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—The suprachiasmatic nucleus (SCN) regulates the functioning of the body in accordance with circadian rhythms thanks to the pacemaker neurons present in it and afferents modulating these neurons. One of the afferents is represented by nerve fibers containing only the first enzyme for the synthesis of catecholamines, tyrosine hydroxylase (TH). In ontogeny, the concentration of these fibers (amount per unit volume of tissue) reaches a maximum on the 10th postnatal day (P10), and then gradually decreases. The aim of this work was to verify our assumption that, in TH-containing fibers in SCN of rats, L-DOPA is synthesized from L-tyrosine as the final secretory product, and the efficiency of this synthesis is higher in the early postnatal period than in adults. The synthesis of L-DOPA was evaluated by an increase in the total content of L-DOPA in SCN and in the incubation medium after a two-hour incubation of SCN in a medium with or without L‑tyrosine. We found that the addition of L-tyrosine to the incubation medium led to a multifold increase in the total L-DOPA content in SCN and in the medium, which is evidence of the synthesis of L-DOPA as a final product in TH-containing fibers. A comparative analysis of the synthesis of L-DOPA in SCN at P10 and P60 showed that the synthesis rate (a ratio between the total content of L-DOPA in SCN and in the incubation medium to the incubation time) at P60 exceeds the synthesis rate at P10, while the efficiency of L‑DOPA synthesis (a ratio between the rate of L-DOPA synthesis and the total protein content in SCN) is higher at P10. Thus, we obtained evidence of L-DOPA synthesis in TH-containing SCN nerve fibers, and the efficiency of this synthesis in rats in the early postnatal period is higher than in adult animals.

—The suprachiasmatic nucleus (SCN) regulates functions in accordance with circadian rhythms thanks to the pacemaker neurons present in it and afferents modulating their activity. One type of afferent is nerve fibers containing only tyrosine hydroxylase (TH) and secreting (L-dihydroxyphenylalanine) L-DOPA. The aim of this work was to test the hypothesis that L-DOPA comes from TH-containing fibers into neurons containing only aromatic L-amino acid decarboxylase (AAAD), where dopamine is synthesized. The synthesis of dopamine was evaluated by its content in SCN in intact rats on the 10th postnatal day (P10) and on P60, as well as by the total dopamine content in SCN and in the incubation medium after incubation of this nucleus in the medium with or without L-DOPA. It was shown that in intact rats SCN contains dopamine at the same concentration at P10 and P60. Some of the experiments with incubation of SCN slices were performed with rats injected with neurotoxins of monoaminergic neurons to exclude the synthesis of dopamine from L-DOPA in monoaminergic structures. At P10, during incubation of SCN in L-DOPA-containing medium, an increase in dopamine synthesis was observed equally in animals in control (normal) and after exposure to neurotoxins, which indicates synthesis of dopamine only in monoenzymatic AAAD-containing neurons. In a similar experiment at P60, the addition of L-DOPA into the incubation medium also led to an increase in the synthesis of dopamine, however, in animals exposed to neurotoxins to a lesser extent than in the control. This means that in adult animals, dopamine is synthesized in SCN mainly in monoenzymatic AAAD-containing neurons and to a lesser extent in monoaminergic structures. Thus, it was shown that dopamine in SCN is synthesized in monoenzymatic AAAD-containing neurons from L-DOPA secreted by monoenzymatic TH-containing fibers.

—In the past 15 years, it has been shown that dopamine (DA) is synthesized in the brain not only by dopaminergic neurons but also by non-dopaminergic neurons expressing one of the complementary enzymes tyrosine hydroxylase or aromatic L-amino acid decarboxylase (hereinafter, decarboxylase). Moreover, L-DOPA, an intermediate product of DA synthesis, is transported from neurons containing tyrosine hydroxylase to neurons containing decarboxylase. The aim of this work was to test our hypothesis about the presence of DA synthesis by non-dopaminergic neurons in the murine striatum, a key link in the central regulation of motor function. For this, we used a methodological approach we developed that allows us to determine the intensity of cooperative synthesis as the difference between the total DA content in brain slices and in the incubation medium after incubation of the slices in Krebs–Ringer solution and Krebs–Ringer solution with the addition of a competitive L-DOPA membrane carrier inhibitor. Synthetic non-metabolizable 2-amino-2-norbornanecarboxylic acid, which, unlike the previously used inhibitors (L-tyrosine, L-leucine, etc.), does not directly or indirectly affect the functional activity of DA-ergic neurons, was used as an inhibitor for the first time. The use of this inhibitor made it possible to obtain evidence that the DA contained in the striatum of mice is normally synthesized not only by DAergic neurons (in axons), but also by non-dopaminergic neurons that express either tyrosine hydroxylase or decarboxylase. It was also shown that DA synthesis by non-dopaminergic neurons is performed in the striatum of mice with partial DAergic denervation caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a specific neurotoxin. We believe that the synthesis of DA by non-dopaminergic neuronsis an important neuroplasticity mechanism which contributes to the compensation of DA deficiency after the degeneration of nigrostriatal DA-ergic neurons. Thus, for the first time, evidence was obtained for the synthesis of DA by non-dopaminergic neurons in the striatum of healthy mice and mice with DA-ergic denervation of the striatum.

