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ABSTRACT: 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.
Neurochemical Journal 04/2012; 3(4):288-296. · 0.29 Impact Factor
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ABSTRACT: The study has been carried out to verify the authors’ hypothesis that degeneration of dopaminergic (DA-ergic) neurons of the
hypothalamic tuberoinfundibular system and concomitant development of hyperprolactinemia are accompanied by involvement of
compensatory synthesis of dopamine (DA) by non-dopaminergic neurons expressing single complementary enzymes of synthesis of
this neurotransmitter. Degeneration of DA-ergic neurons was produced by a stereotaxic injection into the brain lateral ventricles
of 6-hydroxydopamine (6-HDA)—a specific neurotoxin of DA-ergic neurons. 14 and 45 days after the toxin administration there
were determined concentration of prolactine in peripheral blood by methods of immunoenzyme and radioimmunological analyses
as well as the DA amount in the arcuate nucleus by the method of highly efficient liquid chromatography with electrochemical
detection. In a part of the animals, sections were prepared from the mediobasal hypothalamus (arcuate nucleus and medial eminence)
and perfused with Krebs—Ringer medium; then the DA concentration was determined in the sections and in the incubation medium.
14 days after the neurotoxin administration there were revealed an increase of blood prolactine concentration and a decrease
of DA concentration in the arcuate nucleus in vivo as well a decrease of the total DA amount in the sections and incubation medium in experiments in vitro. 45 days after the neurotoxin administration, all the above parameters returned to the normal level. Thus, the obtained data
indicate that the hyperlactinemia and DA deficit appearing during degeneration of the arcuate nucleus DA-ergic neurons seem
to be compensated due to an enhancement of DA synthesis by non-dopaminergic monoenzyme neurons of arcuate nucleus.
Key wordsdopamine–arcuate nucleus–6-hydroxydopamine–prolactine–rat
Journal of Evolutionary Biochemistry and Physiology 04/2012; 44(1):82-88. · 0.24 Impact Factor
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ABSTRACT: 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.
Journal of Evolutionary Biochemistry and Physiology 04/2012; 43(3):356-364. · 0.24 Impact Factor
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ABSTRACT: An attempt is made to find out, at what stage of ontogenesis an expression of gene and synthesis of tyrosine hydroxylase (TH)
is started, and whether noradrenergic afferents participate in regulation of these processes. The study is carried out on
rats at the 21st embryonal day (E21), P3 and P13 with use of quantitative and semi-quantitative immunocytochemistry and hybridization
in situ. Animals of all ages were subjected to a salt load, in some cases on the background of introduction of and α1-adrenoreceptor
inhibitor, prazozine. According to the obtained data, the TH expression in SON neurons in response to the salt load begins
at P3. The number of VP-ergic neurons expressing TH during the salt load is 3-fold reduced from P3 to P13. Taking into account
that the innervation of VP-ergic SON neurons is realized for this period of development, we formulated a hypothesis that the
TH expression is inhibited by noradrenergic afferents. According to the obtained data, TH is not expressed in osmotically
stimulated VP-ergic neurons on the background of prazozine injection at E21; however, this combined effect results in increased
TH expression at P3 and P13. At P13, i.e., in animals with a more developed afferent innervation, the amount of TH-immunoreactive
neurons is three times lower, than at P3. Thus, in ontogenesis of rats, VP-ergic neurons begin to respond to osmotic stimulation
by inclusion of the TH gene expression and its synthesis at the neonatal period, the both processes being under the inhibitory
control of noradrenergic afferents mediated through α1-adrenoreceptors.
Journal of Evolutionary Biochemistry and Physiology 04/2012; 42(2):174-181. · 0.24 Impact Factor
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ABSTRACT: The dynamics of blood plasma volume were studied for the first time in rats during ontogenesis. The significance of blood
plasma volume is estimated in the transport of physiologically active substances to cells and target organs during development.
The blood plasma volume was measured in male and female rats during embryogenesis on day 18 (E18), perinatal development on
E21 and day 3 of postnatal development (P3), and postnatal development on P15 and P30. Blood plasma volume was measured using
Evans Blue dye method. Body mass was determined in the same animals and correlation was estimated between the blood plasma
volume and body mass. The plasma volume increased 1.9-fold from E18 to E21, 1.4-fold from E21 to P3, 2.1-fold from P3 to P15,
and 3.4-fold from P15 to P30. The body mass increased 5-fold from E18 to E21, 2-fold from E21 to P3, 2.3-fold from P3 to P15,
and 3.2-fold from P15 to P30. The ratio of blood plasma to body mass was the highest on E18 (19%) and decreased twice by E21.
