Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PRL-deficient dwarf mice exhibit marked reduction in dopamine (DA) and in tyrosine hydroxylase (TH) immunoreactivity in the PRL-regulating neurons of the hypothalamic arcuate nucleus (catecholaminergic area A12). Recent studies in this laboratory have revealed that this condition develops postnatally, in that A12 DA fails to increase and the number of TH-positive cells decreases after 21 days of age. The present study was designed to test whether PRL replacement during the early postnatal period would increase DA and TH expression in dwarfs. Ames dwarf (df/df) and normal sibling (DF/?) mice were treated with daily injections of ovine PRL (50 micrograms, ip) or vehicle for 30 days starting on postnatal day 12. Brains were evaluated by catecholamine histofluorescence and TH immunocytochemistry at the end of the treatment period. TH-positive cells were counted in A12 and medial zona incerta (area A13) and also differentially within A12, in dorsal and ventral regions, and at anterior, middle, and posterior levels. Histofluorescence and TH-positive cell number (P < 0.01) in vehicle-treated dwarfs were greatly reduced compared with those in DF/? mice in A12, but not in A13. However, A12 fluorescence in PRL-treated dwarfs was comparable to that in DF/? mice. TH cell counts in A12 of PRL-treated dwarfs were significantly higher (P < 0.01) than those in vehicle-treated dwarfs and not different from those in either group of DF/? mice. Within A12, both dorsal and ventral TH cell numbers were reduced in vehicle-treated dwarfs (P < 0.01); the reduction was greater in the ventral subpopulation (P < 0.01). TH cell counts were lower in middle and posterior (P < 0.05), but not anterior, areas of A12 in vehicle-treated df/df mice compared with those in DF/? mice. TH cell numbers in all A12 regions in PRL-treated dwarfs were not different from those in DF/? mice. Thus, PRL replacement initiated before 2 weeks of age in dwarfs is effective in supporting DA and TH expression in both A12 neurons and median eminence external zone at normal levels, providing direct evidence that the DA/TH deficit in dwarfs is secondary to endogenous PRL deficiency.
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PMID:Prolactin replacement during development prevents the dopaminergic deficit in hypothalamic arcuate nucleus in prolactin-deficient Ames dwarf mice. 810 78

Lactation is a state of hyperprolactinemia resulting in part from suppressed tuberoinfundibular dopaminergic (TIDA) neuronal activity. The suckling stimulus contributes to this suppression despite the fact that the TIDA neurons are a potential site for PRL feedback to increase neuronal activity. This study examined the influence of PRL feedback and the suckling stimulus on tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, during early and midlactation. On day 3 or 10 of lactation, rats were injected intracerebroventricularly with medium (control) or MMQ cells (200,000 cells), a PRL-secreting cell line. On day 6 of lactation, TH activity in the stalk-median eminence was increased 2- or 1.4-fold by MMQ cells or prior treatment with ovine PRL (oPRL; 4 mg/kg, sc), respectively. Removal of pups for 24 h increased TH activity 70% above levels in pup-exposed rats, and MMQ cells or oPRL caused an additional 60% increase. TH messenger RNA (mRNA) levels in the arcuate nucleus were increased 3-fold after removing the pups, but MMQ cells did not alter mRNA levels in either pup-exposed or pup-deprived dams. In contrast to early lactation, MMQ cells did not alter TH activity or mRNA levels in the pup-exposed dams on day 13 and only marginally increased enzyme activity in pup-derived dams. Circulating PRL levels were markedly reduced after removing pups. MMQ cells suppressed circulating PRL levels in both groups of dams on day 6 and in pup-deprived dams on day 13, but had no effect in pup-exposed dams at this time. In a second experiment, pup-exposed dams were injected with bromocriptine, a dopamine agonist, and killed after 4 or 12 h on day 5 or after 12 h on day 12. In some rats, PRL was replaced by injecting oPRL simultaneously with and 8 h after bromocriptine treatment. On day 5 of lactation, bromocriptine reduced and oPRL restored TH activity, whereas on day 12, oPRL was not able to reverse the effect of bromocriptine. These data indicate that the suckling stimulus suppresses TH activity and gene expression in the TIDA neurons in pup-exposed dams. The high endogenous PRL levels associated with the suckling stimulus may activate TH activity in TIDA neurons during early lactation. However, the responsiveness of the TIDA neurons to PRL feedback is attenuated by day 13 of lactation.
