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)

Dopamine-containing neurons of the midbrain are required to control voluntary movements, behavior and motivation. Damage of these neurons in the substantia nigra zona compacta (SNc) is considered as the cause of Parkinson's disease. In this work, the firing characteristics of SNc neurons were studied in vitro. Neurons were identified by intracellular labeling tyrosine hydroxylase (TH) immunocytochemistry, and their electrophysiological characteristics. TH-positive neurons displayed three different firing modes. At around -55 mV neurons exhibited a regular single spike firing mode (pacemaking). At around -65 mV, neurons discharged in an irregular single spike firing mode (idling). At around -75 mV, many neurons exhibited a mode of discharge characterized by low threshold spikes (LTS), oscillations and, on some occasions, bursting. When present, bursts were of short duration and commonly made up of incomplete somatodendritic action potentials. TH-negative neurons also exhibited single spikes and bursting modes of firing. Both types of SNc neurons generated LTS oscillations following a hyperpolarization. However, LTS in TH-negative neurons could be evoked from less negative membrane potentials and produced more prolonged bursts. LTS from both types of neurons could be differentiated. LTS were blocked by 100 microM Ni2+ and became prolonged in the presence of TEA.
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PMID:Firing patterns in substantia nigra compacta identified neurons in vitro. 762 Feb 87

The Weaver (wv) mutation leads to a loss of mesencephalic dopamine cells and nigrostriatal dopamine axons in homozygosity (wv/wv) and to a deficiency of nigral dopaminergic dendrites without a concomitant loss of dopamine cell somata or axons in heterozygosity (wv/+). Previous studies have shown that grafts of foetal dopamine cells from wild-type (+/+) donors can survive when implanted into the wv/wv striatum, supply both an axonal and a dendritic innervation to the host, establish synaptic connections with host striatal neurons, and bring about a functional recovery evidenced by rotational asymmetry tests. The aims of the present study were to examine whether wv/+ dopamine cells maintain a "dendrite-poor" phenotype after transplantation to the denervated striatum, and to compare their functional effects with those of wild-type (+/+) grafts in reversing amphetamine-induced turning behaviour. To that end, +/+ and wv/+ ventral mesencephalic tissue (dissected out from E10-E12 foetal mice and made into a cell suspension by enzymatic and mechanical dissociation) was stereotactically grafted into the right striatum of either wv/wv hosts or +/+ hosts subjected in advance to 6-OHDA lesions of the right substantia nigra. Viability and morphology of grafted neurons were assessed by tyrosine hydroxylase immunocytochemistry on serial sections of the host forebrains. Dopamine cell bodies survived in comparable numbers in the grafts regardless of donor genotype; however, grafts of either genotype contained fewer dopaminergic cells when they were hosted in the wv/wv striatum as compared to the striatum of +/+ mice with 6-OHDA lesions. Despite the survival of cell somata, the dendritic arborisation of wv/+ cells was strikingly poorer than that of +/+ cells in grafts placed into both host types, most likely reflecting their in situ phenotypic abnormality. Recipient wv/wv mice with +/+ and wv/+ grafts exhibited 88% and 83% left rotations, respectively; 6-OHDA hosts with +/+ and wv/+ grafts showed 178% and 165% reversals of asymmetry, respectively. The differences between the effects of +/+ and wv/+ grafts were not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transplantation of mesencephalic cell suspensions from wild-type and heterozygous Weaver mice into the denervated striatum: assessing the role of graft-derived dopaminergic dendrites in the recovery of function. 764 Aug 72

The role of the catecholamines noradrenaline, adrenaline and dopamine on metallothionein (MT) levels of specific areas of the rat brain has been studied. MT-I or MT-I + II levels were measured by radioimmunoassay using specific antibodies that cross-react only slightly with human MT-III (growth inhibitory factor, GIF). The inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (MPT), which depletes brain dopamine, noradrenaline, and adrenaline, increased MT levels in all brain areas studied (frontal cortex, cortex, medulla oblongata plus pons, midbrain, striatum, hippocampus, hypothalamus, and cerebellum) when considering the results of two separate experiments. The alpha- and beta-receptor blockers, phentolamine, and propranolol, alone or together, did not increase brain MT levels in any area of the brain, suggesting that the effect of MPT in vivo is related to inhibition of the synthesis of dopamine rather than of noradrenaline and adrenaline. Dopamine, noradrenaline, and serotonin increased MT-I levels in primary cultures of neurons, whereas decreased them in astrocyte-enriched primary cultures. Since MT-I levels are about ten times higher in astrocytes than in neurons, the increased brain MT levels induced by MPT may reflect the suppression of the normal inhibitory effect of dopamine on astrocyte MT levels. The increase in MT concentrations induced in most parts of the brain by immobilization stress was not prevented by MPT, phentolamine, or propranolol, suggesting that it was not mediated by the central monoamines.
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PMID:Regulation of metallothionein-I+II levels in specific brain areas and liver in the rat: role of catecholamines. 786 87

