Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The neurotoxic effect of glutamate in cultured mouse mesencephalic dopaminergic neurons was investigated. Neuron-rich cell cultures were prepared from 13-14-day-old fetal mouse ventral mesencephalic tissue. Cultures were exposed to glutamate for 10 min and evaluated for glutamate neurotoxicity (GNT) 18-24 hr later by tyrosine hydroxylase (TH) immunostaining, microtubule associated protein-2 (MAP2) immunostaining, and radiolabeled dopamine uptake assay. In glutamate-exposed cultures, the number of TH-positive neurons and the level of dopamine uptake were reduced to 40% (35-45%) and 50% (47-52%), respectively, of control cultures. The number of MAP2-positive neurons was also reduced to 47%, indicating that the GNT was not restricted or selective to dopaminergic neurons. It is concluded that GNT was mediated by the N-methyl-D-aspartic acid (NMDA) receptor from the following observations: 1) GNT was completely blocked by MK-801, an NMDA receptor antagonist; 2) NMDA itself was as toxic as glutamate; 3) 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptor, did not block GNT; 4) kainate did not show neurotoxicity at a low concentration; and 5) two modulators of the NMDA receptor, 7-chlorokynurenic acid and magnesium, were effective in blocking GNT. Protective effects of phorbol myristate acetate, a tumor promoter, and gangliosides (GM1 and GT1b) on GNT were also demonstrated. Possible interactions between GNT and several protein kinase cascades were also investigated. Forskolin, an activator of adenyl cyclase and protein kinase A, showed some protective effect on GNT. But okadaic acid, an inhibitor of phosphatases, and genistein, a tyrosine kinase inhibitor, did not show any protective effect. These results suggest that 1) glutamate is capable of causing neuronal death in the substantia nigra; 2) GNT on dopaminergic neurons is mainly mediated by the NMDA receptor under the conditions of our study; 3) protein kinase C translocation is a key mechanism of GNT; and 4) there is an interplay of a signal transduction system in the pathomechanism of GNT.
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PMID:Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture. 790 39

In previous studies, we have demonstrated that chronic administration of morphine or cocaine produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing actions of these and other drugs of abuse. Since this neural pathway is also implicated in the reinforcing actions of ethanol, it was of interest to determine whether chronic ethanol exposure results in similar biochemical adaptations. Indeed, as seen for chronic morphine and cocaine treatments, we show here that chronic ethanol treatment increased levels of tyrosine hydroxylase and glial fibrillary acidic protein immunoreactivity, and decreases levels of neurofilament protein immunoreactivity, in the VTA. Also like morphine and cocaine, ethanol increases levels of cyclic AMP-dependent protein kinase activity in the NAc. These actions of ethanol required long-term exposure to the drug, and were in most cases not seen in the substantia nigra or caudateputamen, components of the nigrostriatal dopamine system studied for comparison. Altered levels of tyrosine hydroxylase in catecholaminergic cells frequently reflect altered states of activation of the cells. Moreover, increasing evidence indicates that ethanol produces many of its acute effects on the brain by regulating NMDA glutamate and GABAA receptors. We therefore examined the influence of chronic ethanol treatment on levels of expression of specific glutamate and GABA receptor subunits in the VTA. It was found that long-term, but not short-term, ethanol exposure increased levels of immunoreactivity of the NMDAR1 subunit, an obligatory component of NMDA glutamate receptors, and of the GluR1 subunit, a component of many AMPA glutamate receptors; but at the same time, long-term ethanol exposure decreased immunoreactivity levels of the alpha 1 subunit of the GABAA receptor complex. These changes are consistent with an increased state of activation of VTA neurons inferred from the observed increase in tyrosine hydroxylase (TH) expression. These results demonstrate that chronic ethanol exposure results in several biochemical adaptations in the mesolimbic dopamine system, which may underlie prominent changes in the structural and functional properties of this neural pathway related to alcohol abuse and alcoholism.
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PMID:Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. 886 59