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PMID:The responsiveness of tuberoinfundibular dopaminergic neurons to prolactin feedback is diminished between early lactation and midlactation in the rat. 853 41

It is known that dopamine (DA) is the major PRL-inhibiting factor, and vasoactive intestinal peptide (VIP) is one of the most potent and physiological PRL-releasing factors. We have investigated the implication of DA and VIP in PRL gene expression and peptide secretion regulation during the physiological hyperprolactinemic states of pregnancy and lactation. Pregnant rats were studied on days 8, 15, and 20 of pregnancy. Lactating rats suckled by eight pups were studied on days 3 and 8 of postpartum, and nonsuckling postpartum rats were used as controls. Plasma estradiol, progesterone, and PRL were measured by RIA, as well as pituitary immunoreactive (IR-) PRL, pituitary IR-VIP, and hypothalamic IR-VIP. DA was studied by measuring changes in gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. TH, PRL, and VIP messenger RNA (mRNA) were assessed by Northern blot hybridization. The results showed very high plasma PRL levels in early pregnancy and during lactation, whereas plasma PRL concentrations were normalized at the end of gestation and in nonsuckling control rats. The physiological hyperprolactinemia of both early pregnancy and lactation correlated with higher pituitary PRL mRNA levels and lower pituitary IR-PRL content. Moreover, hypothalamic TH mRNA levels were lower in early pregnancy and lactation than at the end of gestation and in nonsuckling rats, respectively. The hypothalamic IR-VIP content was lower on day 8 of pregnancy than on days 15 and 20. However, VIP gene expression in the hypothalamus did not change throughout pregnancy. During lactation, neither hypothalamic IR-VIP content nor VIP mRNA was significantly altered. In the pituitary, IR-VIP content did not significantly change, and VIP mRNA levels were higher on day 15 of pregnancy than on the other days. During lactation, the pituitary IR-VIP content was very low on day 8 compared with those on day 3 of lactation and in nonsuckling control rats. VIP mRNA 1.0-kilobase transcript levels were higher in the lactating rats than in the control animals. These data show that both early pregnancy and lactation are physiological hyperprolactinemic states in which increased PRL mRNA accumulation coincides with decreased IR-PRL content in the pituitary and higher plasma IR-PRL, indicating regulation at the gene expression level and of PRL secretion. Low TH gene expression also occurs during hyperprolactinemia, suggesting that the diminution of DA activity that occurs during early pregnancy and lactation might be the major regulator of PRL alterations. If hypothalamic VIP plays a role as a neuroendocrine PRL-releasing factor during pregnancy and lactation, this may occur at the secretory level, as suggested by the alterations in IR-VIP, with no modifications in VIP mRNA accumulation, in the hypothalamus. Pituitary VIP does not seem to be a major regulator of PRL secretion during pregnancy, whereas during lactation, it regulates PRL secretion in a paracrine and/or autocrine manner.
