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PubMed1998

The effect of phenylalanine on DOPA synthesis in PC12 cells.

DOPA synthesis from phenylalanine was studied in PC12 cells incubated with m-hydroxybenzylhydrazine, to inhibit aromatic L-amino acid decarboxylase. DOPA synthesis rose with increasing concentrations of either phenylalanine or tyrosine; maximal rates (approximately 55 pmol/min/mg protein for tyrosine; approximately 40 pmol/min/mg protein for phenylalanine) occurred at a medium concentration of approximately 10 microM for either amino acid. The Km for either amino acid was about 1 microM (medium concentration). At tyrosine concentrations above 30 microM, DOPA synthesis declined; inhibition was observed at higher concentrations for phenylalanine (> or =300 microM). These effects were most notable in the presence of 56 mM potassium. Measurements of intracellular phenylalanine and tyrosine suggested the Km for either amino acid is 20-30 microM; maximal synthesis occurred at 120-140 microM. In the presence of both phenylalanine and tyrosine, DOPA synthesis was inhibited by phenylalanine only at a high medium concentration (1000 microM), regardless of medium tyrosine concentration. The inhibition of DOPA synthesis by high medium tyrosine concentrations was antagonized by high medium phenylalanine concentrations (100, 1000 microM). Together, the findings indicate that for PC12 cells, phenylalanine can be a significant substrate for tyrosine hydroxylase, is a relatively weak inhibitor of the enzyme, and at high concentrations can antagonize substrate inhibition by tyrosine.

Animals↗
PubMed1984

Carbamazepine decreases catecholamine turnover in the rat brain.

The anticonvulsant carbamazepine (100 mg/kg i.p.) increased the levels of 3-methoxy-4-hydroxyphenylglycol sulfate in the rat brain as well as its accumulation after inhibition of acid transport by probenecid. It did not interfere with 3-methoxy-4-hydroxyphenylglycol sulfation in vivo. However, this was not corroborated by the results of turnover studies. The depletion of brain norepinephrine after inhibition of tyrosine hydroxylase or dopamine (DA) beta-hydroxylase rather tended to be decreased and the accumulation of DA in the rat heart after DA beta-hydroxylase inhibition was diminished. Carbamazepine also reduced the depletion of striatal DA after tyrosine hydroxylase inhibition and the accumulation of striatal dopa after central decarboxylase inhibition, but did not affect the levels of the deaminated DA metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid, even after pretreatment with probenecid. Therefore, carbamazepine seems to reduce catecholamine turnover in spite of its enhancing action on the firing of norepinephrine and DA neurons reported in the literature. These apparently paradoxical effects might be explained by an interference with the catecholamine storage mechanism. Two other anticonvulsants, diphenylhydantoin and phenobarbital, in doses approximately equieffective to that of carbamazepine with respect to their anticonvulsant action, showed similar although somewhat weaker effects on DA, but not on norepinephrine turnover. Within the catecholamine hypothesis of affective disorders, the reduction of catecholamine turnover by carbamazepine might explain the reported antimanic and antipsychotic effects in patients.

Animals↗
PubMed2005

The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD.

In the past decades, there have been numerous studies in the gene therapy for Parkinson's disease (PD), especially in delivering genes of enzymes for dopamine (DA) synthesis. Gene therapy in PD appears to be at the brink of the clinical study phase. However, there are many questions that need to be solved before this approach can be contemplated clinically, especially the question about the control of DA production because too much DA could cause toxicity. Until recently, few studies have investigated the relation between DA production and PD improvement and respective expressed human tyrosine hydroxylase (hTH), human GTP-cyclohydrolase 1 (hGCH1), and human aromatic acid decarboxylase (hAADC) in ex vivo gene therapy for PD. Now, we have developed a simple, fast, and reliable method to assay the activities of TH and AADC and have provided the possibility of ex vivo gene therapy for PD by genetically modifying cells with separate hTH, hGCH1, and hAADC genes. Using the method, we found though hTH, hGCH1, and hAADC genes were expressed, respectively, they could fulfil the function of DA synthesis by incubating together in vitro, and more DA was synthesized in vitro when hTH, hGCH1, and hAADC genes were expressed together rather than hTH and hAADC genes expressed or hTH expressed. The result suggests that we could easily control DA production in ex vivo gene therapy before transplantation. By combining this method and microdialysis, we also could further investigate the DA production in vitro and in vivo and then decide the optimal number and ratio of different transduced cells to improve the therapy of PD. Thus, the method has potential use in ex vivo gene therapy of PD.

