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)

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) reuptake inhibitor fluoxetine, the selective alpha 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70-150% in the locus coeruleus after 2 weeks of drug and by 71-115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30-48% in the paraventricular nucleus of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. 135 83

We ascertained 8 multigenerational pedigrees afflicted with multiple cases of bipolar and recurrent major depressive disorder. Alterations in dopaminergic and noradrenergic neurotransmission have been implicated in the pathogenesis of this disease, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of these two catecholamines. As TH mutations could underlie susceptibility to manic-depression, we carried out a linkage analysis between this disease in 8 families and two RFLP probes that map to the TH gene region on the short arm of chromosome 11. Evidence of linkage was not found in 7 of 8 kindreds.
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PMID:Tyrosine hydroxylase gene not linked to manic-depression in seven of eight pedigrees. 135 73

Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression.
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PMID:Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. 167 67

Electroconvulsive shock (ECS) is a highly effective therapy for the treatment of major depression, but its mechanisms of action are not known. We report that repeated ECS in rats produces enduring changes in two clinically relevant stress-responsive brain systems: (a) the hypothalamic-pituitary-adrenal axis regulated by corticotropin-releasing hormone (CRH) in the paraventricular nucleus; and (b) the NE system in the locus coeruleus regulated by tyrosine hydroxylase (TH). CRH and TH mRNA levels in these brain regions were assessed by in situ hybridization histochemistry. A single interaural ECS elevated TH but not CRH mRNA measured 24 h later. Repeated daily treatments (3, 7, or 14) elevated both mRNAs, maximally with 7, correlating with the time course of clinical efficacy. The elevations persisted for 3 (CRH) or 8 wk (TH) after the ECS. No other therapeutic treatment is known to produce such long-lasting changes in central nervous system gene expression. The time course of events (delayed onset, long duration) implicate CRH as a principal mediator of the antidepressant effects of ECS. The locus coeruleus-NE system may be important in initiating the central nervous system response.
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PMID:Repeated electroconvulsive shock produces long-lasting increases in messenger RNA expression of corticotropin-releasing hormone and tyrosine hydroxylase in rat brain. Therapeutic implications. 791 18

A variety of biologic studies have demonstrated abnormal regulation of the norepinephrine (NE) system in patients with major depression, suggesting a role for NE in the etiology of depression. Brain NE and dopamine levels can be rapidly reduced by blocking synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). In the current investigation, AMPT was administered to drug-free depressed patients to evaluate the effect on mood of diminished catecholamine levels. Seventeen drug-free patients meeting DSM-III-R criteria for major depressive episode were tested with AMPT and an active placebo control, diphenhydramine. Testing was accomplished in a double-blind, crossover fashion, with random assignment to test conditions. Each test included baseline evaluation, 2 days with administration of either AMPT or diphenhydramine, and a follow-up day. Diphenhydramine was used as an active control because of the significant sedation associated with AMPT. Behavioral ratings, including visual analogue scales for a variety of feeling states, the Hamilton Depression Rating Scale (HDRS), and plasma for 3-methoxy-4-hydroxyphenelethyleneglycol (MPHG) and homovanillic acid (HVA) levels, were obtained. AMPT significantly reduced plasma HVA by 70% and MHPG by 50%, but it had no significant effects on the HDRS. AMPT also significantly increased visual analogue ratings of "tired" and decreased ratings of "energetic." Diphenhydramine significantly decreased HDRS scores, but the change was small and was not clinically apparent. The lack of AMPT effects on depressed mood, in conjunction with a prior report that large reductions in plasma tryptophan do not systematically alter depressed mood, indicate that monoamine deficiency by itself is insufficient explanation of the cause of depression. The role of the noradrenergic system needs to be considered in relationship to the many other neurobiologic factors that could be involved in the pathophysiology of depression.
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PMID:Effects of alpha-methyl-para-tyrosine (AMPT) in drug-free depressed patients. 886 98

We selected 83 patients with bipolar disorder type I or unipolar recurrent major depression and 71 healthy controls for genetic analysis of the tyrosine hydroxylase and the dopamine D4 receptor gene. No significant association was found between bipolar disorder type I and unipolar recurrent major depression and the polymorphisms located near these genes. Therefore, the hypothesis that the tyrosine hydroxylase and the dopamine D4 receptor genes may be involved in the etiology of bipolar disorder and unipolar recurrent major depression is not supported in our study.
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PMID:Analysis of the tyrosine hydroxylase and dopamine D4 receptor genes in a Croatian sample of bipolar I and unipolar patients. 912 19