This index varied from 5.4 to 4.8% during postnatal development. No sex-related differences in these indices were found in
rats. The results obtained make it possible to determine the total content of physiologically active substances on the basis
of their plasma concentration and, thereby, estimate the efficiency of secretory organs.
Russian Journal of Developmental Biology 04/2012; 37(5):301-305. · 0.34 Impact Factor
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V G Khaindrava,
E A Kozina,
V S Kudrin,
V G Kucheryanu,
P D Klodt,
V B Narkevich,
E V Bocharov,
A K Nanaev,
G N Kryzhanovsky,
K S Raevskii, M V Ugrumov
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ABSTRACT: Degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system is the key stage in the pathogenesis of Parkinson's disease. The first symptoms of this disease are observed after degeneration of 70-80% neurons, which occurs over 20-30 years. The clinical stage of Parkinson's disease begins after this period. Late diagnostics of Parkinson's disease contributes to low efficiency of therapy for this disorder. Detailed study of the pathogenesis and development of preclinical diagnostic methods for Parkinson's disease are the urgent problems. This work was designed to develop a new experimental model of the preclinical and clinical stages of the disease. Experimental modeling was performed on C57Bl/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This agent is converted into the MPP(+)-neurotoxin in brain DAergic neurons. We showed that MPTP in a dose of 4 mg/kg has no effect on the nigrostriatal DAergic system. MPTP in a dose of 8-16 mg/kg produced the toxic effect only on DAergic axons, which simulates the preclinical stage of Parkinson's disease. MPTP in a dose of 20-40 mg/kg had the toxic effect on neuronal axons and bodies, which simulates the clinical stage of Parkinson's disease. The data suggest that progressive degeneration of DAergic neurons is accompanied by activation of compensatory mechanisms for functional deficiency of these cells.
Bulletin of Experimental Biology and Medicine 03/2011; 150(5):566-9. · 0.27 Impact Factor
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M V Ugrumov,
V G Khaindrava,
E A Kozina,
V G Kucheryanu,
E V Bocharov,
G N Kryzhanovsky,
V S Kudrin,
V B Narkevich,
P M Klodt,
K S Rayevsky,
T S Pronina
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ABSTRACT: 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.
Neuroscience 03/2011; 181:175-88. · 3.38 Impact Factor
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M V Ugrumov
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ABSTRACT: Besides the dopaminergic (DA-ergic) neurons possessing the whole set of enzymes of DA synthesis from l-tyrosine and the DA membrane transporter (DAT), the neurons partly expressing the DA-ergic phenotype have been first discovered two decades ago. Most of the neurons express individual enzymes of DA synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC) and lack the DAT. A list of the neurons partly expressing the DA-ergic phenotype is not restricted to so-called monoenzymatic neurons, e.g. it includes some neurons co-expressing both enzymes of DA synthesis but lacking the DAT. In contrast to true DA-ergic neurons, monoenzymatic neurons and bienzymatic non-dopaminergic neurons lack the vesicular monoamine transporter 2 (VMAT2) that raises a question about the mechanisms of storing and release of their final synthetic products. Monoenzymatic neurons are widely distributed all through the brain in adulthood being in some brain regions even more numerous than DA-ergic neurons. Individual enzymes of DA synthesis are expressed in these neurons continuously or transiently in norm or under certain physiological conditions. Monoenzymatic neurons, particularly those expressing TH, appear to be even more numerous and more widely distributed in the brain during ontogenesis than in adulthood. Most populations of monoenzymatic TH neurons decrease in number or even disappear by puberty. Functional significance of monoenzymatic neurons remained uncertain for a long time after their discovery. Nevertheless, it has been shown that most monoenzymatic TH neurons and AADC neurons are capable to produce l-3,4-dihydroxyphenylalanine (L-DOPA) from l-tyrosine and DA from L-DOPA, respectively. L-DOPA produced in monoenzymatic TH neurons is assumed to play a role of a neurotransmitter or neuromodulator acting on target neurons via catecholamine receptors. Moreover, according to our hypothesis L-DOPA released from monoenzymatic TH neurons is captured by monoenzymatic AADC neurons for DA synthesis. Such cooperative synthesis of DA is considered as a compensatory reaction under a failure of DA-ergic neurons, e.g. in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease.Thus, a substantial number of the brain neurons express partly the DA-ergic phenotype, mostly individual complementary enzymes of DA synthesis, serving to produce DA in cooperation that is supposed to be a compensatory reaction under the failure of DA-ergic neurons.