Animals↗
PubMedDate not supplied

Coexistence of GAD-65 and GAD-67 with tyrosine hydroxylase and nitric oxide synthase in amacrine and interplexiform cells of the primate, Cebus apella.

The expression of glutamate decarboxylase forms, GAD-65 and GAD-67, in GABAergic cells was studied by immunocytochemistry in the retina of the New World monkey, Cebus apella. In the innermost rows of the inner nuclear layer (INL), somata that express GABA correspond to about 45% of the total number of cells in the central retina and about 25% on the periphery. Three subsets of GABAergic amacrine cells were identified along the horizontal meridian: about 5% express only GAD-65 and 40% GAD-67, and approximately 50% contain both forms of GAD. In the INL, GAD-65 immunoreactivity was detected in broad bands around strata 1, 3, and 5. GAD-67 immunoreactivity was observed throughout all strata. Somata that expressed GAD-67 exclusively stratified only in narrow bands around strata 2 and 4 of the INL and colocalized with beta2 and beta3 subunits of GABA-A receptor. Interplexiform and amacrine cells that express GABA also express tyrosine hydroxylase (TH) or nitric oxide synthase (NOS). GAD-67 colocalized with TH or NOS in presumed amacrine cells of the inner plexiform layer (IPL) and ganglion cell layer (GCL). GAD-65 was expressed in the TH- and NOS-immunoreactive interplexiform and amacrine cells, respectively. Different from what has been described in other mammals, TH and NOS were coexpressed in some neurons, indicating a partial overlap in retinal cell populations containing dopamine or nitric oxide in this primate.

Amacrine Cells↗
PubMed1983

The relation between spiperone binding, behavioural changes, and in vivo tyrosine hydroxylation in the rat striatum.

Spiperone 0.1-10 mg/kg i.p. increased the accumulation of Dopa in the rat striatum after Dopa decarboxylase inhibition. Approximately 50% of the rats treated with doses 1 mg/kg or higher showed cataleptic symptoms. Binding studies performed on the striatal tissues from these rats showed a dose-dependent lowering of the maximal binding of spiperone. The decrease in B max was significant at doses of spiperone 1 mg/kg or higher. Thus at 1 and 10 mg/kg, significant effects on binding, Dopa accumulation, and behaviour were found to coexist.

Animals↗
PubMed1989

Effects of prolactin on tyrosine hydroxylase activity of central dopaminergic neurons of male rats.

Previous work from our laboratory has indicated that ovine prolactin can produce a rapid stimulation (within 1 h) of dopamine release from nigrostriatal and mesolimbic dopaminergic neurons of male rats. In the present experiment we attempted to determine whether this effect of prolactin was a function of an increase in the activation of dopamine synthesis. To examine this possibility we used the drug NSD 1015. This drug is a decarboxylase inhibitor that leads to dopa accumulation and is used as an index of in vivo tyrosine hydroxylase activity. Our results demonstrated that ovine prolactin increased turnover of dopamine but had no effect upon tyrosine hydroxylase activation (up to 4 h) in both dorsal and ventral striatal dopaminergic neurons. In contrast, ovine prolacting had a clear effect (within 4 h) on tyrosine hydroxylase activity in mediobasal hypothalamic dopaminergic neurons. These results suggest that ovine prolactin can differentially alter synthesis/release processes of dopamine from these sites.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Evidence for histamine as a transmitter in rat carotid body sensor cells.

Carotid bodies harboring sensor cells for oxygen have a strategic location at the bifurcation of the carotid artery, which supplies the brain. Upon arterial hypoxia they transmit signals to the respiratory center, which increases the frequency of breathing. Dopamine is considered as the predominant transmitter of the rat carotid body sensor cells. Here we show that the rat carotid body sensor cells are the first cell type known to have the complete apparatus to synthesize, store and release both dopamine and histamine. The tyrosine hydroxylase positive dopaminergic sensor cells of juvenile rats express the histamine biosynthesis enzyme, histidine decarboxylase. Moreover, the sensor cells have not only vesicular monoamine transporter 1 (VMAT1) transporting catecholamines but also VMAT2, which is highly specific for histamine. Additionally, we found that these cells possess components of the neuroendocrine exocytosis apparatus, synaptosome-associated protein of 25 kDa (SNAP 25) and syntaxin1. The amount of histamine determined in the rat carotid body (164 pmol/carotid body) is more than 10-fold higher compared with that of dopamine. As a main effect, hypoxia significantly increased histamine release from isolated rat carotid bodies as it has been shown for dopamine. Finally, RT-PCR experiments indicate the presence of histamine receptors H1, H2 and H3 in the carotid body. Our data suggest that histamine is synthesized, stored and released upon hypoxia by dopaminergic sensor cells of the rat carotid body.

