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)

Circadian variations in the activity of tyrosine hydroxylase, tyrosine aminotransferase, and tryptophan hydroxylase were observed in the rat brain stem. Tyrosine hydroxylase exhibited a bimodal pattern with peaks occurring during both the light and dark phases of the circadian cycle. Tyrosine aminotransferase had one daily peak of activity occurring late in the light phase, whereas tryptophan hydroxylase activity was maximal late in the dark phase. Circadian fluctuations in tyrosine hydroxylase activity did not correlate well with circadian variations in the turnover rates of norepinephrine or dopamine nor with levels of these catecholamines. This supports the idea that although tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of catecholamines, other factors must also be involved in the in vivo regulation of this process. Administration of alpha-methyl-p-tyrosine (AMT) methyl ester HCl (100 mg/kg) had no effect on the activity of tryptophan hydroxylase, but effectively eliminated the peak of tyrosine hydroxylase activity that occurred during the light phase. AMT also lowered levels of tyrosine aminotransferase, but only at times near the daily light to dark transition. These chronotypic effects of AMT emphasize the importance of "time of day" as a factor that must be taken into account in evaluating the biochemical as well as the pharmacological and toxicological effects of drugs.
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PMID:Circadian variations in the activity of tyrosine hydroxylase, tyrosine aminotransferase, and tryptophan hydroxylase: relationship to catecholamine metabolism. 611 1

Treatment of rats with L-DOPA (251.25 mg as the methyl ester HCl/kg) plus benserazide (B, 50 mg/kg) (L-DOPA+B), twice daily (i.p.) for 5 days or 12 days resulted in the dopamine (DA) neurons of the substantia nigra pars compacta becoming subsensitive to the rate-depressing effects of D-amphetamine (i.v.) 16 to 24 h after the last chronic drug dose. In contrast, pretreated rats were significantly less sensitive than control rats to the rate depressant effects of apomorphine (i.v.) after 12, but not 5 days of L-DOPA+B-pretreatment. After 5, but not 12 days of L-DOPA+B-pretreatment, a significant increase in the number of spontaneously active DA neurons was noted in the substantia nigra pars compacta. Caudate tyrosine hydroxylase was examined and a significant increase in apparent Vmax was noted after 5 days of L-DOPA+B, with no apparent change being noted in Km for cofactor. At this time, no change was noted in caudate DA or HVA concentrations. Several distinct processes may be occurring in response to the L-DOPA+B-pretreatment: (1) the DA autoreceptors located on cell bodies in the substantia nigra have become subsensitive after 12 days of L-DOPA+B-pretreatment; (2) the subsensitivity to D-amphetamine seen after both chronic schedules is probably unrelated to the subsensitive DA autoreceptors and may depend upon homeostatic alterations in neurotransmitter systems other than those utilising DA; (3) the activation of tyrosine hydroxylase may be a reflection of the increase in the number of spontaneously active units.
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PMID:Chronic L-DOPA-pretreatment of rats: an electrophysiological and biochemical study in the basal ganglia. 612 29

A coordinated series of immunohistochemical and biochemical analyses have been conducted in the hamster to examine the dependence of substance P and tyrosine hydroxylase (TH) expression by second-order olfactory neurons, and the level of dopamine in the main olfactory bulb (MOB), on the integrity of carnosine- and olfactory marker protein (OMP)-containing primary afferent neurons. Substance P-like immunoreactivity (SPLI) is localized in external tufted cells and centrifugal afferents of the MOB; TH immunoreactivity has a wider distribution, in external tufted, middle tufted, periglomerular, and deep short-axon cells as well as in centrifugal afferents. To characterize the SPLI, this material was isolated by guanidine-HCl extraction and passage over a C18 SEP-PAK. The SPLI coelutes on HPLC with authentic substance P and, following oxidation, coelutes with substance P sulfoxide. It is sensitive to alpha-chymotrypsin and is resistant to trypsin. Thus, the SPLI in the MOB behaves as authentic substance P. Intranasal irrigation with 0.17 M ZnSO4 results in peripheral deafferentiation of the MOB for up to 8 months as evidenced by a persistent loss of OMP immunoreactivity and shrinkage of the olfactory nerve layer and glomeruli. By these criteria, the vomeronasal inputs to the accessory olfactory bulb are not destroyed and the spared vomeronasal receptor neurons do not innervate the vacated peripheral projection field in the MOB. The loss of peripheral inputs to the MOB is accompanied by marked and parallel reductions in the incidences of SPLI- and TH-positive second-order neurons despite an increase in the density of neuronal somata in the glomerular layer. Biochemical quantifications following peripheral deafferentation also demonstrate significant decreases of both substance P and dopamine, together with the expected decrease of carnosine. In contrast, the SPLI and the TH and serotoninlike immunoreactivities in centrifugal afferents as well as the TH immunoreactivity in deep interneurons do not appear to be reduced, and the MOB content of norepinephrine in centrifugal afferents is unaffected. These results collectively indicate that the loss of inputs from the primary olfactory receptor neurons can reduce the levels of at least two different, putatively neuroactive compounds (substance P and dopamine) in at least three classes of second-order neurons (external tufted, middle tufted, and periglomerular cells). The control of central neuron phenotype by the peripheral olfactory neurons thus appears to be a phenomenon of broad influence. It may play a role in processing chemosensory information as well as offering a system in which to study neuronal plasticit
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PMID:Substance P and catecholaminergic expression in neurons of the hamster main olfactory bulb. 619 81