One of the features of the developing suprachiasmatic nucleus (SCN), the "biological clock" of the body, is the early expression of dopamine (DA) receptors in the absence of dopaminergic neurons as a source of DA. Only recently we showed that DA in SCN is synthesized together by nerve fibers containing only tyrosine hydroxylase (TH) and neurons containing only aromatic L-amino acid decarboxylase (AADC). This study was aimed to assess specific characteristics of the phenotype of TH-fibers in ontogenesis. For this purpose, PCR and immunohistochemical analysis of the expression of genes and proteins such as TH, AADC, vesicular monoamine transporter (VMAT), and receptors for DA (D1, D2) was performed. We have detected numerous TH-immunoreactive fibers in SCN of young and adult rats. VMAT was observed in some of them, which suggests vesicular storage of L-DOPA. Considering the key role of TH-fibers in cooperative synthesis of DA, we assumed the presence of their dopamine regulation. Using double immunolabeling, we showed that D1 and D2 are present in TH-fibers in adult rats, and only D1 in young rats. According to PCR, D1 and D2 are also expressed in neurons of SCN in adult rats and only D1 in young rats. Thus, it was shown for the first time that VMAT and D1 are coexpressed in TH-fibers synthesizing L-DOPA in SCN in young and adult rats, and also D2 receptors in adult rats, which suggests vesicular storage and dopamine regulation of L-DOPA secretion, respectively.

—In the early 2000s, it was shown that dopamine is synthesized not only by dopaminergic neurons that possess the necessary set of enzymes, tyrosine hydroxylase and aromatic L-amino acid decarboxylase (AAD), but also by non-dopaminergic (monoenzymatic) neurons containing one of the enzymes. In this case, L-3,4-dihydroxyphenylalanine (L-DOPA), which is synthesized in neurons containing tyrosine hydroxylase, is transferred to neurons containing AAD, where dopamine is synthesized. The evidence for cooperative dopamine synthesis in our previous studies was a decrease in the total dopamine synthesis during incubation of a suspension of neurons of the tuberoinfundibular system (TIS) of fetuses or TIS slices from adult rats in the presence of a neutral amino acid that is a competitive inhibitor of the membrane L-DOPA carrier. In this work, the previously applied methodological approach was improved by using only sections of TIS and 2-amino-2-norbornanecarboxylic acid, a synthetic non-metabolizable L-DOPA membrane carrier inhibitor. This made it possible to confirm the presence of cooperative dopamine synthesis in TIS in fetuses and adult rats, and to obtain additional evidence of this synthesis in the form of an increase in the intercellular content of L-DOPA during inhibition of its membrane carrier. In addition, using an improved method we quantitatively characterized the synthesis of dopamine by nondopaminergic neurons and compared it in fetuses and adult rats. It was shown that the proportion of cooperative dopamine synthesis from the total dopamine synthesis by monoenzymatic and dopaminergic neurons in TIS in rat fetuses is 1.8 times higher than in adult animals. A six-fold increase in the synthesis of dopamine by rat TIS monoenzymatic neurons from the end of the prenatal period to adulthood are of particular interest from the standpoint of the functional role of dopamine produced by monoenzymatic neurons. Thus, in ontogeny, the proportion of dopamine synthesis by nondopaminergic monoenzymatic neurons in the general synthesis of dopamine is significantly reduced and the absolute value of cooperative dopamine synthesis increases by many times.

A labeled norepinephrine analogue was prepared by bromination of norepinephrine with subsequent debromination with tritium or deuterium gas. The yield of tritiated norepinephrine was 10–20% with a molar radioactivity of 27 Ci/mmol. The biological activity of tritiated norepinephrine was evaluated by analyzing its specific capture by noradrenergic neutrons in thick sections of the brainstem and midbrain of Wistar rats, and in a suspension of cells of pheochromocytoma PC12 expressing the membrane transporter of norepinephrine. It is shown that tritium-labeled norepinephrine synthesized by the proposed method does not differ in biological activity from the natural norepinephrine.

The study of new religious movements (NRMs) has not lost its relevance in the sociology of religion. New nontraditional religious groups from year to year are making increasingly significant contribution to the religious life of the world community. The scientific research of the NRM phenomenon is among priorities in science of religion. Systematization and transfer of knowledge on the subject is the main components of study of it. On this basis, the authors believe that significant importance has the procedure of typologyzation of NRMs. Construction and the practical use of typologies always aroused interest among researchers of new religious movements. It is believed that the popularity of the typological method in sociology reached its heyday in the 50–70s of the XXth century – during the boom of mass emergence of NRMs in Western Europe and the US. The authors of this paper suggest to colleagues’ attention the original theoretical construct taking into account the values and needs. The most multipurpose criterion for comparing multiple NRMs or their adepts is the principle of consumption as a civilizational sign of the information society. Well-known sociological concepts of A. Maslow’s “hierarchy of needs” and P. Sorokin’s “cultural mentalities” have been used as a “building” material for the development of our systems. The authors have attempted to demonstrate with practice and abstract examples how it is possible to use a two-dimensional typology in applied aims. The constructed scheme can be useful in theoretical investigations. It is designed to better understand the reasons for which the potential or existing adepts seek membership in one or another NRM. In practical use, the typology allows to make a confessional portrait of a selected for the study region.