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PMID:Prolactin gene expression and secretion during pregnancy and lactation in the rat: role of dopamine and vasoactive intestinal peptide. 859 12

The present study explores the significance of brain dopamine phenotype for individual variation in the neuroendocrine stress response of the rat. For this purpose, we used two Wistar rat lines previously selected for high or low responsiveness of the dopamine system to apomorphine using the gnawing response as the selection criterion. Systemic administration of the drug evoked in apomorphine-susceptible (apo-sus) rats a vigorous gnawing response, whereas apomorphine-unsusceptible (apo-unsus) rats did not gnaw under these conditions. These two rat lines represent individuals displaying extreme differences in gnawing behavior that otherwise coexist in a normal Wistar population. In this study basal and stress-induced hypothalamic-pituitary-adrenal activity and PRL release were measured in chronically cannulated, freely moving rats that endured a conditioned emotional response. Tyrosine hydroxylase messenger RNA (mRNA), corticosteroid receptor mRNA, and in vivo retention of [3H]corticosterone were measured in rat brain sections using in situ hybridization and in vivo autoradiography. The result show that 1) apo-sus rats had a markedly reduced PRL response to stress compared to apo-unsus animals, whereas basal levels were not significantly different. A12 dopaminergic neurons in the arcuate nucleus expressed significantly higher levels of tyrosine hydroxylase mRNA in apo-sus rats, suggesting that the reduced stress-induced PRL release could be due to an increased inhibitory control by dopaminergic neurons; 2) in apo-sus rats, stress resulted in a sustained elevation of ACTH and free corticosterone levels, whereas the total corticosterone levels were not different between the two rat lines; 3) under basal morning conditions, apo-sus rats had significantly higher plasma ACTH, but, in contrast, lower free corticosterone than apo-unsus rats; total plasma corticosterone levels were not different; 4) the basal evening ACTH level was elevated in apo-sus rats; after removal of the adrenals in the morning, this increased ACTH level in apo-sus rats persisted into the afternoon 6 h postadrenalectomy; and 5) hippocampal mineralocorticoid (MR), but not glucocorticoid (GR), receptor capacity for the ligand comparable between the groups; the MR of apo-sus rats displayed an increased retention of [3H]corticosterone in all hippocampal cell fields measured 24 h adrenalectomy; MR and GR mRNA in hippocampus as well as GR mRNA in the paraventricular nucleus were not significantly different in the two rat lines. In conclusion, the data suggest a common genetic background for individual variation in stress responsiveness and dopamine phenotype. High dopamine reactivity is linked to a reduced PRL and an increased ACTH response after stress. These high dopamine responders display a hyporesponsive adrenal cortex and corticosteroid feedback resistance associated with altered brain corticosteroid receptor properties.
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PMID:Divergent prolactin and pituitary-adrenal activity in rats selectively bred for different dopamine responsiveness. 861 1

The activity of the A14 and A12 hypothalamic dopaminergic (DAergic) neurons were characterized throughout a day of pseudopregnancy to establish their relationship to the generation of PRL surges during that time. Double-label immunocytochemistry was performed using fos-related antigens as markers of neuronal activity, and tyrosine hydroxylase antibody to identify DAergic neurons of the periventricular nucleus and the arcuate nucleus (ARN). Dopamine concentrations were measured with HPLC with electrochemical detection from micropunched samples to approximate synthetic activities of A14 and A12 neurons. Serum PRL levels were determined by RIA. On the fifth and sixth day of pseudopregnancy, five rats/time point were killed at 1100 h, 1300 h, 1500 h, 1800 h, 2100 h, 2400 h, 0300 h, and 0600 h. When the serum PRL was low, the incidence of fos-related antigens/tyrosine hydroxylase double-labeled neurons was high, and it decreased twice a day by 1500 and 0300 h in the periventricular nucleus, rostral ARN, dorsomedial subpopulation of the middle ARN, and in the caudal ARN, corresponding to the initiation of PRL surges. Concentrations of DA were high in these areas, and decreased before PRL surges in agreement with the immunocytochemical data. These findings suggest a semicircadian rhythm in the activities of A14 and A12 neurons which, in concert with PRL releasing factors, contribute to the generation of PRL surges in pseudopregnant animals.