Dopa was isolated from rat brain by cation exchange chromatography and determined by a radioenzymatic method using catechol-O-methyl-transferase and [3H]-S-adenosyl-methionine as cofactor. The product [3H]-methoxytyrosine was purified by cation and anion exchange chromatography. For identification of presumed endogenous dopa isolated from rat brain and rat blood plasma the [3H]-labelled product was purified further by thin-layer chromatography. In the brain of rats killed by decapitation, dopa in a concentration of 7 ng/g was identified. When unstressed rats were killed by focussed microwave irradiation at 2.450 MHz and 8 kW for 1.3 s dopa levels as high as 20 ng/g were measured. The regional distribution of dopa in brain or rats killed by microwaves was similar to the distribution of catecholamines, dopa levels being highest in c. striatum and lowest in cerebellum. Inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine methylester HCl, 250 mg/kg i.p. 90 min before death did not change the brain dopa levels in rats killed by decapitation or in rats killed by microwaves. Compounds, such as haloperidol, chlorpromazine, apomorphine and pentobarbital which are known to increase or decrease catecholamine synthesis did not change the basal level of dopa. The data indicate that in rat brain, the main portion of dopa is associated with catecholamine-containing nerve terminals and that this portion is present in a pool which is only slowly metabolized. A second very small pool of dopa must exist, which is serving as precursor pool for catecholamines and which is turned over at a higher rate. It can be concluded that the basal dopa level cannot be used as an indicator of catecholamine synthesis.
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PMID:Endogenous dopa in rat brain. Occurrence, distribution and relationship to changes i catecholamine synthesis. 679 Oct 35

Nitrous oxide increases locomotor activity in mice. Other locomotor stimulants are thought to act via central dopaminergic mechanisms and can be divided into two groups as determined by their antagonism by tyrosine hydroxylase inhibitors or by reserpine pretreatment. The purpose of the present study was to determine if nitrous oxide fits one or the other of the groups. Mice were acclimatized for 1 h to exposure chambers (4 L filtration flasks), in air, delivered at 4 L min-1 and then exposed to N2O:O2 (50:50), also delivered at 4 L min-1. Locomotor activity was evaluated at 10 min intervals throughout the experiment. Racemic alpha-methyltyrosine methyl ester HCl (200 mg kg-1), administered at the beginning of acclimatization, almost totally eliminated the nitrous oxide effect but not that of methylphenidate HCl (20 mg kg-1). Reserpine pretreatment (5 mg kg-1, 18 h) totally eliminated the nitrous oxide effect but not that of amphetamine (5 mg kg-1). The results suggest that nitrous oxide requires both the newly synthesized and the main storage pools of dopamine and do not allow assignment of the agent, specifically, to either of the groups.
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PMID:Locomotor effects of nitrous oxide in mice: requirement of newly-synthesized and main intraneuronal storage pools of dopamine. 809 74

Functional effects of prenatal cocaine exposure may be mediated in part by changes in catecholaminergic development. The present study examined whether cocaine administration influenced fetal brain activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. Subcutaneous (s.c.) injection of pregnant rats with 40 mg/kg of cocaine HCl daily from gestational day (GD) 8 to GD20 resulted in an 8.7% stimulation of fetal whole-brain TH activity compared to controls. We then switched to a s.c. implantation procedure involving Silastic capsules filled with 80 mg of cocaine base dissolved in polyethylene glycol (PEG). Implantation of 2 such capsules on GD18 produced a 28% increase in fetal TH activity measured only 3 days later on GD21. Subsequent experiments demonstrated that GD14 implantation was equally effective in stimulating fetal TH activity on GD17, but that the enzyme was unaffected in the brains of the treated dams. When cocaine-containing capsules were implanted on GD18, removed on GD21, and the females were allowed to deliver normally, offspring TH activity was still elevated on postnatal day 10 but not later. Finally, the presence of cocaine implants from GD18 to GD21 had no influence on fetal brain neurotransmitter and metabolite concentrations, however, the treated dams exhibited significant reductions in dopamine (DA) and the serotonin metabolite, 5-hydroxyindoleacetic acid. We conclude that maternal cocaine implants rapidly but transiently stimulate TH activity in the fetal brain, and that such stimulation prevented the DA depletion observed in the dams.
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PMID:Prenatal cocaine administration stimulates fetal brain tyrosine hydroxylase activity. 809 47