A tetranucleotide repeat polymorphism in the first intron of the tyrosine hydroxylase (TH) locus was examined in a group of 118 adult suicide attempters and 78 control subjects. The suicide attempters were diagnosed according to DSM-III-R criteria at the index attempt and represented the following diagnoses: major depression (18), dysthymia (13), anxiety disorders (16), adjustment disorders (29), psychoactive substance abuse disorders (27) and psychotic disorders (15). A significant variation in the prevalence of carriers of the TH-K3 allele (high for suicide attempters with adjustment disorders, P = 0.0023) and a tendency toward a variation of the TH-K1 allele (low among all suicide attempters, P = 0.046) was observed. In light of other data the variation of TH-K1 and TH-K3 suggests that these alleles may reflect predisposition for a common phenotype with altered vulnerability for psychiatric disorders.
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PMID:Tyrosine hydroxylase allelic distribution in suicide attempters. 933 98

The present study was conducted to determine the effects of REM sleep deprivation on the levels of tyrosine hydroxylase (TH) and norepinephrine transporter (NET) mRNA in the locus coeruleus (LC) of rats. The animals were deprived of REM sleep for 1, 3 or 5 days, then killed and changes in the mRNA levels were determined using in situ hybridization. The levels of both TH and NET mRNA increased in animals deprived of REM sleep for 3 days or longer whereas no change in these messages were observed in the LC of control animals. REM sleep deprivation has been used as a mode of treatment for major depression. Others have shown that treatment with tricyclic antidepressants also results in increased levels of TH and NET mRNA in LC. Our results suggest that the antidepressant effect of REM sleep deprivation and tricyclic antidepressants may share similar molecular changes in the norepinephrine system.
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PMID:REM sleep deprivation increases the levels of tyrosine hydroxylase and norepinephrine transporter mRNA in the locus coeruleus. 967 21

An abnormal expression of noradrenergic proteins (e.g., tyrosine hydroxylase, norepinephrine transporters) in the locus coeruleus has recently been demonstrated in subjects with major depression and/or victims of suicide. Monoamine oxidase A (MAO-A) is a key enzyme in the catabolism of biogenic amines and is expressed in brain noradrenergic neurons. In this study, the binding of [3H]Ro41-1049 to MAO-A was measured by quantitative autoradiography at multiple levels along the rostral-caudal axis of the noradrenergic locus coeruleus from subjects with major depression and age- and postmortem interval-matched control subjects who were psychiatrically normal. [3H]Ro41-1049 binding to MAO-A was unevenly distributed along the axis of the locus coeruleus, paralleling an uneven number of neuromelanin-containing (noradrenergic) neurons throughout the nucleus. Accordingly, there was a significant correlation between the number of neuromelanin-containing neurons per section and the specific binding of [3H]Ro41-1049 at any particular level of the locus coeruleus in control subjects (r(2)=0.25; p<0.001) and in subjects with major depression (r(2)=0.14; p<0. 001). Moderate levels of [3H]Ro41-1049 binding were observed in regions surrounding the locus coeruleus, including the central gray and the dorsal and median raphe nuclei. No significant differences in [3H]Ro41-1049 binding to MAO-A were observed at any level of the locus coeruleus, or raphe nuclei, comparing subjects with major depression to psychiatrically normal control subjects. These findings demonstrate that the pathophysiology of major depression is not likely to involve abnormalities in MAO-A.
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PMID:Quantitative distribution of monoamine oxidase A in brainstem monoamine nuclei is normal in major depression. 1056 37

The hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic and/or extrahypothalamic regions is believed to contribute to the pathophysiology of major depression in an experimental animal chronically exposed to stress. In the present study, we examined the effects of chronic variable stress (CVS) and novel stress (footshock) on the CRH immunoreactivity in the hypothalamic paraventricular nucleus (PVN) and subdivision of PVN, and the extrahypothalamic bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA). We observed a significant reduction in CRH levels in the whole PVN, lateral parvocellular part of PVN, BNST and CeA 24 hours after the last stressor of CVS for 13 days. A novel stressor after CVS caused a marked increase in CRH levels in these four regions, followed a further reduction observed 24 hours later. Since the CVS-induced modulation of CRH levels are consistent with an alteration of tyrosine hydroxylase levels in the locus coeruleus, CRH-norepinephrine (NE) interaction in the terminal projection of forebrain NE systems, PVN, BNST and CeA where NE stimulates CRII release, might contribute to the bi-directional change in CRH. The CVS-induced bi-directional changes in CRH of PVN, BNST and CeA might play a role in the formation of the pathophysiology of major depressive disorders.
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PMID:[Reduction and sensitization of CRH neuron in rat hypothalamic and extrahypothalamic regions after chronic variable stress]. 1269 Jun 38


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