Dopamine (DA), synthesized in the mediobasal hypothalamus by dopaminergic neurons containing two enzymes of DA synthesis - tyrosine hydroxylase and decarboxylase of aromatic L-amino acids, or by monoenzymatic non-dopaminergic neurons containing one DA synthesis enzyme in cooperation, is known to have an inhibitory effect on prolactin secretion. Deterioration of this inhibitory control leads to an increase in prolactin concentration in the blood and to the development of hyperprolactinemia syndrome. In a rat model of hyperprolactinemia induced by administration of a neurotoxin causing degeneration of dopaminergic and noradrenergic neurons, the level of DA first decreases, leading to an increase in prolactin level (decompensation stage), while later both levels are restored to normal (compensation stage). However, the mechanism of such compensation is still not clear. The aim of the present study was to analyze whether the increase in cooperative synthesis of DA by monoenzymatic neurons during hyperprolactinemia is a manifestation of a compensatory mechanism representing a particular case of neuroplasticity. The level of cooperative synthesis in the hyperprolactinemia model and in the control was estimated as the level of synthesis of DA and L-dihydroxyphenylalanine (L-DOPA) - an intermediate product of DA synthesis, when L-DOPA transfer from neurons containing tyrosine hydroxylase into neurons containing aromatic L-amino acid decarboxylase is inhibited. The level of DA synthesis during the decompensation stage was not changed, while during the compensation stage it was lower than the control. Along with a reduction in DA level, during the compensation stage an increase in the extracellular L-DOPA level in the medium was detected. Thus, the compensation of DA deficiency after degeneration of dopaminergic neurons in the mediobasal hypothalamus is due to the increase in cooperative synthesis of DA by monoenzymatic neurons containing one of the complementary enzymes of the DA synthesis pathway.

Mice with previously implanted electrodes for recording the cortical electroencephalogram and electromyograms underwent all-day baseline videopolysomnography with a 12/12 light cycle, after which animals received doses of 24 or 48 mg/kg of the neurotoxin precursor MPTP (1-methyl-4-phenyl-1.2.3.7-tetrahydropyridine) or physiological saline (controls) and recording was continued for 14 days. At the end of the experiments, morphological monitoring of the extent of lesions to the dopaminergic system was performed. Increases in motor activity and the total duration of waking during the dark part of the night were seen after administration of MPTP, as compared with controls. These changes were accompanied by decreases in the durations of rapid and (at the level of a tendency) slow-wave sleep. These changes were apparent by recording day 7 and were significant by day 14; they were more marked after treatment at a dose of 48 mg/kg than after the smaller dose. No changes were seen during the light period of the day. Morphological monitoring demonstrated a 70% reduction in the number of dopamine-containing neurons in the compact zone of the substantia nigra after administration of MPTP (48 mg/kg) and a 35% drop after MPTP (24 mg/kg).

The paper summarizes the literature and author's data on the development of early (preclinical) diagnosis of Parkinson's disease (PD). Implementation of this diagnosis will promote the use of preventive therapy and change investments in diagnosis and treatment of patients. The paper declares that at present the only approach to early diagnosis of PD is positron-emission tomography of the nigrostriatal dopaminergic system, but it cannot be used for preventive examination due to its high cost. The authors consider that a less specific, but more promising approach to the development of early diagnosis of PD is the search for markers in body fluids, mainly in the blood, in patients at the prodromal stage of PD. Indeed, a number of markers as changes in the level of metabolites of monoamines, sphingolipids, urates, and indicators of oxidative stress were found in patients selected for the risk group of the prodromal stage of PD, according to characteristic premotor symptoms. In addition, it is assumed that the search for blood markers at an earlier - pre-prodromal stage is possible only in animal models of PD at the early preclinical stage. This approach can also be used to verify blood markers identified in patients at the clinical stage of PD. It is also evident that the complex socio-economic factors influencing the incidence of PD is different in developed versus developing countries. The societal and medical costs of Parkinson's are huge and efforts to improve early preclinical diagnosis of PD will lead to considerable economical and societal benefits. For instance this will allow efficient selection of patients for preclinical diagnostic tests. To assess the effectiveness of this strategy considering the uncertainty of socio-economic issues, a modification of the «cost-utility» analysis is proposed. For the first time, a Markov model of PD including preclinical diagnostic tests and possible neuroprotective therapy was developed and studied. Analytical outcomes of this process suggest that the idea of developing a new multimodal strategy is promising from a socio-economic point of view.В статье обобщены данные литературы и собственные данные авторов о разработке ранней (доклинической) диагностики болезни Паркинсона (БП). Внедрение этой диагностики будет способствовать использованию профилактической терапии и изменит инвестиции в диагностику и лечение пациентов. В статье подчеркивается, что в настоящее время единственным подходом к ранней диагностике БП является позитронно-эмиссионная томография нигростриатной дофаминергической системы, но она не может быть использована для профилактического обследования из-за высокой стоимости. Авторы считают, что менее специфичным, но более перспективным подходом к разработке ранней диагностики БП является поиск маркеров в гуморальных средах, преимущественно в крови, у пациентов на продромальной стадии БП. Действительно, ряд маркеров в виде изменений уровня метаболитов моноаминов, сфинголипидов, уратов и индикаторов окислительного стресса был обнаружен у пациентов, отобранных в группу риска продромальной стадии БП, по характерным премоторным симптомам. Кроме того, предполагается, что поиск маркеров крови на более ранней, препродромальной, стадии возможен только на животных моделях БП на ранней доклинической стадии. Этот подход также может использоваться для валидации маркеров крови, выявленных у пациентов на клинической стадии БП. Показано, что совокупности социально-экономических факторов, влияющих на заболеваемость БП, различны для развитых и для развивающихся экономик; это позволит более рационально отбирать пациентов, подлежащих доклинической диагностике. Для оценки ее эффективности при неопределенности некоторых экономических параметров предложена модификация метода «затраты — полезность». Впервые построена и исследована марковская модель БП, включающая доклиническую диагностику и превентивную терапию. Расчеты показали, что идея разработки нового метода весьма перспективна с социально-экономической точки зрения.