Journal of chemical neuroanatomy 09/2009; 38(4):241-56. · 1.75 Impact Factor
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ABSTRACT: Non-dopaminergic neurons expressing individual complementary enzymes dopamine (DA) synthesis were shown to produce DA in cooperation [Ugrumov, M., Melnikova, V., Ershov, P., Balan, I., Calas A., 2002. Tyrosine hydroxylase- and/or aromatic L-amino acid decarboxylase-expressing neurons in the rat arcuate nucleus: ontogenesis and functional significance. Psychoneuroendocrinology 27, 533-548; Ugrumov, M.V., Melnikova, V.I., Lavrentyeva, A.V., Kudrin, V.S., Rayevsky, K.S., 2004. Dopamine synthesis by non-dopaminergic neurons expressing individual complementary enzymes of the dopamine synthetic pathway in the arcuate nucleus of fetal rats. Neuroscience 124, 629-635]. This study was aimed at testing our hypothesis that the cooperative synthesis of DA in non-dopaminergic neurons is an adaptive reaction under functional insufficiency of the dopaminergic system. Functional insufficiency of the tuberoinfundibular dopaminergic system was provoked by 6-OHDA-induced degeneration of dopaminergic neurons in the arcuate nucleus in adult rats. Bienzymatic (dopaminergic) neurons and monoenzymatic neurons expressing tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC) were detected with a double-immunofluorescent technique on cryostat sections. The 6-OHDA-induced degeneration of dopaminergic neurons was accompanied by a significant increase of the number of monoenzymatic TH neurons and AADC neurons that appears to support our hypothesis. The reaction of bienzymatic and monoenzymatic neuron populations to the 6-OHDA administration occurred to be region-specific. The former disappeared in the dorsomedial region of the arcuate nucleus while the latter increased in the ventrolateral region. Thus, degeneration of dopaminergic neurons in the arcuate nucleus of adult rats is accompanied by the expression of individual enzymes of DA synthesis in non-dopaminergic neurons that may be an adaptive reaction.
Journal of Chemical Neuroanatomy 08/2005; 30(1):27-33. · 2.43 Impact Factor
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ABSTRACT: This study was aimed to test our hypothesis about dopamine (DA) synthesis by non-DAergic neurons expressing individual complementary enzymes of the DA synthetic pathway in cooperation, i.e. L-dihydroxyphenylalanine (L-DOPA) synthesized in tyrosine hydroxylase (TH)-expressing neurons is transported to aromatic L-amino acid decarboxylase (AADC)-expressing neurons for conversion to DA. The mediobasal hypothalamus of rats at the 21st embryonic day was used as an experimental model because it contains mainly monoenzymatic TH neurons and AADC neurons (>99%) whereas the fraction of bienzymatic (DAergic) neurons does not exceed 1%. The fetal substantia nigra containing DAergic neurons served as a control. DA and L-DOPA were measured by high performance liquid chromatography in: (1) cell extracts of the cell suspension prepared ex tempora; (2) cell extracts and incubation medium after the static incubation of the cell suspension with, or without exogenous L-tyrosine; (3) effluents of the incubation medium during perifusion of the cell suspension in the presence, or the absence of L-tyrosine. Total amounts of DA and L-DOPA in the incubation medium and cell extracts after the static incubation were considered as the indexes of the rates of their syntheses. L-Tyrosine administration caused the increased L-DOPA synthesis in the mediobasal hypothalamus and substantia nigra. Moreover, L-tyrosine provoked an increase of DA synthesis in the substantia nigra and its decrease in the mediobasal hypothalamus. This contradiction is most probably explained by the L-tyrosine-induced competitive inhibition of the L-DOPA transport to the monoenzymatic AADC-neurons after its release from the monoenzymatic TH neurons. Thus, this study provides convincing evidence of cooperative DA synthesis by non-DAergic neurons expressing TH or AADC in fetal rats at the end of the intrauterine development.