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson's disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease. Recently, we reported that nimodipine, a blocker of L-type calcium channels, prevents dopaminergic MPTP-induced neurotoxicity in C57B1/6 black mice. The present study extended these rodent findings to the non-human primate model of Parkinson's disease and assessed the effects of nimodipine, continuously applied by pellet for 18 days, on behavioural, biochemical and histological parameters, following systemic application of MPTP in common marmosets (Callithrix jacchus). The experimental design involved five groups of common marmosets and a total of 24 animals. Monkeys assigned to group I (n = 4) received subcutaneously implanted vehicle pellets 7 days prior to subcutaneous saline injections (control). Monkeys of group II (n = 4) were treated with nimodipine pellets (80 mg) and saline injections. Marmosets in group III (n = 8) were treated with vehicle pellets and received 4 times MPTP (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 h for a total of 4 days). Monkeys in group IV (n = 4) and V (n = 4) were treated as group-III animals except for the implantation of nimodipine pellets (80 mg and 120 mg, respectively) 7 days prior to toxin exposure. In common marmosets MPTP induced severe parkinsonian symptoms, a pronounced dopamine depletion in the caudate-putamen (more than 99% of control) and a loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (50% percent of control) 7 days after MPTP-administration. Pretreatment with nimodipine (120 mg pellets) did neither attenuate the behavioural impairments in MPTP-treated animals nor antagonize the striatal neurotoxin-induced dopamine depletion, but almost completely prevented (in a dose-dependent manner) the MPTP-induced decrease of nigral tyrosine hydroxylase immunoreactive cells. These data suggest that application of nimodipine, during the observation period of 7 days, protects against MPTP-induced neurotoxicity in common marmosets at the cellular nigral level, but not at the synaptic striatal level, implicating differential mechanisms of actions of MPTP-induced neurotoxicity at the nigral versus the striatal level.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level. 900 22

The effects of Selegiline hydrochloride (Selegiline HCl) on the intracellular Ca2+ contents of primarily cultured rat striatal, mesencephalic neuronal cells and PC-12 cells were examined by the use of a Ca2+ imaging analyzer. In the former two cell types, Selegiline HCl (10(-5)-10(-6) M) induced a transient inflow of extracellular Ca2+ through the voltage-dependent N-type Ca2+ channel. In addition, all cells indicating an increase in the intracellular Ca2+ content were found to be catecholaminergic neurons which showed a positive reaction with anti-tyrosine hydroxylase antibodies. Furthermore, a transient intracellular influx of Ca2+ was observed in the NGF-pretreated PC-12 cells. From these results, it is suggested that Selegiline HCl elicits various functions, including antioxidation, activation of neurotrophic factor biosynthesis and neuronal protection probably via an unidentified specific proteins of tyrosine hydroxylase-positive neurons.
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PMID:[Effects of selegiline hydrochloride on intracellular Ca2+ contents in cultured neuronal cells]. 998 54

The dynamics of the levels and metabolism of dopamine, norepinephrine, and serotonin were studied in pituitaries of male and female rainbow trout at different stages of gonadal development. In female rainbow trout, the turnover of dopamine (calculated using the inhibitor of tyrosine hydroxylase alpha-methyl-p-tyrosine methyl-ester HCl), serotonin metabolism, and norepinephrine levels decreased in the advanced stage of exogenous vitellogenesis with respect to the initial stage. However, data obtained in males did not show changes in either serotonergic or noradrenergic metabolism during the last stages of gonadal development. However, an increase of dopaminergic turnover was noticed in the male fish at the end of spermiation. Finally, pituitary dopaminergic activity was significantly higher in immature (prepubescent stage) than in adult fish.
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PMID:Changes in the pituitary metabolism of monoamines (dopamine, norepinephrine, and serotonin) in female and male rainbow trout (Oncorhynchus mykiss) during gonadal recrudescence. 1022 29

To investigate the impact of strain and sex in the l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson's disease, C57BL/6 and BALB/c mice were treated with either systemic MPTP-HCl (4 x 15 mg/kg) or saline and were examined in a number of behavioral tests. Furthermore, neostriatal and ventral striatal monoamine contents were determined, and the numbers of tyrosine hydroxylase-immunostained cells were counted in the substantia nigra and ventral tegmental area. Open-field testing showed that locomotor activity was drastically reduced as an acute effect of MPTP in both strains; however, subsequent recovery to control levels was faster in BALB/c mice than in C57BL/6. Nest building also indicated strain-dependent effects, since it was delayed only in C57BL/6 mice treated with MPTP. The other tests (grip test, pole test, rotarod, elevated plus-maze), although partly sensitive for over-all strain or gender differences, turned out not to be useful to compare MPTP effects in these two strains. Neurochemically, MPTP led to more severe neostriatal dopamine depletions in C57BL/6 (-85%) than in BALB/c mice (-58%). Histologically, a loss of tyrosine hydroxylase immunoreactivity (-25%) was observed only in the substantia nigra of C57BL/6 animals. Thus, our analysis consistently showed that the C57BL/6 mouse strain is more susceptible to MPTP than the BALB/c strain. Sex differences in MPTP sensitivity were not observed in our mice. The implications of these findings for the search for genes related to susceptibility to neurodegeneration are discussed.
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PMID:MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. 1110 91


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