The results of study of sleep-wakefulness cycle in experimental models of pre-clinical and early clinical stages of Parkinson's disease present and compared to some clinical examples. The conclusion is, the increase in activity level and decrease in total amount of slow wave and paradoxical sleep in model animals are taking place at the same circadian period of the secretion of pineal melatonin as sleep disorders in patients.

L-DOPA accumulation in the extracellular medium was detected when the transfer of L-DOPA from the neurons containing tyrosine hydroxylase to the neurons containing aromatic L-amino acid decarboxylase was blocked, under conditions of inhibition of the L-DOPA degradation enzyme. Thus, the missing proof confirming the existence of cooperative synthesis of dopamine by neurons non-dopaminergic was obtained.

The results of long-term research of formation of the circadian rhythm of skin temperature (CRT) in children during puberty are described. For this purpose, the skin temperature (T) of children, adolescents, and young adults of both sexes in the age range of 8–22 years was monitored for 48 h using a Thermochron iButton device. The age-related mesor dynamics, which reflects establishment of body thermoregulation during puberty, follows a wave pattern. The first T maximum is observed in children 10–11 years of age and the second one, in adolescents 14–15 years of age. Note that the overall dynamics in boys and girls are synchronous, but the mesor for girls aged 8 to 17 years is significantly higher. In adults aged 20–22 years, men display a higher mesor value as compared to women. The dynamics of CRT amplitude is stable until the age of 12–13 years with a subsequent decrease in amplitude in boys and an increase in girls at the age of 14–15 years. The subjects of both sexes display a drastic increase in the amplitude at the age of 16–17 years and a considerable decrease by the age of maturity (20–22 years). The CRT amplitude in boys is significantly larger as compared with girls, being similar in adult males and females. Monitoring of the sleep-wake cycle has shown that diurnal thermoregulation changes at certain ages (for boys, 10–11 years and for girls, 10–11 and 16–17 years); the night temperature is higher than the day values.

One of the most important functions of the neuroendocrine system is that of regulating reproduction, particularly the inhibition of prolactin secretion in the hypophysis by dopamine (DA) synthesized in the arcuate nucleus. Apart from DA, noradrenaline (NA) also has a role in controlling prolactin secretion. While the role of DA in this regulation is known, that of NA remains incompletely understood. Previous studies have suggested that in conditions of functional insufficiency of the dopaminergic system, NA suppresses compensatory DA synthesis in the dopamine-producing neurons of the arcuate nucleus. The aim of the present work was to clarify the role of NA in the control of dopamine-producing neurons in the arcuate nucleus. This was addressed using two pharmacological models: 1) exclusion of dopaminergic and noradrenergic neurons and/or their axons in the arcuate nucleus, and b) exclusion of dopaminergic neurons only, to allow the role of the noradrenergic component to the catecholaminergic regulation of prolactin secretion to be assessed. In conditions of functional insufficiency of dopaminergic neurons, retention of the noradrenergic innervation of the arcuate nucleus was found to lead to decreased expression of the first enzyme in DA synthesis – tyrosine hydroxylase – and exacerbation of DA deficiency. This is evidence for noradrenergic inhibitory control of the expression of tyrosine hydroxylase in arcuate nucleus neurons.

