurons vegetative gangliyev and terminations of sensory nerves, acceleration of aggregation of thrombocytes. Other structural analogs of S., e.g. 5-metoksitriptamin (Mexaminum), 5 methylserotonin, N-alkyl-replaced a triptakhmin or serotonin, harmin, harman, indole-3-acetamidine, are partial (partial) agonists. In high doses they weaken effects of Page.

S. antagonists belong to different classes of chemical connections. Selectively acting S. antagonists are derivatives of lysergic acid (see) — diethyl amide lysergic to-you (DALY), 2-brom-DLK, metisergid. These are competitive antagonists of S. on action on unstriated muscles. Many other substances, napr, cyproheptadine, derivatives of an indole and Carbolenum, and also neuroleptics from among derivatives of a fenotiazin (aminazine) and the butyrohair dryer (pipampe-ron) — strong, but nonspecific antagonists of serotonin since they interfere with action on unstriated muscles also of a histamine, catecholamines, acetylcholine, ions of barium and potassium.

DLK and metisergid counteract exciting action of S. on nervous cells of a brain, but do not eliminate its influence on neurons vegetative gangliyev. Competitive antagonists of S. on action on vegetative a ganglion are morphine and other narcotic analgetics. S.'s influence on ganglionic neurons is nonspecific weakened mestnoanesteziruyushchy and m-holinoblokiruyushchimi (atropine) by means, fenotiazina, derivatives of an indole (m-hlorbenzilbu-fotenidin-bromide) and guanidine. Coronary and pulmonary chemoreflex (reflex bradycardia and hypotension) arising owing to exciting influence of S. on the terminations of afferent fibers of vagus nerves in heart and lungs are not eliminated with either DLK, or morphine, but are suppressed tipindoly, and also nek-ry derivatives of an indole and guanidine.

According to presence of the antagonists who are specifically suppressing certain effects of S., serotonergic receptors of cells subdivide into different types.

S.'s agonists use hl. obr. in pilot studies. From S. antagonists in medical practice apply metisergid, cyproheptadine, tsinanserin and pizotifen (sandomigran). They are appointed at a carcinoid syndrome and a dumping syndrome, at angioneurotic disturbances of the allergic nature and bronchial asthma, and also at migraine.

Agonists and S. antagonists it is possible to consider as one of subgroups of so-called serotonergic means. Carry substances to other subgroup of these means, to-rye unlike agonists and S. antagonists do not interact with serotoninovy receptors, and influence seroto-ninergichesky processes by change of synthesis, deposition, release or the return capture of S. serotoninsoderzhashchy cells.

So, inhibitors of synthesis of serotonin (d-chlorphenylalanine, etc.) and the substances breaking S.'s deposition, napr Reserpinum (see), tetrabenazin, etc., devastate stocks labilno and steadily connected S. in enterokhromaffinny, mast and serotonergic nervous cells. Devastation of depot C. in serotonergic neurons leads to oppression of their function. Strengthening of function of these neurons is caused Phenaminum (see) and inhibitors of the return capture of S., napr, to tsitalopra, femoksetin, klomipramin.

Serotonin as drug

In the medical practician S. is used in the form of salt with adipinic to - that, i.e. in the form of serotonin of adipate.

Serotonin adipate (Serotonini adipinas) — inodorous crystal powder, white or white with a creamy shade. Let's dissolve in water, it is difficult alcohol-soluble.

Causes effects, inherent S., including reduction of smooth muscles of internals, narrowing of blood vessels, increases quantity of thrombocytes in blood and increases their aggregation, reduces a bleeding time.

Apply as styptic means at a hemorrhagic syndrome of various genesis, napr, at Verlgof's disease, a ge-morragichestey vasculitis, hypo - and aplastic anemia, a thromboasthenia, etc.

Enter intravenously and intramusculary in a single dose of 0,005 g, to-rugo at good tolerance it is possible to increase up to 0,01 g. For intravenous injections of 0,005 — 0,01 g of drug part in 100 — 150 ml of isotonic solution of sodium of chloride and enter kapelno with a speed no more than 30 drops of 1 min. If necessary for drop introduction to a vein in the beginning drug can be dissolved in 5 — 10 ml of isotonic solution of sodium of chloride, and then to add this solution to 100 — ml of 5% of solution of glucose, plasma or stored blood.

For intramuscular introduction of 0,005 — 0,01 g of drug dissolve 0,5% of solution of novocaine in 5 ml. Injections do 2 times in bucketed days not less 4th hour. A daily dose for adult 0,015 — 0,02 g. The course of treatment usually makes 10 days.

Bystry administration of solutions C. in a vein can cause pain on the course of a vein and other side effects: unpleasant feelings in heart, difficulty of breath, increase in the ABP, weight in the head, diarrhea, reduction of a diuresis. It is recommended to apply antihistaminic and other antiallergic means to weakening of side effect of S.

To page it is contraindicated at acute and hron. glomerulonephritis, hron. a nephrosis, an idiopathic hypertensia of the II-III stages, bronchial asthma, a Quincke's edema, acute fibrinferments and tendency to tromboobrazovanigo.

Form of release: powder and ampoules on 1 ml of 1% of solution.

See also Serotoninopeksiya .



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V. V. Menshikov; E. A. Gromova, V. K. Muratov (stalemate. physical.), S. I. Zolotukhin, A. Ya. Ivleva, I. V. Komissarov (pharm.)

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