Neuroscience 01/2004; 124(3):629-35. · 3.38 Impact Factor
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ABSTRACT: The GnRH producing neurons are the key link of neuroendocrine regulation of the adult reproductive system. Synthesis and secretion of GnRH are, in turn, under the afferent catecholaminergic control. Taking into account that catecholamines exert morphogenetic effects on target cells during ontogenesis, this study was aimed at investigation of the effects of catecholamines on development of GnRH neurons in rats during ontogenesis. We carried out comparative quantitative and semiquantitative analyses of differentiation and migration of GnRH neurons in fetuses of both sexes under the conditions of normal metabolism of catecholamines (administration of saline) or their pharmacologically induced deficiency (administration of -methyl-para-tyrosine). The inhibition of catecholamine synthesis from day 11 of embryogenesis led to an increasing number of GnRH neurons in rostral regions of the trajectory of their migration over the brain: in the area of olfactory tubercles on day 17 and in the area of olfactory bulb on days 18 and 21. In addition, the optical density of GnRH neurons located in the rostral regions of migration was higher in the fetuses after administration of -methyl-para-tyrosine during embryogenesis, as compared to the control. It has been concluded that catecholamines stimulate the migration of GnRH neurons and affect their differentiation.
Russian Journal of Developmental Biology 12/2003; 35(1):16-24. · 0.34 Impact Factor
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ABSTRACT: This is the study first attempting to evaluate distribution of neurons expressing serotonin 5-hydroxytriptamine 1B (5-HT(1B)) receptors in hypothalamus by using immunocytochemistry. The 5-HT(1B)-immunoreactive neurons were widely distributed in hypothalamus. Accumulations of 5-HT(1B) neurons occurred in magnocellular nuclei, supraoptic nucleus, paraventricular nucleus (dorsolateral part) and accessory perifornical, circular and retrochiasmatic nuclei. Magnocellular neurons manifested an intense immunostaining suggesting a high level of 5-HT(1B) receptors. Large and middle-sized neurons with different 5-HT(1B) staining patterns were scattered throughout lateral hypothalamus, periventricular nucleus and lateral preoptic area. Immunofluorescent double-labeling revealed a great overlapping of the distribution 5-HT(1B) neurons and dense network of neuropeptide Y-immunoreactive fibers in paraventricular, supraoptic and arcuate nuclei. The potential functional significance of 5-HT(1B) receptors in the 5-HT control of endocrine functions and feeding are discussed.
Neuroscience Letters 09/2002; 328(2):155-9. · 2.11 Impact Factor
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ABSTRACT: This study has determined the ontogenetic schedule of the arrival of the axons from the hypothalamus and the diagonal band in the median eminence in rats by using the fluorescent lipophilic carbocyanine dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) as a retrograde tracer. After fixation of the brain, the crystals of the dye were implanted in the median eminence on the 13th, 14th, 15th, 16th, 17th, 20th embryonic days, and on the 2nd postnatal day. This was followed by fluorescent staining of the neuronal cell bodies in the hypothalamus. According to our data, the axons of rare hypothalamic neurons first reached the primordium of the median eminence on the 14th embryonic day. For two subsequent days, the number of neurons projecting the axons to the median eminence appeared to increase considerably. They were widely distributed through the hypothalamus and in the ventromedial region of the more rostral forebrain. Till the 20th embryonic day, the majority of the fluorescent neurons were concentrated mainly in the paraventricular nucleus (dorsal and medial parts) and the arcuate nucleus, and to a lesser extent in the medial preoptic nucleus, the supraoptic nucleus, the diagonal band, and the retrochiasmatic nucleus. In neonates, DiI-labelled neurons appeared additionally in the accessory dorsolateral nucleus, medial preoptic area lateral to the diagonal band, anterior hypothalamic area, and in the anterior periventricular nucleus. Thus, the axons of differentiating neurons arrive in the median eminence from the 14th embryonic day till the neonatal period, providing the pathway for the neurohormone transfer to the hypophysial portal circulation.