Dopamine that is synthesized by neurons of the arcuate nucleus plays a key role in the regulation of the reproductive function of the body by inhibition of prolactin secretion. Earlier we showed that dopamine in the arcuate nucleus is synthesised not only by dopaminergic neurons that have enzymes for this but also neurons that express only one of the complementary enzymes, tyrosine hydroxylase or decarboxylase of aromatic L-amino acids. Here, we examined the original hypothesis that dopamine synthesis in mono-enzymatic neurons is under inhibitory control of noradrenergic afferents. We performed a comparison of the secretory activity of dopamine-synthesizing neurons of the arcuate nucleus in two groups of rats. In one group, we pharmacologically induced degeneration of the larger part of the dopaminergic neurons but saved noradrenergic afferentation of the arcuate nucleus. In another group, we induced degeneration of the same group of neurons and destroyed noradrenergic afferents. The data we obtained suggest that (i) noradrenergic innervation in the arctuate nucleus receive predominantly neurons that contain only one enzyme of dopamine synthesis, tyrosine hydroxylase and (ii) noradrenaline inhibits expression of tyrosine hydroxylase in mono-enzymatic neurons and the first stage of dopamine synthesis, i.e., conversion of L-tyrosine into L-dihydroxyphenylalanine in these neurons.

Parkinson’s disease (PD) is one of the most widespread neurodegenerative diseases; it develops as a result of the death of dopaminergic (DA-ergic) neurons of the nigrostriatal system of the brain. It has been shown in autopsy material that the neurodegenerative process spreads to other populations of neurons of the peripheral and central nervous system. In PD patients the tuberoinfundibular DA-ergic system (TIDAS) undergoes degradation; however, no experimental models exist that can reproduce the combined degradation of the nitrostriatal system and the TIDAS. In this work, we analyzed the state of the TIDAS during presymptomatic and symptomatic stages of parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These stages of parkinsonism develop as a result of subthreshold and threshold degradation of the nigrostriatal DA-ergic system. To evaluate the morphofunctional state of the TIDAS, we determined: (a) the number of neurons with tyrosine hydroxylase (TH), a key enzyme of DA synthesis; (b) the sizes of the terminals of TH-positive axons; (c) the levels of TH in the neuronal somas and the terminals of axons; and (d) the contents of DA, noradrenaline, and 3,4-dihydroxyphenyl acetic acid. According to the data that was obtained during the presymptomatic stage, for the TIDAS no changes were found in all the measured parameters. During the symptomatic stage, we observed (a) a decrease in DA content by 50%; (b) a decrease in the level of TH protein in axonal terminals and an increase in neuronal somas; and (c) an increase in the turnover of DA by 149% as compared to the control. The data we obtained suggest that the functional activity of the TIDAS was insufficient; this was seen in the form of alterations of DA metabolism, a decrease in the level of synthesis, probably in axonal terminals, and compensatory acceleration of the functional cycle from synthesis to enzymatic degradation. Although no changes in the number of neurons and axons that express TH was found in the TIDAS, the question of organic degradation of the TIDAS in parkinsonism is still open because TH is a marker of not only DA-ergic neurons that degenerate in the presence of neurotoxins but also of non-DA-ergic neurons that are insensitive to neurotoxins. Thus, during experimental modeling of Parkinsonism, we observed at least the metabolic characteristics of TIDAS degradation only at the symptomatic stage of the disease.

The age-related features of the circadian rhythm of skin temperature were studied using the Termochron iButton method in two age groups of subjects: eight-to nine-year-old boys and girls and young men and women aged 20–22 years. For this purpose, the temperature was monitored for 48 h at a recording interval of 10 min. The following authentic chronobiological differences were revealed: the temperature mesor was higher in the girls than in the boys and in the young men it was higher than in the young women. The circadian rhythm’s amplitude was higher in the boys and the young women. Studies of the chronological values in different 24-h periods showed that the average level of temperature at night was lower in all subjects. The amplitude in the adults did not differ in different 24-h periods, whereas it was higher in the children at night.

The effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone (GnRH) during embryogenesis of Wistar rats was studied. The neurons producing GnRH were detected immunocytochemically on days 18 and 21 of embryonic development and on day 15 of postnatal development of rats with normal serotonin metabolism and rats in which the synthesis of serotonin was inhibited by p-chlorophenylalanine. The total number of GnRH neurons in serotonin deficiency was larger than in the case of its normal metabolism at all developmental stages studied. This is an indirect evidence for the inhibitory effect of serotonin on the formation of GnRH neurons. To confirm the morphogenetic effect of serotonin, we studied the rate of formation of GnRH neurons by injecting bromodeoxyuridine in the formation period of these neurons. It was found that serotonin deficiency had no effect on the time of formation of GnRH neurons: over 97% of neurons formed on days 11 to 15 of embryonic development both in the experimental and control groups. Note that, in serotonin deficiency, the maximum number of GnRH neurons formed one day later than in the normal state. Thus, serotonin inhibits the proliferation of GnRH neuron progenitor cells and thereby has a morphogenetic effect on the development of these neurons.

