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

The adipose tissue-derived hormone leptin regulates body weight homeostasis by decreasing food intake and increasing energy expenditure. The weight-reducing action of leptin is thought to be mediated primarily by signal transduction through the leptin receptor (LR) in the hypothalamus. We have used immunohistochemistry to localize LR-immunoreactive (LR-IR) cells in the rat brain using an antiserum against a portion of the intracellular domain of LR that is common to all LR isoforms. The antiserum recognized the short and long isoforms of LR in transfected hematopoietic BaF3 cells. To examine the chemical nature of target cells for leptin, direct double-labeling immunofluorescence histochemistry was applied. The results show extensive distribution of LR-like immunoreactivity (LR-LI) in the brain with positively stained cells present, e.g., in the choroid plexus, cerebral cortex, hippocampus, thalamus, and hypothalamus. In the hypothalamus, strongly LR-IR neurons were present in the supraoptic nucleus (SON) and paraventricular nucleus (PVN), periventricular nucleus, arcuate nucleus, and lateral hypothalamus. Weaker LR-IR neurons were also demonstrated in the lateral and medial preoptic nuclei, suprachiasmatic nucleus, ventromedial and dorsomedial nuclei, and tuberomammillary nucleus. Confocal laser scanning microscopy showed LR-LI in the periphery of individual cells. In magnocellular neurons of the SON and PVN, LR-LI was demonstrated in vasopressin- and oxytocin-containing neurons. In parvocellular neurons of the PVN, LR-LI was demonstrated in many corticotropin-releasing hormone-containing neurons. LR-IR neurons were mainly seen in the ventromedial aspect of the arcuate nucleus, where LR-LI co-localized with neuropeptide Y. In the ventrolateral part of the arcuate nucleus, LR-LI was present in many large adrenocorticotropic hormone-IR proopiomelanocortin-containing neurons and in a few galanin-, neurotensin-, and growth hormone-releasing hormone-containing neurons. In the dorsomedial arcuate nucleus, few tyrosine hydroxylase (dopamine)-containing neurons were seen to have LR-LI. Melanin-concentrating hormone-containing neurons in the lateral hypothalamus had LR-LI. Based on the immunohistochemical results, possible interactions of leptin with brain mechanisms are discussed.
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PMID:Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. 941 31

Considerable evidence suggest that some responses to smoking and nicotine are mediated by forebrain beta-endorphinergic opioid mechanisms. It has also been demonstrated that nicotine stimulates rat tuberoinfundibular dopaminergic activity. Since we have proposed that interactions between mediobasohypothalamic (MBH) dopaminergic and beta-endorphinergic mechanisms have a key role in neuroendocrine integration, we investigated the effects of chronic nicotine treatment and withdrawal on: (1) MBH concentrations of proopiomelanocortin (POMC, precursor for beta-endorphin biosynthesis) mRNA; (2) MBH concentrations of tyrosine hydroxylase (TH, rate limiting enzyme in catecholamine biosynthesis) mRNA; (3) corresponding serum prolacin, corticosterone, luteinizing hormone (LH), and testosterone concentrations. POMC and TH mRNA levels were measured by RNase protection/solution hybridization assay; serum hormone levels were measured by radioimmunoassay. Adult male rats received subcutaneous injections of either nicotine or saline during the dark period of each day on an increasing frequency (1-3 injections/day) and dosage (0.4-0.5 mg nicotine/kg body weight) schedule over 4 weeks. The rats were sacrificed after 4 weeks treatment and at 1, 3, 7, 14 and 21 days withdrawal. Chronic daily nicotine administration induced significant changes in serum corticosterone, serum prolactin, MBH TH mRNA, and MBH POMC mRNA concentrations that tended to persist through day 3 of withdrawal; serum prolactin and MBH POMC mRNA concentrations were suppressed whereas serum corticosterone and MBH TH mRNA concentrations were stimulated. None of the parameters were significantly different from control levels following 7 or more days of withdrawal from nicotine, except for a significant decrease of MBH POMC mRNA concentrations on day 21. Chronic daily nicotine or withdrawal did not significantly alter serum LH or testosterone concentrations. These results suggest that chronic nicotine inhibited POMC gene expression and thus, probably, biosynthesis of beta-endorphin and other opiomelanocortins. We hypothesize that suppression of forebrain beta-endorphin synthesis in response to long-term nicotine exposure produces a chronically opioid deficient condition which may play an important role in maintaining nicotine self-administration and in mediating some changes during the nicotine withdrawal syndrome.
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PMID:Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation. 969 29