Anatomy and Embryology 10/2001; 204(3):239-52. · 1.42 Impact Factor
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ABSTRACT: The influence of serotonin afferents on tyrosine hydroxylase expression in differentiating neurons of the rat arcuate nucleus was studied in vivo and in vitro. In the in vivo study, pchlorophenylalanine inhibited serotonin synthesis in fetal brain from the 11th to the 20th embryonic day. We then used semiquantitative immunocytochemistry to evaluate tyrosine hydroxylase levels in neurons of the arcuate nucleus in fetuses at the 21st embryonic day or in offspring at the 35th postnatal day. Serotonin depletion significantly decreased the tyrosine hydroxylase content in neurons of males and females at the 21st embryonic day and in males at the 35th postnatal day. For the in vitro study, embryonic neurons of the arcuate nucleus were cocultured with embryonic neurons of the raphe nucleus, the main source of serotonin innervation of the brain, including the arcuate nucleus. Co-culture of the neurons resulted in a gender-specific increase of the tyrosine hydroxylase level in the neurons of the arcuate nucleus. In turn, the neurons of the raphe nucleus showed increased levels of serotonin in both males and females, with no sexual dimorphism. Thus, our results suggest a stimulatory, long-lasting effect of serotonin afferents on tyrosine hydroxylase expression in the differentiating neurons of the rat arcuate nucleus during prenatal ontogenesis.
Neural plasticity. 02/2001; 8(4):271-84.
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ABSTRACT: 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.
Journal of Evolutionary Biochemistry and Physiology 01/2001; 37(5):556-561. · 0.24 Impact Factor
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ABSTRACT: The ratio of neuron populations expressing either tyrosine hydroxylase or aromatic L-amino acid decarboxylase, which are enzymes of dopamine synthesis, was estimated quantitatively in the accurate nucleus of male and female rats on the 21st day of intrauterine development, the 9th day of postnatal development, and in adult animals. The enzymes in neurons were revealed by double immunocytochemical labeling, followed by identification under a fluorescence microscope. At all the developmental stages, three neuron populations differing in the expression of these enzymes were revealed. By the end of the prenatal period, most of the neurons (99%) contained only one of the enzymes, and the proportion of neurons expressing both enzymes (dopaminergic neurons) did not exceed 1%. During postnatal development, the proportion of neurons with one enzyme proved to decrease, whereas that of dopaminergic neurons increased. However, the latter proportion, even in adult animals, did not exceed 50% of the total number of neurons expressing the enzymes of dopamine synthesis. Thus, the population of neurons expressing both enzymes increases during rat ontogeny, whereas the number of neurons expressing only one enzyme decreases.
Biology Bulletin 12/2000; 28(1):64-70. · 0.20 Impact Factor
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ABSTRACT: In this quantitative and semiquantitative immunocytochemical study, the authors evaluated the differentiation of neurons expressing tyrosine hydroxylase (TH) and/or aromatic L-amino acid decarboxylase (AADC) in the mediobasal hypothalamus (MBH) of male and female rats on embryonic day 18 (E18), E20, and postnatal day 9 (P9). Four neuronal populations were distinguished according to either enzyme expression or neuron location. The earliest and most prominent first population was represented by TH-immunoreactive (IR)/AADC-immunonegative (IN) neurons that were detected initially at E18 and always were located in the ventrolateral region of the MBH. The second population of TH-IN/AADC-IR neurons was observed first at E20 and, after that time, was distributed dorsomedially. The third minor population of TH-IR/AADC-IR neurons initially was detected at E20 and was located dorsomedially. The fourth population was represented by TH-IR/AADC-IN neurons that were distributed in the dorsomedial region at any studied age. The numbers of TH-IR and AADC-IR neurons increased from their initial detection at E18 and E20 until P9. The area of TH-IR and AADC-IR neurons also increased from E18 to E20 and from E20 to P9, respectively. Both TH-IR and AADC-IR neurons showed sex differences in the neuron number, size, and optic density (OD). The numbers of TH-IR neurons in males exceeded those of females at E20 and at P9, although, at P9, sexual dimorphism was a characteristic only of the ventrolateral population. The area and OD of TH-IR neurons from females exceeded those from males in the entire mediobasal hypothalamus (MBH) at E18 and E20 but only in its dorsomedial region at P9. Sexual dimorphism also was an attribute of AADC-IR neurons at E20 and P9. Their number, size, and OD were significantly higher in females than in males. Thus, the MBH of perinatal rats contained two major populations of TH-IR/AADC-IN or TH-IN-AADC-IR neurons and a minor population of TH-IR/AADC-IR neurons. The differentiating neurons expressing either enzyme showed sexual dimorphism.