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PMID:Dopaminergic neurons of periventricular and arcuate nuclei of pseudopregnant rats: semicircadian rhythm in Fos-related antigens immunoreactivities and in dopamine concentration. 875 24

Dwarf tyrosine hydroxylase-human GH (TH-hGH) transgenic mice carrying the hGH reporter gene targeted by the TH promoter express hGH in those regions of the hypothalamus responsible for regulation of pituitary GH secretion. Central expression of the hGH gene decreases GH-releasing hormone (GHRH) and increases somatostatin, which ultimately impacts on pituitary function by reducing the overall amount of GH produced. In the present study, we sought to determine if the reduction of pituitary GH in TH-hGH mice could be attributed to a decrease in somatotrope cell numbers and/or an impairment of somatotrope function. Pituitaries from TH-hGH or wild-type (WT) male and female mice were enzymatically dispersed, counted, and immunostained for GH, PRL, TSH, and ACTH. The total number of pituitary cells recovered from TH-hGH pituitaries was approximately one-half of that from WT controls. However, the proportion of cells that stained for GH and PRL were virtually identical (males, GH-TH-hGH, 58.1 +/- 1.0% [mean +/- SEM] vs. WT, 60.7 +/- 1.0%; PRL-TH-hGH, 43.4 +/- 2.2% vs. WT, 43.1 +/- 0.7%; females, GH-TH-hGH, 47.9 +/- 2.3% vs. WT, 41.5 +/- 3.5%; PRL-TH-hGH, 43.3 +/- 3.2% vs. WT, 47.1 +/- 3.3%). In contrast, percentages of both TSH- and ACTH-containing cells were increased in TH-hGH pituitaries relative to controls (males, TSH-TH-hGH, 15.1 +/- 2.3% vs. WT, 9.6 +/- 1.5%; ACTH-TH-hGH, 24.5 +/- 2.5% vs. WT, 10.9 +/- 0.9%; females: TSH-TH-hGH, 11.3 +/- 0.7% vs. WT, 7.5 +/- 0.6%; ACTH-TH-hGH, 19.8 +/- 1.6% vs. WT, 9.3 +/- 0.8%; P < 0.05). Calculation of the absolute number of each cell type per pituitary demonstrated TH-hGH mice to have about one-half the number of GH and PRL cells, whereas TSH and ACTH cell populations were comparable with that of their WT counterparts. Immunocytochemical localization of GH cells within pituitary sections from TH-hGH mice revealed that somatotropes were confined primarily to the lateral wings of the adenohypophysis, in contrast to the heterogeneous distribution of GH-immunostained cells in WT pituitaries. To assess the functional capacity of the somatotrope populations, pituitary cells from TH-hGH and WT mice were challenged with mouse GHRH (0.01-10 nM). The quantity of GH released (as assessed by both RIA and reverse hemolytic plaque assay) under basal and stimulated conditions did not differ among TH-hGH and WT pituitary cell cultures. Similarly, GHRH induced intracellular cAMP levels were comparable. These results indicate that proliferation of pituitary somatotropes and lactotropes is much more sensitive to changes in GHRH input than is the capability of developing regulated GH secretory function.
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PMID:The tyrosine hydroxylase-human growth hormone (GH) transgenic mouse as a model of hypothalamic GH deficiency: growth retardation is the result of a selective reduction in somatotrope numbers despite normal somatotrope function. 889 26

In the ewe, photoperiod modulates LH and PRL secretion as well as median eminence (ME) dopaminergic activity. The studies reported here were designed to characterize the functional significance of this photoperiodic modulation of ME dopaminergic neuron activity in relation to the regulation of LH and PRL secretion. The aim of the first experiment was to assess whether photoperiodic changes in hypothalamic dopaminergic activity were temporally linked to changes in either PRL or LH secretion. The purpose of the second experiment was to determine whether melatonin mimicked the effects of photoperiod on ME dopaminergic activity. In the first experiment, LH and PRL secretion, hypothalamic tyrosine hydroxylase (TH) activity, and catecholamine contents were determined in ovariectomized estradiol-treated ewes either during long days (LD; control group) or after 5, 25, and 76 short days (SD). SD were associated with a stimulation of LH secretion and a decrease in ME TH activity, which were both expressed only in the 76 SD group. In contrast, the SD-induced inhibition of PRL secretion was already maximal in the 25 SD group. In the second experiment, LH secretion and hypothalamic dopaminergic activity were studied in ovariectomized estradiol-treated ewes kept in LD and then treated for 0 (control), 25, or 77 days with melatonin implants producing a SD-like effect on LH secretion. Melatonin induced a decrease in PRL secretion (observed after 25 days of treatment), as well as a stimulation of LH secretion and a decrease in ME TH activity and dopamine content (observed only after 77 days of treatment). In conclusion, the decrease in ME dopaminergic activity associated with SD exposure or the SD-like effect of melatonin appears unrelated to the regulation of PRL secretion. The SD-like effect of melatonin on ME dopaminergic activity suggests that melatonin mediates the effect of SD on this activity. The regulation of ME dopaminergic activity can thus be considered a probable step in the photoperiodic regulation of LH secretion.