Excitotoxins are valuable tools in neuroscience research as they can help us to discover the extent to which certain neurones are necessary for different types of behaviour. They have distinctive neurotoxic effects depending on where they are infused, and this study was conducted to delineate the neurotoxic profiles of excitotoxins in the laterodorsal tegmental nucleus (LDTg). Two 0.1 microl infusions of 0.1 M ibotenate, 0.1 M quinolinate, 0.04-0.1 M NMDA, or 0.05-0.015 M AMPA, were made unilaterally into the LDTg under either pentobarbitone or Avertin anaesthesia. The injection needle was oriented at an angle of 24 degrees from vertical in the mediolateral plane. After 23-27 days, sections through the mesopontine tegmentum were processed using standard histological procedures for NADPH-diaphorase histochemistry, tyrosine hydroxylase or 5-hydroxytryptamine immunohistochemistry, and Cresyl violet. Lesions were assessed in terms of the size of the damaged area (identified by reactive gliosis), the extent of cholinergic cell loss in the mesopontine tegmentum (by counting NADPH-diaphorase-positive neurones), and neuronal loss induced in the locus coeruleus and dorsal raphe nucleus. Ibotenate induced compact lesions in the LDTg (more than 80% cholinergic loss) and did little damage to the locus coeruleus and dorsal raphe nucleus. Quinolinate and low doses of AMPA and NMDA made very small lesions with less than 35% cholinergic loss, while at higher doses, AMPA and NMDA induced large areas of reactive gliosis but killed only a proportion of the cholinergic neurones. AMPA appeared to have a particular affinity for noradrenergic neurones in the locus coeruleus, with the 0.015 M dose injected into the LDTg typically destroying the majority of these neurones. The results are discussed in the context of what is known about the mechanisms of excitotoxins and the glutamate receptor profile of mesopontine neurones.
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PMID:Discriminable excitotoxic effects of ibotenic acid, AMPA, NMDA and quinolinic acid in the rat laterodorsal tegmental nucleus. 916 37

Glutamate-mediated excitotoxicity plays an important role in the degeneration of nigrostriatal dopamine (DA) neurons induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), although the role of the N-methyl D-aspartate (NMDA) receptor subtype in this process is still uncertain. We studied glutamate receptor subtype agonist-induced ionic currents in acutely dissociated DAergic neurons from the rat substantia nigra zona compacta (SNc) using the nystatin-perforated patch-clamp whole-cell recording technique. The results fall into four main categories. First, single neurons, freshly isolated from SNc, exhibited a large soma and multipolar morphology, responded to DA, and stained positively for tyrosine hydroxylase (TH). Second, rapid application of L-glutamate (> 10(-5) M) induced an inward current with minimal desensitization at a clamp voltage of -60 mV. Third, kainic acid (KA) or alpha-amino-3-hydroxy-5-methyl-isoxazole (AMPA) induced an inward current that was similar to the glutamate-induced current while, in the same neuron, NMDA (10(-4) M) failed to induce any current response in Mg2+-free solution that contained 10(-5) M glycine at a clamp voltage of -60 mV. Under the same experimental conditions, NMDA induced a clear current response in isolated substantia nigra reticulata (SNr) neurons. Fourth, the specific NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV, 10(-4) M) failed to block 10(-4) M glutamate-induced inward current, while the specific KA/AMPA receptor antagonist 6-cyano-7-nitroguinoxaline-2, 3-dione (CNQX, 10(-5) M) completely blocked the glutamate-induced current. These results indicate that in single SNc DAergic neurons of 2-week-old rats, L-glutamate-induced inward current is mediated by non-NMDA receptors rather than by NMDA receptors.
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PMID:Dissociated dopaminergic neurons from substantia nigra zona compacta in young rats lack functional NMDA receptors. 947 23

Altered glutamatergic neurotransmission appears to be central to the pathophysiology of Parkinson's disease; consequently, considerable effort has been made to elucidate neuroprotective mechanisms against such toxicity. In the present study, the possible neuroprotective effect of glutamate receptor antagonists against MPP+ neurotoxicity on dopaminergic terminals of rat striatum was investigated. Different doses of glutamate receptor antagonists were coinfused with 1.5 microg of MPP+ into the striatum; kynurenic acid, a nonselective antagonist of glutamate receptors (30 and 60 nmol), partially protected dopaminergic terminal degeneration in terms of rescue of dopamine levels and tyrosine hydroxylase immunohistochemistry. Dizocilpine, a channel blocker of the NMDA receptor (1, 4, and 8 nmol), and 7-chlorokynurenic acid, a selective antagonist at the glycine site of the NMDA receptor (1 and 10 nmol), failed to protect dopaminergic terminals from MPP+ toxicity. However, 6-cyano-7-nitroquinoxaline-2,3-dione (0.5 and 1 nmol) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (1 nmol), two AMPA-kainate receptor antagonists, protected against MPP toxicity. Our findings suggest that the toxic effects of MPP+ on dopaminergic terminals are not mediated through a direct interaction with the NMDA subtype of glutamate receptor, but with the AMPA-kainate subtype.
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PMID:The non-NMDA glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline, but not NMDA antagonists, block the intrastriatal neurotoxic effect of MPP+. 1042 73