Hyperprolactinemia is neurodegenerative disease that develops in humans as a result of degeneration of dopaminergic (DA-ergic) neurons of the arcuate nucleus, which synthesize DA, a neurohormone inhibiting prolactin secretion by pituitary lactotropes. The design and detailed analysis of good experimental models of hyperprolactinemia may help us to understand the causes and mechanisms of the disease development and develop early diagnostics and treatment of the disease. Hyperprolactinemia is usually modeled in experiments using 6-hydroxydopamine (6-HDA), a neurotoxin causing degeneration of DA-ergic neurons of the arcuate nucleus. However, 6-HAD also induces degeneration of noradrenergic (NA-ergic) axons involved in the regulation of prolactin secretion. Therefore, in this study, we evaluated the role of NA in the development of hyperprolactinemia during degeneration of DA-ergic neurons of the arcuate nucleus. To this aim, we compared changes in DA and NA metabolism in the arcuate nucleus and the blood level of prolactin in rats after treatment with 6-HDA alone and 6-HDA in the presence of desmethylimipramine, drug that prevents degeneration of NA-ergic neurons. Studies were performed in 14 days after toxin administration, i.e., at a time point when toxin-induced degenerative processes are finished, and in 45 days, i.e., after initiation of compensatory processes. We found that, in 14 days after administration of pharmacological agents, hyperprolactinemia, which resulted from DA deficit due to degeneration of DA-ergic neurons of the arcuate nucleus, is enhanced when NA-ergic afferents are protected, which may be related to the inhibitory effect of NA on DA synthesis. The latter hypothesis is supported by the fact that in 45 days after treatment with 6-HDA alone, i.e., after combined degeneration of DA-ergic and NA-ergic neurons, DA synthesis in the arcuate nucleus returns back to the normal level, which is accompanied by recovery of the normal blood level of prolactin. In contrast, in 45 days after administration of 6-HDA and desmethylimipramine, NA synthesis increases to the normal level but DA synthesis in the arcuate nucleus remains at low level, which is accompanied by an increased blood level of prolactin. Thus, our data suggest that NA inhibits DA synthesis in the arcuate nucleus and prevents a compensatory increase in DA synthesis and the normalization of the blood level of prolactin during degeneration of DA-ergic neurons.

The work has been carried out on mice of the Tg8 line with knockout of gene of monoamineoxidase A with an increase of serotonin and noradrenaline content in the brain, and on mice of the C3H line with unchanged genome and normal concentration of monoamines. An immunocytochemical study has been performed of development of neurons producing gonadotropin-releasing hormone (GnRH) under conditions of excess of serotonin and noradrenaline in the mice in embryogenesis. The GnRH-neurons were revealed at the 18th day of embryonic development in telencephalon along trajectory of their migration from olfactory bulbs to the retrochiasmatic area. In telencephalon of mouse embryos of the Tg8 line, a redistribution of the GnRH-neurons along their migration trajectory was observed as compared with embryos of the C3H line mice. The percent of the GnRH-neurons in the Tg8 mouse embryos in caudal parts of the migration trajectory was lower than in rostral parts, the opposite distribution of the neurons being observed in the C3H line mouse embryos; at the excess of serotonin and noradrenaline in the Tg8 line mouse embryos, the total amount of GnRH-neurons in the brain was lower than in the C3H mice. In males of the Tg8 line mice under conditions of excess of serotonin and noradrenaline the optical density of neurons, which correlated with the GnRH concentration in the cell, was higher than in control mice. Thus, in the Tg8 mice under conditions of the serotonin and noradrenaline excess, migration of the GnRH-neurons to their final anlage in hypothalamus is accelerated as well as the total number of the GnRH-neurons decreases, which indicates a decrease of proliferation of cells-precursors and the earlier differentiation of neurons.

Results of long-term research of becoming circadian rhythm of temperature (CRT) of human skin of shoulder during puberty are presented. For this purpose, 48-hour monitoring T at children, teenagers and mature young men and female from 8 till 22-th years with application of a method "Thermochron iButton" has been led. Age dynamics of mesor, reflecting process of becoming thermoregulation of organism during puberty, has wave character. The first wave with maximum T was observed at children of 10-11 years, second maximum T--at teenagers of 14-15 years. And at persons man's and female dynamics of mesor is synchronous, however, at girls from 8 till 17 years mesor authentically above. At adult people mesoris above at young men. Dynamics of amplitude CRT does not vary till 12-13 years, in 14-15 years at boys the size of amplitude decreases, and at girls increases. In 16-17 years at children amplitude sharply increases with the subsequent significant decrease by the period of a maturity (20-22 years). At boys, amplitude of CRT it is authentic more, than at girls, at adult people this parameter does not differ. At research of a cycle a dream-wakefulness periods in which changes daily thermoregulation are revealed: at boys in the age of 10-11 years, and at girls at 10-11 and in 16-17 years. During these periods T at night is above, than in the afternoon.

Studying individual circadian psychophysiological rhythms in children and adolescents, the authors showed that different rhythmological indices, such as fluctuation amplitude, mean level, and rhythm phase, change with age in different manners. Changes in one or more of these indices reflect a complex stagewise process of the formation of functions in human ontogeny. Additionally, a mismatch between individual and social (school load) rhythms may result in desynchronosis.