Animals↗
PubMed1987

Differential effect of functional olfactory deprivation on the GABAergic and catecholaminergic traits in the rat main olfactory bulb.

The effects of the unilateral olfactory naris closure were studied immunohistochemically in the main olfactory bulb of adult rats. In the olfactory deprived bulbs, the tyrosine hydroxylase-immunoreactive elements in the glomeruli and the juxtaglomerular region decreased drastically, whereas the glutamate decarboxylase-immunoreactive elements in these regions showed no appreciable changes, indicating the differential effects of olfactory deprivation on catecholaminergic and GABAergic traits in spite of their coexistence in some neurons in these regions.

Animals↗
PubMed1995

Stimulation of rat striatal tyrosine hydroxylase activity following intranigral administration of sigma receptor ligands.

The effects of sigma ligands on turning behavior and striatal tyrosine hydroxylase activity were determined following microinjection of two chemically dissimilar sigma ligands into the rat substantia nigra. Striatal tyrosine hydroxylase activity was monitored by measuring the amount of 3,4-dihydroxyphenylalanine (DOPA) formed following inhibition of DOPA decarboxylase activity with m-hydroxybenzylhydrazine (NSD-1015). The sigma ligands, 1,3-di-o-tolylguanidine (DTG) and (-)-deoxy-N-benzylnormetazocine, produced a significant increase both in contralateral turning and in tyrosine hydroxylase activity. The DTG-induced increase in tyrosine hydroxylase activity was not antagonized by intranigral injection of the NMDA receptor antagonist, 3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). CPP alone produced significant contralateral turning that was not accompanied by an increase in striatal tyrosine hydroxylase activity, indicating that turning per se is not sufficient to activate striatal tyrosine hydroxylase. The DTG-induced increase in tyrosine hydroxylase activity was antagonized by general anesthetics such as halothane and chloral hydrate. These results indicate that occupancy of sigma receptors in the substantia nigra is associated with an activation of dopamine formation in dopaminergic terminals in the striatum and support the concept that sigma activity in the substantia nigra produces an activation of dopamine-mediated responses in the striatum.

Animals↗
PubMed1985

1-Aminooxy-3-aminopropane, a new and potent inhibitor of polyamine biosynthesis that inhibits ornithine decarboxylase, adenosylmethionine decarboxylase and spermidine synthase.

1-Aminooxy-3-aminopropane was shown to be a potent competitive inhibitor (Ki = 3.2 nM) of homogenous mouse kidney ornithine decarboxylase, a potent irreversible inhibitor (Ki = 50 microM) of homogeneous liver adenosylmethionine decarboxylase and a potent competitive (Ki = 2.3 microM) of homogeneous bovine brain spermidine synthase. It did not inhibit homogeneous bovine brain spermine synthase and it did not serve as a substrate for spermidine synthase. The compound did not inhibit tyrosine aminotransferase, alanine aminotransferase or aspartate aminotransferase, which are pyridoxal phosphate-containing enzymes like ornithine decarboxylase. The inactivation of adenosylmethionine decarboxylase was partially prevented by pyruvate, which is the coenzyme of adenosylmethionine decarboxylase, and by the substrate, adenosylmethionine. 1-Aminooxy-3-aminopropane at 0.5 mM concentration inhibited the growth of HL-60 promyelocytic leukemia cells and this inhibition was prevented by spermidine but not by putrescine.

Adenosylmethionine Decarboxylase↗
PubMed1998

Involvement of protein tyrosine phosphorylation in the effect of green tea polyphenols on Ehrlich ascites tumor cells in vitro.