The locus coeruleus is innervated by proopiomelanocortin (POMC)-derived peptide immunoreactive fibres. The biological effects of ( melanocyte-stimulating hormone (aMSH) and [-endorphin on second messengers (cAMP, inositol phosphates) and gene transcription were studied in the locus cceruleus-derived cell line CATH.a. RT-PCR analysis revealed the presence of four MSH receptor subtypes (1, 3, 4 and 5). Activation of these receptors by diacetyl alphaMSH stimulated cAMP accumulation in a dose-dependent manner (EC50: 4 x 10(-9) M). Diacetyl alphaMSH stimulated transcription from reporter genes driven by the c-fos or tyrosine hydroxylase promoter. This effect was abolished when protein kinase A was inactivated with a dominant inhibitory mutant. RT-PCR analyses revealed the presence of delta-, but not mu-and kappa-opioid receptor. Pharmacological analysis showed that beta-endorphin (EC50: 2.5 x 10(-8)M), but not N-acetyl beta-endorphin, antagonized the biological effect of diacetyl alphaMSH on cAMP production and gene transcription. Since N-acetylation regulates the biological activity of alphaMSH and beta-endorphin in an opposite manner, we propose a model where the rate of secretion dictated by the bioelectric activity of the presynaptic neuron modulates POMC-derived peptide maturation and the resulting biological signal sensed by the postsynaptic plate.
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PMID:Melanocortin receptors and delta-opioid receptor mediate opposite signalling actions of POMC-derived peptides in CATH.a cells. 975 Nov 58

This study used a hypothalamo-pituitary disconnected (HPD) sheep model to investigate the central regulation of long-term cycles in voluntary food intake (VFI) and body weight (BW). VFI, BW, and circulating concentrations of metabolic hormones [alpha-melanocyte-stimulating hormone (alpha-MSH), insulin-like growth factor-1 (IGF-1), insulin, and leptin] were measured in HPD and control Soay rams exposed to alternating 16 weekly periods of long and short days for 80 wk. In the controls, the physiology was cyclical with a 32-wk periodicity corresponding to the lighting regimen. VFI and BW increased under long days to a maximum early into short days, and there were associated increases in blood concentrations of alpha-MSH, insulin, and leptin. In the HPD rams, there were no significant photoperiod-induced changes in any of the parameters. VFI increased after surgery for 8 wk and then gradually declined, although BW increased progressively and the HPD rams became obese. Concentrations of alpha-MSH, insulin, and leptin in peripheral blood were permanently increased (>200%), and levels of IGF-1 decreased (<55%). The HPD lesion effectively destroyed the entire median eminence [no nerve terminals immunostained for tyrosine hydroxylase (TH) and gonadotropin-releasing hormone] and the adjacent arcuate nucleus (no perikarya immunostained for proopiomelanocortin or TH, and no cells expressed neuropeptide Y mRNA). The results support the conclusion that arcuate hypothalamic systems generate long-term rhythms in VFI, BW, and energy balance.
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PMID:Hypothalamic control of photoperiod-induced cycles in food intake, body weight, and metabolic hormones in rams. 1140 81

Clinical studies demonstrate that the antidepressant efficacy of St John's wort (Hypericum) is comparable to that of tricyclic antidepressants such as imipramine. Onset of efficacy of these drugs occurs after several weeks of treatment. Therefore, we used in situhybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract, and hypericin (an active constituent of St John's wort) on the expression of genes that may be involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine (15 mg kg(-1)), Hypericum (500 mg kg(-1)), and hypericin (0.2 mg kg(-1)) given daily by gavage for 8 weeks but not for 2 weeks significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 16-22% in the hypothalamic paraventricular nucleus (PVN) and serotonin 5-HT(1A) receptor mRNA by 11-17% in the hippocampus. Only imipramine decreased tyrosine hydroxylase (TH) mRNA levels in the locus coeruleus (by 23%), and only at 8 weeks. The similar delayed effects of the three compounds on gene transcription suggests a shared action on the centers that control HPA axis activity. A second study was performed to assess the effects of long-term imipramine and Hypericum administration on stress-induced changes in gene transcription in stress-responsive circuits. Repeated immobilization stress (2 h daily for 7 days) increased mRNA levels of CRH in the PVN, proopiomelanocortin (POMC) in the anterior pituitary, glutamic acid decarboxylase (GAD 65/67) in the bed nucleus of the stria terminalis (BST), cyclic AMP response element binding protein (CREB) in the hippocampus, and TH in the locus coeruleus. It decreased mRNA levels of 5-HT(1A) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Long-term pre-treatment with either imipramine or Hypericum reduced to control levels the stress-induced increases in gene transcription of GAD in the BST, CREB in the hippocampus, and POMC in the pituitary. The stress-induced increases in mRNA levels of CRH in the PVN and TH in the locus coeruleus were reduced by imipramine but not by Hypericum. The stress-induced decreases in BDNF and 5-HT(1A)mRNA levels were not prevented by either drug. Taken together, these data show: (1) that Hypericum and hypericin have delayed effects on HPA axis control centers similar to those of imipramine; and (2) that select stress-induced changes in gene transcription in particular brain areas can be prevented by long-term treatment with either the prototypic tricyclic antidepressant imipramine or the herbiceutical St John's wort. However, imipramine appears to be more effective in blocking stress effects on the HPA axis than the plant extract.
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PMID:St John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats. 1152 69