Dopamine can change the membrane potential, regulate cyclic nucleotides, and modulate transmitter release in central neurons. In the olfactory bulb (OB), the dopamine synthetic enzyme, tyrosine hydroxylase, is largely confined to neurons in the glomerular layer. After demonstrating dopamine D2 receptors in the glomerular and olfactory nerve (ON) layers, Nickell et al. [W.T. Nickell, A.B. Norman, L.M. Wyatt, M.T. Shipley, Olfactory bulb DA receptors may be located on terminals of the olfactory nerve, NeuroReport, 2 (1991) 9-12.] proposed that these receptors may reduce transmitter release due to their localization to ON presynaptic boutons. We have previously demonstrated that olfactory receptor neurons use glutamate to excite OB neurons through activation of glutamate receptors subtypes, NMDA and AMPA/kainate [D.A. Berkowicz, P.Q. Trombley, G.M. Shepherd, Evidence for glutamate as the olfactory receptor cell neurotransmitter. J. Neurophysiol., 71 (1994) 2557-2561]. Here, we used a hemisected turtle OB preparation and patch-clamp recording techniques to assess dopamine modulation of the ON/OB neuron synapse. We found that dopamine (10-300 microM) reversibly decreased the excitatory postsynaptic response to ON stimulation. This effect could be overcome by recruiting additional nerve fibers by increasing the intensity of ON stimulation. Quinpirole (10 microM), a D2 agonist, mimicked the effects of dopamine. Conversely, sulpiride (300 microM), a D2 antagonist, prevented the inhibitory effects of dopamine on synaptic transmission. Whereas dopamine appeared to equally affect the NMDA and AMPA/kainate receptor-mediated components of the synaptically evoked response, it had no direct effect on membrane currents evoked by exogenous glutamate, kainate or NMDA applied to cultured OB neurons. Our data, therefore, support the notion that dopamine modulates synaptic transmission between olfactory receptor neurons and OB neurons via a presynaptic mechanism involving D2 receptor activation. Our abstract (Berkowicz et al. (1994) Neuroscience Abs. 20:328) is the first report of these results.
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PMID:Dopaminergic modulation at the olfactory nerve synapse. 1065 Jan 34

Light has been shown to increase dopamine synthesis and release in vertebrate retinas, but the retinal circuits mediating the light signal are unknown. We utilized three antibodies which recognize phosphorylated forms of tyrosine hydroxylase (TH) at serines 19, 31, and 40 to study the effects of light and neuroactive drugs on TH phosphorylation in the rat retina. Phosphorylated TH and total TH immunoreactivities were co-localized exclusively in retinal neurons whose shape and location are characteristic of dopaminergic interplexiform cells. Phosphorylated TH was weak to absent in darkness, but light strongly stimulated phosphorylation in all the three serine residues. Light-induced phosphorylation of TH induction by light was uniformly blocked by a combination of NMDA and AMPA glutamate receptor antagonists. In darkness, the combination of NMDA+AMPA induced phosphosphorylation of TH at serines 19 and 40 but it was weak at serine 31. A GABA(A) antagonist had the same effect. An agonist of depolarizing (ON) bipolar cells, L-(+)-2-amino-4-phosphonobutyric acid, did not prevent light-induced phosphorylated TH formation. Carbachol, a non-specific cholinergic agonist, selectively induced phosphorylation of TH at serine 31 in darkness, an effect which was blocked by the nicotinic antagonist, d-tubocurarine. These results show that retinal circuits involving glutamatergic, GABAergic and cholinergic synapses influence phospho-TH formation at different serine residues in this enzyme. Gamma amino butyric acid (GABA) and glutamate influence TH phosphorylation at serines 19 and 40, whereas cholinergic inputs affect its phosphorylation at serine 31.
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PMID:Influence of light and neural circuitry on tyrosine hydroxylase phosphorylation in the rat retina. 1093 46