The Journal of Comparative Neurology 10/2000; 425(2):167-76. · 3.81 Impact Factor
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ABSTRACT: The objective of this study was to determine the schedule of the arrival of the axons from the hypothalamus to the posterior lobe of the pituitary (PL) in rats during ontogenesis by using the fluorescent lipophilic carbocyanine dye 1,1'-dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate (DiI) as a retrograde tracer. After preliminary fixation of the brain, DiI crystals were implanted in the PL on embryonic day 15 (E15), E16, E17, and E19 as well as on postnatal day 2 (P2) and P9. This was followed by a DiI retrograde diffusion along the plasma membrane and subsequent staining of hypothalamic neuronal cell bodies. The supraoptic nucleus (SO) contained an accumulation of fluorescent cells that extended toward the diamond-like swelling of the third ventricle as early as E15. These data suggest that the magnocellular neurons of the SO send their axons to the PL at the very beginning of differentiation, perhaps even before reaching their final position. The initial axons of the neurons of the paraventricular nucleus proper (PV) appeared to reach the PL significantly later, at E17. In addition to the SO and the PV, accessory magnocellular nuclei contributed to the innervation of the PL in perinatal rats. The neurons of the retrochiasmatic accessory nucleus first sent their axons to the PL on E16-E17. Axons that originated from other accessory hypothalamic nuclei reached the PL after birth, suggesting a delay in their involvement in the regulation of visceral functions compared with other magnocellular nuclei. Thus, the axons of magnocellular neurons reach the PL unexpectedly early in embryogenesis, raising the possibility of the functional significance of vasopressin and oxytocin as fetal neurohormones.
The Journal of Comparative Neurology 08/2000; 422(3):327-37. · 3.81 Impact Factor
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ABSTRACT: The role of the neuroendocrine system in the development of cell-mediated immunity has been studied in fetal rats. The spontaneous and mitogen-induced proliferation of liver lymphocytes and thymocytes was evaluated in vitro in rats at the 22nd prenatal day following surgical ablation of the forebrain (encephalectomy) or of the entire brain and pituitary (decapitation) in rat fetuses in utero at the 18th day. Non-operated and sham-operated fetuses served as controls. The ablation of the entire brain and pituitary in rat fetuses resulted in an increase (40-60%) of spontaneous proliferation of liver and thymic cells in comparison with sham-operated fetuses. The ablation of the forebrain including the hypothalamus caused a decrease in the mitogenic proliferative response of thymocytes and liver lymphocytes for 40 and 20%, respectively. The ablation of the entire brain including the hypothalamus and pituitary resulted in a 80% decrease of the proliferative response of thymocytes and in the full suppression of proliferation of liver lymphocytes. The immune proliferative response was restored by the LHRH administration either systemically to operated fetuses (0.2 microg/fetus) or to the cell culture (10(-9) and 10(-7) M). It was concluded that the central nervous system was important for maturation of the immune system in rats during the prenatal period. In particular, neuroendocrine system are likely to play a major role as LHRH treatment in vitro and in vivo appeared to contribute to this regulation.
Journal of Reproductive Immunology 06/2000; 47(1):17-32. · 2.97 Impact Factor
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ABSTRACT: This study has determined in rats the ontogenetic schedule of the onset of pituitary prolactin (PRL) synthesis and release as well as of the establishment of the dopamine (DA) inhibitory control of PRL secretion. RIA recognized PRL traces in the pituitary at the 18th embryonic day (E18), although a clearly detectable amount of this hormone was first measured at E20, suggesting the onset of PRL synthesis. The PRL level in the pituitary increased significantly by E22, in females to a higher extent than in males. Decapitation of fetuses did not cause any change in the PRL plasma level in males showing no PRL release from the pituitary until term. Conversely, there was a slight but significant fall of plasma PRL in decapitated females, suggesting PRL release from the pituitary. An inhibition of DA receptors on lactotropes of fetuses resulted in an increased level of plasma PRL at E20, but not at E18, while the pituitary content of PRL remained unchanged. The same treatment at E22 caused a significant increase of the PRL concentration in plasma and a concomitant fall in the pituitary that could be prevented by preliminary encephalectomy. These data show that the tuberoinfundibular DA system begins to inhibit PRL release from lactotropes between E20 and E22, completely arresting PRL release from the pituitary in males but not in females.
European Journal of Endocrinology 10/1998; 139(3):337-42. · 3.42 Impact Factor