Prolactin (PRL) has been implicated in central actions including those that result in its own regulation and/or the suppression of gonadotropin secretion. It is not clear, however, which neuronal systems may mediate the central effects of PRL. Here, using dual immunohistochemistry for c-Fos and either tyrosine hydroxylase (TH) or proopiomelanocortin (POMC), we have assessed neuronal activation, following centrally administered PRL, within two neuronal networks that have been shown to participate in the inhibitory regulation of reproductive function. Male rats received one intracerebroventricular injection of either PRL (5 microg) or saline (vehicle control) 5 days after cannulae were inserted into the lateral ventricles. Ninety minutes after treatment, animals were perfused with 4% paraformaldehyde, the brains were removed and 30-microm frozen sections were cut throughout the entire hypothalamic region. Parallel sets of sections were processed for both c-Fos immunoreactivity (ir) and either TH-ir or POMC-ir. PRL increased the mean number of c-Fos-ir neurons within the rostral arcuate nucleus (9.3 +/- 2.0 vs. 5.0 +/- 1.2 cells/section, for PRL and control rats, respectively; p < 0.05). Within the TH-ir neurones, PRL induced a significant increase in c-Fos in the dorsomedial portion of the mid-arcuate nucleus (p < 0.05). In contrast, there was no significant increase in the expression of c-Fos within the POMC neurones of the arcuate nucleus. PRL also induced c-Fos expression in the supraoptic nucleus (SON) (11.7 +/- 3.2 vs. 3.0 +/- 1.4 cells/section for PRL and control rats, respectively; p < 0.05), but not in the medial preoptic nucleus, ventromedial nucleus or the dorsomedial nucleus, areas reported to either contain gonadotropin-releasing hormone neurones or express PRL receptors. The results from this study show immediate early gene activation within both the arcuate nucleus and the SON of the hypothalamus following acute PRL administration. While the role of PRL-responsive neurones in the SON remains to be elucidated, these findings support the notion that the central actions of PRL could be mediated via the TH neurones of the dorsomedial arcuate nucleus and/or by a population of neurones in the rostral arcuate nucleus that contain neither TH nor POMC.
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PMID:Hypothalamic targets for prolactin: assessment of c-Fos induction in tyrosine hydroxylase- and proopiomelanocortin-containing neurones in the rat arcuate nucleus following acute central prolactin administration. 1175 95

Epinephrine, norepinephrine, and corticosterone responses to hypoglycemia are impaired in diabetic rats. Recurrent hypoglycemia further diminishes epinephrine responses. This study examined the sympathoadrenal system and hypothalamo-pituitary-adrenal axis for molecular adaptations underlying these defects. Groups were normal (N) and diabetic (D) rats and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (D-hypo) or hyperinsulinemic hyperglycemia (D-hyper). D-hypo and D-hyper rats differentiated effects of hypoglycemia and hyperinsulinemia. Adrenal tyrosine hydroxylase (TH) mRNA was reduced (P < 0.05 vs. N) 25% in all diabetic groups. Remarkably, mRNA for phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, was reduced (P < 0.05 vs. all) 40% only in D-hypo rats. Paradoxically, dopamine beta-hydroxylase mRNA was elevated (P < 0.05 vs. D, D-hyper) in D-hypo rats. Hippocampal mineralocorticoid receptor (MR) mRNA was increased (P < 0.05 vs. N) in all diabetic groups. Hippocampal glucocorticoid receptor (GR), hypothalamic paraventricular nucleus (PVN) GR and corticotropin-releasing hormone (CRH), and pituitary GR and proopiomelanocortin (POMC) mRNA levels did not differ. We conclude that blunted corticosterone responses to hypoglycemia in diabetic rats are not due to altered basal expression of GR, CRH, and POMC in the hippocampus, PVN, and pituitary. The corticosterone defect also does not appear to be due to increased hippocampal MR, since we have reported normalized corticosterone responses in D-hypo and D-hyper rats. Furthermore, impaired epinephrine counterregulation in diabetes is associated with reduced adrenal TH mRNA, whereas the additional epinephrine defect after recurrent hypoglycemia is associated with decreases in both TH and PNMT mRNA.
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PMID:Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and hypothalamo-pituitary-adrenal axis. 1549 9