The work studied effect of serotonin on development of the system of luteinizing hormone-realizing hormone (LHRH) in rats at the prenatal period. LHRH-neurons located along its migration pathway were revealed immunocytochemically at the 18th day of embryonal development (E18 and so on) after serotonin synthesis inhibition by daily intraperitoneal injections of n-chlorophenylalanine from E11 to E17 (experimental group). In control animal group, the saline was injected. The percent content of LHRH-neurons located in the forebrain rostral part was higher in the experimental group as compared to control. The opposite quantitative ratio of neurons was observed in the more caudal (hypothalamic) area. This indicates deceleration of the LHRH-neuronal migration under conditions of serotonin deficit. Study of the LHRH-neuron differentiation showed that in the experimental group the neuron optical density correlating with the LHRH content in the cell decreased as compared to the control group both in males and in females. The size of LHRH-neurons on n-chlorophenylalanine administration decreased, but only in females. Thus, serotonin affects both migration and differentiation of LHRH-neurons.

Besides dopaminergic (DA-ergic) neurons having all enzymes of DA synthesis, tyrosine hydroxylase (TH) and aromatic l -amino acid decarboxylase (AADC), “monoenzymatic” neurons expressing only one of them were found in the brain, mostly in the mediobasal hypothalamus (MBH). The aim of this study was to test our hypothesis that DA is synthesized by monoenzymatic neurons, i.e. l -3,4-dihydroxyphenylalanine ( l -DOPA), which produced in the monoenzymatic TH neurons is transported in the monoenzymatic AADC neurons for DA synthesis. Incubation of MBH in Krebs-Ringer solution with l -leucine, a competitive inhibitor of l -DOPA uptake, was used to prevent a hypothetical l -DOPA capture into AADC-containing neurons. Incubation of the substantia nigra containing DA-ergic neurons under the same conditions served as the control. According to our data, the l -leucine administration provoked a decrease of DA concentration in MBH and in the incubation medium but not in the substantia nigra and respective incubation medium, showing a decrease of cooperative synthesis of DA in MBH. This conclusion was supported by an observation of higher concentration of l -DOPA in the incubation medium under perfusion of MBH with Krebs-Ringer solution containing tolcapone, an inhibitor of catechol-O-methyltransferase, and l -leucine than under perfusion with the same solution, but without l -leucine. Functional interaction between monoenzymatic TH and AADC neurons was indirectly confirmed by finding in electron microscopy their close relations in MBH. Besides monoenzymatic AADC neurons, any AADC-possessing neurons, catecholaminergic and serotoninergic, apparently, could participate in DA synthesis together with monoenzymatic TH neurons. This idea was confirmed by the observation of close topographic relations between monoenzymatic TH neurons and those containing both enzymes, i.e. DA-ergic, noradrenergic or adrenergic. Thus, monoenzymatic neurons possessing TH or AADC and being in close topographic relations can synthesize DA in cooperation.

Among most important functions of the neuroendocrine system is the regulation of reproduction, including the inhibitory control of prolactin secretion by dopamine (DA) synthesized in the arcuate nucleus (AN). Besides DA, noradrenaline (NA) contributes to this regulation though, in contrast DA, its concrete functional role remains to be uncertain. In the previous studies, it has been suggested that NA inhibits compensatory synthesis of DA in DA-producing neurons of AN under the failure of the dopaminergic system though no evidence were obtained. Therefore, the goal of this study was to specify the role of NA in the regulation of DA-producing neurons in AN. Two pharmacological models were used to this aim: a) switching off dopaminergic and noradrenergic neurons and their afferents in An or b) switching of only dopaminergic neurons and afferents that allowed us to recognize NA role in the complex catecholaminergic regulation of prolactin secretion. According to our data, the maintaining of the noradrenergic innervation of AN under the neurotoxin-induced failure of dopaminergic neurons resulted in the decrease of the expression of tyrosine hydroxylase (TH), the first enzyme ofDA synthesis, thereby enhancing DA deficit. This is considered as direct evidence of noradrenergic inhibitory control of TH expression in the neurons of AN.

Problem of the present work was studying age features circadian rhythm of temperature of a skin with application of a method "Termochron iButton". Day-night rhythm of a skin temperature at two age-grades was investigated: boys and girls of 8-9 years and young men and girls of 20-22 years. For this purpose monitoring temperature during 48 hours with an interval of registration 10 minutes has been lead. Are revealed authentic chronobiological differences: mesor temperatures above at girls, than at boys, and at young men, above, than at girls. Amplitude of a circadian rhythm is above at boys and at girls. Researches chronobiological parameters in the different terms of day have shown, that an average level of temperature at night below at all examinees. The amplitude at adult people in the different terms of day does not differ, while at children it above in the night term.

The effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone (GnRH) during embryogenesis of Wistar rats was studied. The neurons producing GnRH were detected immunocytochemically on days 18 and 21 of embryonic development and on day 15 of postnatal development of rats with normal serotonin metabolism and rats in which the synthesis of serotonin was inhibited by p-chlorophenylalanine. The total number of GnRH neurons in serotonin deficiency was larger than in the case of its normal metabolism at all developmental stages studied. This is an indirect evidence for the inhibitory effect of serotonin on the formation ofGnRH neurons. To confirm the morphogenetic effect of serotonin, we studied the rate of formation of GnRH neurons by injecting bromodeoxyuridine in the formation period of these neurons. It was found that serotonin deficiency had no effect on the time of formation of GnRH neurons: over 97% of neurons formed on days 11 to 15 of embryonic development both in the experimental and control groups. Note that, in serotonin deficiency, the maximum number of GnRH neurons formed one day later than in the normal state. Thus, serotonin inhibits the proliferation of GnRH neuron progenitor cells and thereby has a morphogenetic effect on the development of these neurons.