Organotypic cultures of fetal or early postnatal striatum were used to assess striatal patch formation and maintenance in the presence or absence of dopaminergic and glutamatergic influences. Vibratome-cut slices of the striatum prepared from embryonic day 19 to postnatal day 4 rat pups were maintained in static culture on clear membrane inserts in Dulbecco's modified Eagle's medium/F12 (1:1) with 20% horse serum. Some were co-cultured with embryonic day 12-16 ventral mesencephalon and/or embryonic day 19 to postnatal day 4 cortex, which produced a dense dopaminergic innervation and a modest cortical innervation. Donors of striatal and cortical tissue were previously injected with bromo-deoxyuridine (BrdU) on embryonic days 13 and 14 in order to label striatal neurons destined to populate the patch compartment of the striatum. Patches of BrdU-immunoreactive cells were maintained in organotypic cultures of late prenatal (embryonic days 20-22) or early postnatal striatum in the absence of nigral dopaminergic or cortical glutamatergic influences. In slices taken from embryonic day 19 fetuses prior to the time of in vivo patch formation, patches were observed to form after 10 days in vitro, in 39% of nigral-striatal co-cultures compared to 6% of striatal slices cultured alone or in the presence of cortex only. Patches of dopaminergic fibers, revealed by tyrosine hydroxylase immunoreactivity, were observed in the majority of nigral-striatal co-cultures. Immunostaining for the AMPA-type glutamate receptor GluR1 revealed a dense patch distribution in nearly all cultures, which developed in embryonic day 19 cultures after at least six days in vitro. These findings indicate that striatal patch/matrix organization is maintained in organotypic culture, and can be induced to form in vitro in striatal slices removed from fetuses prior to the time of in vivo patch formation. Furthermore, dopaminergic innervation from co-cultured pieces of ventral mesencephalon enhances patch formation in organotypic cultures.
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PMID:Development of striatal patch/matrix organization in organotypic co-cultures of perinatal striatum, cortex and substantia nigra. 1131 90

There is considerable evidence that drug reward and brain stimulation reward (BSR) share common neural substrates. Although it is known that exposure to drugs of abuse causes a variety of molecular changes in brain reward systems, little is known about the molecular consequences of BSR. We report that repeated exposure to rewarding stimulation of the medial forebrain bundle (MFB) selectively decreases expression of GluR1 (an AMPA receptor subunit) in the VTA, without effect on expression of several other proteins (GluR2, NMDAR1, tyrosine hydroxylase). This effect of BSR on GluR1 expression is opposite of that caused by intermittent exposure to cocaine and morphine, which are known to elevate GluR1 expression in the VTA. Considering that elevated GluR1 expression in the VTA has been associated with increased sensitivity to drug reward, the finding that BSR and drugs of abuse have opposite effects on GluR1 expression in this region may provide an explanation for why the reward-related effects of many drugs (cocaine, morphine, amphetamine, PCP, nicotine) do not sensitize with repeated testing in BSR procedures that quantify reward strength.
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PMID:Repeated exposure to rewarding brain stimulation downregulates GluR1 expression in the ventral tegmental area. 1142 7

Previous studies have analyzed photoreceptor development, some inner retina cell types, and specific neurotransmitters in the zebrafish retina. However, only minor attention has been paid to the morphology of the synaptic connection between photoreceptors and second order neurons even though it represents the transition from the light sensitive receptor to the neuronal network of the visual system. Here, we describe the appearance and differentiation of pre- and postsynaptic elements at cone synapses in the developing zebrafish retina together with the maturation of the directly connecting second order neurons and a dopaminergic third order feedback-neuron from the inner retina. Zebrafish larvae were examined at developmental stages from 2 to 7dpf (days postfertilization) and in the adult. Synaptic maturation at the photoreceptor terminals was examined with antibodies against synapse associated proteins. The appearance of synaptic plasticity at the so-called spinule-type synapses between cones and horizontal cells was assessed by electron microscopy, and the maturation of photoreceptor downstream connection was identified by immunocytochemistry for GluR4 (AMPA-type glutamate receptor subunit), protein kinase beta(1) (mixed rod-cone bipolar cells), and tyrosine hydroxylase (dopaminergic interplexiform cells). We found that developing zebrafish retinas possess first synaptic structures at the cone terminal as early as 3.5dpf. Morphological maturation of these synapses at 3.5-4dpf, together with the presence of synapse associated proteins at 2.5dpf and the maturation of second order neurons by 5dpf, indicate functional synaptic connectivity and plasticity between the cones and their second order neurons already at 5dpf. However, the mere number of spinules and ribbons at 7dpf still remains below the adult values, indicating that synaptic functionality of the zebrafish retina is not entirely completed at this stage of development.
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PMID:Synaptic plasticity and functionality at the cone terminal of the developing zebrafish retina. 1288 62


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