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PMID:Characterization of the short day-induced decrease in median eminence tyrosine hydroxylase activity in the ewe: temporal relationship to the changes in luteinizing hormone and prolactin secretion and short day-like effect of melatonin. 897 40

The key role of the suprachiasmatic nucleus in the diurnal regulation of anterior pituitary hormone secretions, including PRL, is well established. However, the pathway via suprachiasmatic signals reach the pituitary is ill defined. To determine whether suprachiasmatic efferents innervate neuroendocrine cells, the anterograde tracer, Phaseolus vulgaris leukoagglutinin, was injected iontophoretically into the suprachiasmatic nucleus in parallel with ip administration of fluorogold (20 mg/BW in saline). After visualization of anterogradely labeled processes with a dark blue chromogen. Vibratome sections were immunostained for fluorogold. As fluorogold labeling resulted in dense immunopositive granules without diffuse cytoplasmic labeling, selected sections were further immunostained for cytoplasmic tyrosine hydroxylase (dopamine). Anterogradely labeled suprachiasmatic efferents were observed in the medial preoptic area, periventricular regions, and the lateral aspects of the arcuate and ventromedial nuclei of the hypothalamus, whereas the median eminence and organum vasculosum laminae terminalis lacked labeled suprachiasmatic projections. All of the aforementioned regions contained a high number of cells immunoreactive for fluorogold. However, immunolabeling for fluorogold revealed no retrogradely labeled (ergo neuroendocrine) cells in the suprachiasmatic nucleus. Retrogradely labeled cells in all of these hypothalamic sites, with the exception of the median eminence and organum vasculosum laminae terminalis, were targets of suprachiasmatic nucleus axon terminals. In the preoptic area, anterior hypothalamus, periventricular area, and arcuate nucleus, subpopulations of dopamine cells were retrogradely labeled. In all of these areas, both retrogradely labeled and nonlabeled dopamine cells were frequently found to be in contact with dark blue, anterogradely labeled suprachiasmatic efferents. Electron microscopic examination confirmed the putative connections to be synaptic. This experiment provided evidence that the circadian pacemaker suprachiasmatic nucleus sends efferents onto neuroendocrine cells, but has no contacts with fenestrated capillaries. It was found that a population of median eminence-projective cells targeted by suprachiasmatic axons in the hypothalamus contains dopamine. These observations indicate no direct effect of the circadian pacemaker on the anterior hypophysis, but offer an indirect pathway via circadian signals, mediated by hypothalamic neural systems, that may regulate pituitary hormone secretion, in particular PRL.