The work has been carried out on mice of the Tg8 line with knockout of gene of monoamineoxidase A with an increase of serotonin and noradrenaline content in the brain, and on mice of the C3H line with unchanged genome and normal concentration of monoamines. An immunocytochemical study has been performed of development of neurons producing gonadotropin-releasing hormone (GnRH) under conditions of excess of serotonin and noradrenaline in the mice in embryogenesis. The GnRH-neurons were revealed at the 18th day of embryonic development in telencephalon along trajectory of their migration from olfactory bulbs to the retrochiasmatic area. In telencephalon of mouse embryos of the Tg8 line, a redistribution of the GnRH-neurons along their migration trajectory was observed as compared with embryos of the C3H line mice. The percent of the GnRH-neurons in the Tg8 mouse embryos in caudal parts of the migration trajectory was lower than in rostral parts, the opposite distribution of the neurons being observed in the C3H line mouse embryos; at the excess of serotonin and noradrenaline in the Tg8 line mouse embryos, the total amount of GnRH-neurons in the brain was lower than in the C3H mice. In males of the Tg8 line mice under conditions of excess of serotonin and noradrenaline the optical density of neurons, which correlated with the GnRH concentration in the cell, was higher than in control mice. Thus, in the Tg8 mice under conditions of the serotonin and noradrenaline excess, migration of the GnRH-neurons to their final anlage in hypothalamus is accelerated as well as the total number of the GnRH-neurons decreases, which indicates a decrease of proliferation of cells-precursors and the earlier differentiation of neurons.

Individual daily and many-day time course of hormonal excretion was studied in boys of various ages. Cosinor analysis was used to determine the parameters of circadian and infradian rhythms. Time course of the mesor and amplitude circadian rhythms of testosterone, aldosterone, and luteinizing hormone (LH) in 5 groups (from 4 to 28 years of age) evidenced changes of this rhythm with age. The aldosterone mesor rhythm reduced as the boy grew older till he reached the adolescence, whereas testosterone and LH mesor increased, this increase being particularly marked by adolescence as regards testosterone and by youth in what concerns LH. The rhythm amplitude (mesor %) of aldosterone and testosterone was the maximal in children aged 7-8, then it reduced; LH amplitude was the highest in adolescents aged 13-14. A 40-day investigation of testosterone and aldosterone excretion in boys and youths has revealed infradian rhythms with periods of 2.5 to 5.5 days. These rhythms were characterized by age-specific differences as to the mesor size and oscillation amplitude, not differing by the periods. Infradian rhythms with periods of 5 to 13.5 days and testosterone excretion rhythm 21-day long were detected in youths. These results permit a conclusion that the structure of these hormones circadian and infradian rhythms may serve to characterize the age-specific and individual features of the endocrine gland functioning.

The reactivity of human foetal pancreas was determined by the increase of insulin secretion in vitro in response to the effect of glucose, arginine, theophylline, cyclic AMP and somatotrophic hormone (STH). The results of the experiments have shown that the beta-cells of the islet system in the pancreas of 7-9 weeks old embryos are as yet not able to respond to the main physiological stimulus, glucose, but respond already to cAMP, STH, arginine with glucose. The glands of 10-14 weeks old foetuses are already able to react to glucose and respond to all other stimuli, except arginine. Taken for comparison, the glands of 19-22 weeks old foetuses respond to glucose by the increase of insulin secretion.

In experimental hypercorticism the average daily concentration of glucocorticoids in blood plasma is 4 times higher than in control one, the amplitude of the circadian rhythm increases almost 3 times, the time of maximum concentration does not change. The adrenocorticotrophic hormone (ACTH) average circadian concentration decreases twofold. The adrenalectomy results in abrupt smoothing down of the circadian rhythm of glucocorticoids concentration and in increasing (in 2,4 times) of the average circadian concentration of ACTH. The pattern of circadian rhythm remains, however the acrophase of hormone secretion is shifted. The circadian rhythm of cells devision in esophagus epithelium changes. The maximum of mitotic index is absent in adrenalectomized rats and the amplitude of its circadian variations decreases. In experimental hypercorticism the biphase rhythm of mitoses in induced.

Publisher Summary The development of the function of the endocrine pancreas in man begins as early as in the prenatal period. For evaluating the role of insulin in the process of fetal development, it is important to know the time when the hormone appears in the gland and begins to be secreted into the blood as well as the levels of insulin at various periods of time of prenatal life. It is also important to know the degree of maturation of the hormonal receptors in beta cells during early ontogenesis in man. This chapter discusses the time of appearance of immunoreactive insulin in fetal pancreas and to follow the changes in the content and concentrations of the hormone in the gland and the blood stream. Insulin release under stimulation depends on the critical concentration of cyclic AMP in beta cells. The chapter describes the inability of arginine to stimulate insulin secretion in human foetuses.

A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.