Green tea extract and its polyphenolic components have been found to possess anticarcinogenic, antimutagenic, antihypertensive and antihepatotoxic effects, and several mechanisms have been proposed for these effects. In this study, the effects of five tea polyphenols, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-) epicatechin-3-gallate (ECG), ( -) epicatechin (EC) and (+)-catechin (C), were examined on the viability of Ehrlich ascites tumor cells in vitro and a possible relationship with tyrosine phosphorylation was determined. Proteins extracted from the cells treated with the tea polyphenols were separated by SDS-PAGE, and tyrosine-phosphorylated proteins were detected by immunoblotting with anti-phosphotyrosine antibody and the extent of phosphorylation determined. EGC (100 microM) caused a significant decrease in cell viability to 4.1 +/- 0.2% of the control value, and this correlated with a stimulation of protein tyrosine kinase (PTK) activity. EGCG (100 microM) also caused a slight decrease in cell viability (approximately 70% of the control value) but this and the other polyphenols, which had no effect on cell viability likewise, had no effect on tyrosine phosphorylation. Tyrosine phosphorylations of 42 and 45 kDa proteins were also observed for EGC. Further evaluation of the effect of EGC showed that the activity of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis in cells, decreased significantly as well. A significant correlation has therefore been observed between a cellular event, namely, a reduction in the viability of Ehrlich ascites tumor cells and an association with a tyrosine phosphorylation of 42 and 45 kDa proteins by the polyphenol EGC.

Animals↗
PubMed1995

Aging. Increased responsiveness of colorectal mucosa to carcinogen stimulation and protective role of folic acid.

Recent investigations have demonstrated a protective role for folic acid in dysplasia and neoplasia, through an unknown mechanism. The current study was designed to evaluate whether the protective role of folic acid is due, in part, to its antiproliferative properties. In addition, because colorectal neoplasia is more common with increasing age, we have compared results in both old (22 months) and young (3 months) rats. Colorectal mucosal explants of rats treated with the known carcinogen methylazoxymethanol, were supplemented with folic acid. Ornithine decarboxylase was then measured as an index of cellular proliferative activity. We observed that supplemental folic acid suppressed carcinogen-induced ornithine decarboxylase activity by 64% in the old and 74% in the young rats. Furthermore, a similar phenomenon was observed for tyrosine kinase, which was measured for comparison. The suppression of hyperproliferative activity by supplemental folic acid may contribute to the protective effect of folic acid in colorectal neoplasia.

Aging↗
PubMed2006

Synthesis, protein levels, activity, and phosphorylation state of tyrosine hydroxylase in mesoaccumbens and nigrostriatal dopamine pathways of chronically food-restricted rats.

Chronic food restriction (FR) enhances the rewarding and motor-activating effects of abused drugs, and is accompanied by changes in dopamine (DA) dynamics and increased D-1 DA receptor-mediated cell signaling and transcriptional responses in nucleus accumbens (NAc). However, little is known about effects of FR on DA synthetic activity in the mesoaccumbens and nigrostriatal pathways. In Experiment 1 of the present study, tyrosine hydroxylase (TH) gene expression was measured in ventral tegmental area and substantia nigra, using real-time RT-PCR and in situ hybridization; no differences were observed between FR and ad libitum fed (AL) rats. In Experiment 2, TH protein levels, determined by Western blot, were found to be elevated in NAc and caudate-putamen (CPu) of FR relative to AL rats. In the absence of increased transcription, this may reflect a slowing of TH degradation. In Experiments 3 and 4, DA synthetic activity was assessed by Western blot measurement of TH phosphorylation at Ser40, and HPLC measurement of in vivo tyrosine hydroxylation rate, as reflected by DOPA accumulation following administration of a decarboxylase inhibitor (NSD-1015; 100 mg/kg, i.p.). Basal phospho-(Ser40)-TH levels did not differ between groups but DOPA accumulation was decreased by FR. Decreased DOPA synthesis, despite increased levels of TH protein, may reflect the inhibitory effect of increased DA binding to TH protein or decreased concentrations of cofactor tetrahydrobiopterin. Finally, in response to D-amphetamine (0.5 and 5.0 mg/kg, i.p.), phospho-(Ser40)-TH was selectively decreased in NAc of FR rats. This suggests increased feedback inhibition of DA synthesis-a possible consequence of postsynaptic receptor hypersensitivity, or increased extracellular DA concentration. These results indicate that FR increases TH protein levels, but may decrease the capacity for DA synthesis by decreasing TH activity. According to this scheme, the previously observed upregulation of striatal cell signaling and transcriptional responses to DA receptor agonist administration may include compensatory neuroadaptations.

Analysis of Variance↗
PubMed1986

Regulation of dopamine synthesis in the medial prefrontal cortex: studies in brain slices.