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PMID:Suprachiasmatic efferents avoid phenestrated capillaries but innervate neuroendocrine cells, including those producing dopamine. 904 41

Mice transgenic for heterologous and ectopic GH expression serve as models for studying the feedback effects of elevated nonregulated GH on hypothalamic hypophysiotropic neurons as well as on peripheral function. For example, hypothalamic somatostatin expression has been shown to be increased markedly in mice bearing either bovine (b) or human (h) GH transgenes. Human, but not bovine, GH has lactogenic properties in mice, and appears to stimulate PRL-inhibiting tuberoinfundibular dopaminergic (TIDA) neurons. The present study was designed to determine the effect of a lifelong excess of hGH on dopamine (DA) expression in and numbers of TIDA neurons. Male mice of four transgenic lines were examined. The transgenic animals bore constructs of either bGH or hGH fused to either metallothionein (MT) or phosphoenolpyruvate carboxykinase (PEPCK) promoters; brains of transgenic mice were compared morphologically with those of nontransgenic littermates. Formaldehyde-induced catecholamine histofluorescence and tyrosine hydroxylase (TH) immunocytochemistry were examined in alternate brain sections; cell number was quantified for TIDA neurons (area A12) and a nonhypophysiotropic diencephalic DA area, the medial zona incerta (A13). Body weights were higher (P < 0.01) in PEPCK-GH than in MT-GH transgenic mice, as were serum levels of heterologous GH in those lines. In MT-hGH, but not MT-bGH or PEPCK-bGH, transgenic mice, A12 perikaryal fluorescence was enhanced, and ME fluorescence was reduced compared with those in control animals. The reduced ME DA is likely to reflect stimulation of TIDA neurons, because A12 TH-immunoreactive neuron number was increased by 34% in MT-hGH mice compared with that in controls (P < 0.05). In mice bearing the PEPCK-hGH construct, A12 TH neuron number was increased 47% (P < 0.001) compared with that in littermate controls. There were no differences in A13 cell number among animals, and A12 cell numbers in mice expressing bGH did not differ from control values. These results suggest that although extremely high levels of circulating bGH do not stimulate TIDA neurons, lifelong high levels of hGH have a stimulatory and graded effect on developmental differentiation of these cells for TH and DA production, supporting the concept of PRL as a trophic factor for TIDA neurons.
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PMID:Stimulatory effect of human, but not bovine, growth hormone expression on numbers of tuberoinfundibular dopaminergic neurons in transgenic mice. 920 27

This study examined the responsiveness of dopaminergic neurons to PRL and the expression of PRL receptors in fetal hypothalamic cells. Hypothalamic cells were cultured in medium containing 5 or 25 mM potassium (K+) with or without 5% FBS. Rat PRL (rPRL) treatment (10-1000 ng/ml) for 10 days increased tyrosine hydroxylase (TH) activity 1.6- to 1.8-fold in dopaminergic neurons cultured in serum-containing medium with 25 mM K+, but not in defined medium or any medium with 5 mM K+. The rPRL-induced increase in TH activity was observed at 10-1000 ng/ml after both 1 and 10 days of rPRL treatment, whereas 1 ng/ml was not effective. TH activity was not altered after 1-12 h of rPRL treatment (100 ng/ml), but was increased 1.4-fold after 1-3 days and 1.8-fold after 5-10 days. The colocalization of PRL receptors and TH was evaluated by double labeled immunocytochemistry. PRL receptor immunostaining was observed in most TH-immunoreactive cells cultured in either defined or serum-containing medium with or without 10 days of rPRL treatment (100 ng/ml). As assessed by reverse transcriptase-PCR, the long form, but not the short form, of the PRL receptor was expressed in the hypothalamic cells regardless of medium composition, similar to the expression pattern in adult mediobasal hypothalamus from ovariectomized rats. These data indicate that a factor present in FBS imparts PRL responsiveness to hypothalamic dopaminergic neurons in vitro. The effective PRL concentrations and the time course for PRL's action in vitro are within the physiological range in vivo. The colocalization of PRL receptor in dopaminergic neurons provides anatomical evidence for a direct effect of PRL, with the long form of the PRL receptor being the predominant form in the hypothalamic cells.
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PMID:Prolactin (PRL) receptors are colocalized in dopaminergic neurons in fetal hypothalamic cell cultures: effect of PRL on tyrosine hydroxylase activity. 920 47


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