This study examined the time course effects (8, 16 and 31 days) of fluoxetine administration (1 mg/kg, p.o./day) on serotonin transporter (5-HTT), opioid, tyrosine hydroxylase (TH) and cannabinoid CB1 receptor gene expressions in selected regions of the rat brain. Treatment with fluoxetine progressively decreased (35-55%) 5-HTT gene expression in dorsal raphe nucleus at 8, 16 and 31 days. The results revealed that fluoxetine administration decreased (30%) proenkephalin gene expression in nucleus accumbens shell (AcbS) and caudate-putamen (CPu) (31 days) but was without effect in nucleus accumbens core AcbC. A pronounced and time related decrease (25-65%) in prodynorphin gene expression was detected in AcbC, AcbS, CPu, hypothalamic supraoptic and paraventricular nuclei at all time points as well as in proopiomelanocortin gene expression (20-30%) in the arcuate nucleus (ARC) of the hypothalamus. On days 16 and 31, tyrosine hydroxylase gene expression in ventral tegmental area and substantia nigra and cannabinoid CB1 receptor gene expression in the CPu decreased (approximately 45-50% from vehicle). In conclusion, fluoxetine by inhibiting the reuptake of serotonin produced pronounced and time related alterations in genes involved in the regulation of emotional behaviour, suggesting that these neuroplastic changes may be involved, at least in part, in the clinical efficacy of this drug in neuropsychiatric disorders.
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PMID:Time course of opioid and cannabinoid gene transcription alterations induced by repeated administration with fluoxetine in the rat brain. 1593 43

Lactation is characterized by extreme hyperphagia and negative energy balance resulting from a large energy drain due to milk production and by a suppression of cyclic ovarian function. Increases in neuropeptide Y and agouti-related protein and a decrease in proopiomelanocortin expression in the arcuate nucleus of hypothalamus (ARH) may contribute to the hyperphagia to maintain energy balance and to the suppression of LH secretion associated with lactation. However, little is known about the full extent of neuroendocrine changes in the ARH that may contribute to the various adaptations occurring during lactation. To address this issue, we used Affymetrix microarray to acquire a reliable profile of the lactation-induced transcriptional changes in micropunches containing the ARH and a portion of the ventromedial nucleus of the hypothalamus. Using high stringency criteria, 12 genes were identified as being differentially regulated during lactation, and an additional 10 genes and three transcribed sequences were identified using moderate stringency criteria. Changes in neuropeptide Y, enkephalin, tyrosine hydroxylase, and dynorphin, genes previously shown to be differentially regulated during lactation, provide validation for the microarray analysis. New genes identified as being differentially expressed include those related to neurotransmission, growth factors, signal transduction, and structure remodeling. These data identify new genes in ARH/ventromedial nucleus of the hypothalamus that may play an important role in the adaptations of lactation related to hyperphagia, milk production, and the suppression of cyclic reproductive function and may contribute to elucidating a framework for integrating changes in energy intake with the regulation of reproductive function during lactation.
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PMID:Deoxyribonucleic acid microarray analysis of gene expression pattern in the arcuate nucleus/ventromedial nucleus of hypothalamus during lactation. 1600 21

In avian species, the ultimobranchial anlage is populated with neuronal cells derived from the distal vagal ganglion. We found that ultimobranchial C cells of chick embryos cultured in the presence of nicotinamide continued to grow for at least 60 days and exhibited profound morphological changes, resulting in the formation of dense networks of neuronal fibers. Nicotinamide, thus, facilitated the manifestation of neuronal features in C cells. The neuronal phenotypes of cultured C cells were analyzed in detail by both scanning and transmission electron microscopy. Their neural nature was also positively established by immunostaining with monoclonal antibodies to the neuronal markers neuron-specific class III beta-tubulin (TuJ1), microtubule-associated protein (MAP) 2, and synaptophysin. Confocal laser scanning microscopy confirmed that these neuron-specific proteins are colocalized with calcitonin in both the somata and the neuronal processes of C cells. Furthermore, reverse transcriptase-polymerase chain reaction analyses, performed at various times up to 30 days in culture, indicated that the C cells have persistent gene expression of calcitonin, the catecholamine-synthesizing enzyme tyrosine hydroxylase, proenkephalin, proopiomelanocortin, neuron-specific beta-tubulin (cbeta4), SCG10, and Bcl-2. The morphological responses of C cells to nicotinamide treatment were analyzed quantitatively over a period of 60 days. The area of C-cell colonies, number of processes per colony, and length of processes continued to increase until culture day 45. In conclusion, nicotinamide stimulates long-term survival and neuronal differentiation of chick embryo C cells, and this culture system may provide a useful model for studying neuronal differentiation mechanisms.
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PMID:Nicotinamide promotes long-term survival and extensive neurite outgrowth in ultimobranchial C cells cultured from chick embryos. 1621 94


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