The rapid firing rates and small dopamine (DA) pools that characterize mesoprefrontal DA neurons make these cells more vulnerable to release-dependent changes in intraneuronal DA levels than nigrostriatal DA neurons. In vivo studies of mesoprefrontal DA synthesis are therefore complicated by the necessity to distinguish between effects of dopaminergic drugs on synthesis-modulating autoreceptors and effects resulting from increased end product inhibition of tyrosine hydroxylase (TH) secondary to decreased DA release. We have used brain slices, in which impulse flow-dependent release is apparently attenuated, to compare regulation of tyrosine hydroxylation in striatal and prefrontal nerve terminals. Accumulation of DOPA after decarboxylase inhibition was used as an index of TH activity. Nomifensine, a DA uptake blocker, inhibited DOPA synthesis in striatal but not prefrontal slices. This effect was reversed stereoselectively by sulpiride, suggesting it involved activation of DA receptors by elevated synaptic levels of DA. DOPA synthesis was stimulated in both brain regions by elevated K+; however, only striatal synthesis could be further enhanced by sulpiride. This enhancement was dose dependent, stereoselective and significantly attenuated by EMD 23 448, a putative autoreceptor-selective DA agonist that does not exert direct inhibitory effects on TH activity in vitro. EMD 23 448 had no effect on prefrontal slices at concentrations that produce greater than 50% inhibition of striatal DOPA synthesis. These findings suggest: released DA modulates TH activity in striatal slices via a receptor-mediated mechanism, independent of end product inhibitory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed2002

[Human striatal D-neurons and their significance].

It has recently been reported that the human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme), but not for tyrosine hydroxylase (TH; the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH; the first-step serotonin synthesizing enzyme). These AADC (+)/TH(-)/TPH(-) neurons are named D-neurons. AADC is also the rate-limiting synthesizing enzyme of phenylethylamine (PEA). Although the functions of striatal D-neurons are yet unclear, their functions were discussed in the present review based on recent findings in the literature. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors, including L-dopa or droxidopa (L-threo-DOPS), and by converting them to dopamine (DA) or noradrenaline (NA), respectively. Because the nucleus accumbens is one of the brain regions involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration. Further studies should be conducted to elucidate the functions of this unique cell group in the human striatum.

Animals↗
PubMed2004

Effect of acute antipsychotic administration on dopamine synthesis in rodents and human subjects using 6-[18F]-L-m-tyrosine.

Clinical effects of antipsychotic drugs are thought to be mediated primarily through antagonism of the dopamine D2 receptors. Recent studies have demonstrated increased aromatic decarboxylase activity following acute administration of dopamine D2 receptor antagonists both in vivo and ex vivo. However, this effect has never been demonstrated in human subjects. We studied the effect of acute antipsychotic administration on dopamine synthesis in rodents and healthy human subjects using 6-[18F]-L-m-tyrosine. In rats, we studied the effect of a single subcutaneous injection of haloperidol and risperidone on dopamine synthesis using 6-[18F]-L-m-tyrosine. In our human study, six healthy volunteers underwent two 6-[18F]-L-m-tyrosine PET scans, before and after 3 mg risperidone to measure the rate of accumulation of radioactivity in the striatum as an index of dopamine synthesis. The striatal/cerebellar radioactivity count ratio and the ratio of dopamine metabolites to dopamine concentration was significantly higher in all rodent treatment groups compared to controls. In the PET study we found no significant change in the rate of uptake in the striatum. Our results suggest that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect of antipsychotics on dopamine synthesis in human subjects.

Adult↗
PubMed1977

Age related changes in the effect of electroconvulsive shock (ECS) on the in vivo hydroxylation of tyrosine and tryptophan in rat brain.

A single electroconvulsive shock (ECS) was applied to 40 young (9 months) and 40 old (24 months) male rats. The effect on brain catecholamine synthesis was determined at intervals after ECS by measuring the accumulation of dihydroxyphenylalamine (DOPA) and 5-hydroxytryptophan (5-HTP) in rats pretreated with a central decarboxylase inhibitor (M-hydroxybenzyl hydrazine, NSD 1015). This accumulation permitted an estimation of the in vivo rates of hydroxylation of tyrosine and tryptophan. Control brain DOPA and 5-HTP concentrations were both lower in the older animals. Following ECS there was an increase in brain DOPA concentration (maximal at 60 min after ECS) in both young and old rats, but the increase was much smaller in the older animals. There were no changes in brain 5-HTP at any time after ECS, in either age group. It appears that aging selectively affects the response of the brain dopaminergic neurotransmitter system to stress, and we suggest that this may be a factor in the decreased resistance to stress in older subjects.

5-Hydroxytryptophan↗