The distribution of dopamine (DA) and the biosynthetic enzyme tyrosine hydroxylase (TH) has been studied immunohistochemically in the brain of the adult South African clawed frog, Xenopus laevis. The goals of the present study are, firstly, to provide detailed information on the DA system of the brain of a species which is commonly used in laboratories as an experimental model and, secondly, to enhance our insight into primitive and derived characters of this catecholaminergic system in amphibians. Dopamine-immunoreactive cell bodies are present in the olfactory bulb, the preoptic area, the suprachiasmatic nucleus, the nucleus of the periventricular organ and its accompanying cells, the nucleus of the posterior tubercle, the posterior thalamic nucleus, the midbrain tegmentum, around the solitary tract, in the ependymal layer along the midline of the caudal rhombencephalon, and along the central canal of the spinal cord. In contrast to the DA antiserum, the TH antiserum fails to stain the liquor-contacting cells in the periventricular organ. On the contrary, the latter antiserum reveals additional immunoreactive cell bodies in the olfactory bulb, the isthmic region and the caudal brainstem. Both antisera yield an almost identical distribution of fibers. Distinct fiber plexuses are observed in the olfactory bulb, the basal forebrain, the hypothalamus and the intermediate lobe of the hypophysis. Features that Xenopus shares with other anurans are the larger number of DAi cells, which are generally smaller in size than those observed in urodeles, and the lack of DAi fibers in pallial structures. On the other hand, the paired midbrain DA cell group and the innervation of the tectum of Xenopus resemble those found in the newt rather than those in frogs. Despite the existence of these species differences, the brain of Xenopus offers an excellent model for studying general aspects of neurotransmitter interactions and the development of catecholamine systems in this class of vertebrates.
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PMID:Distribution of tyrosine hydroxylase and dopamine immunoreactivities in the brain of the South African clawed frog Xenopus laevis. 790 28

Mice of different ages and homozygous or heterozygous for the weaver gene (wv) were used to study the time course for the effect of the weaver gene on several striatal dopaminergic parameters. Dopamine uptake was decreased in the homozygous weaver at all ages examined. The deficit in uptake at the earliest age studied, postnatal day 3, was approximately 50% and increased to greater than 70% at older ages. In control mice, dopamine uptake reached a maximum by postnatal day 22, but in homozygous weaver mice, development of uptake activity was curtailed by postnatal day 7. Dopamine content and tyrosine hydroxylase activity were significantly decreased in the homozygous weaver at all ages studied except postnatal days 7 and 10. The magnitude of the deficit in dopamine content ranged from approximately 40% at postnatal days 3 and 5 to about 70% in adults (6 months to 1 year of age). The magnitude of the deficit in tyrosine hydroxylase activity ranged from 40 to 70%. In general, no major differences between heterozygotes and controls were observed for any of the dopaminergic parameters investigated. The results of the present investigation indicate that neurochemical alterations can be observed in the striata of weaver mice as early as postnatal day 3 and raise the possibility that the striatal dopamine transporter may be an early target of the weaver mutation.
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PMID:Age-dependent alterations in dopamine content, tyrosine hydroxylase activity, and dopamine uptake in the striatum of the weaver mutant mouse. 790 25

ACTH peptide fragments demonstrate potent neurotrophic effects on peripheral nerves in situ, central neurons in culture, and have been implicated to have effects on central neurons in vivo. Neurotoxic lesioning of the nigrostriatal system, which depletes the striatum of dopamine, provides a feasible model of central regeneration in which to test these peptides. Male Sprague-Dawley rats were lesioned unilaterally with 6-hydroxydopamine (8 micrograms/4 microliters), infused into the substantia nigra. They were subsequently treated with 10 micrograms/kg IP of Org 2766 [ACTH/MSH(4-9) analogue] or saline every 24 h starting immediately after the infusion and were observed for 2 weeks. Rotational behavior data indicate that Org 2766 significantly decreases ipsiversive turning (p < 0.05), induced by amphetamine (2 mg/kg), as well as accelerating the onset of denervation supersensitivity induced by apomorphine (0.05 mg/kg). Evaluation of dopamine immunohistochemistry, using an anti-tyrosine hydroxylase antibody, demonstrates an enhanced intensity of staining in the ORG 2766-treated tissue compared to its saline counterpart. This difference is confirmed and quantified through specific high-affinity dopamine uptake. Dopamine uptake is about 17% higher in the striata of animals treated with Org 2766. Higher dopamine uptake levels in these ACTH-treated animals correlate with greater fiber density in this group. Therefore, it appears that treatment with the ACTH/MSH(4-9) analogue Org 2766 (10 micrograms/kg/24 h) offers a protective effect from 6-OHDA lesions in the substantia nigra as well as accelerating various compensatory mechanisms involved in functional recovery.
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PMID:Rapid neurotrophic actions of an ACTH/MSH(4-9) analogue after nigrostriatal 6-OHDA lesioning. 790 91

Dopamine has been implicated in the pathophysiology of schizophrenia, and the entorhinal cortex (ERC) is thought to be a site of structural pathology in this disorder. However, relatively little is known about the dopaminergic (DA) innervation of ERC in the primate brain. In this study, immunohistochemical methods and antibodies directed against tyrosine hydroxylase (TH) and dopamine were used to determine the organization of DA axons in the ERC of macaque monkeys. The anti-TH antibody used in this study appeared predominantly to identify DA axons, as demonstrated by its failure to label fibers that were immunoreactive with an antibody against dopamine-beta-hydroxylase in double-labeling experiments. In addition, the regional and laminar distributions of TH-immunoreactive fibers were strikingly similar to those labeled with the anti-dopamine antibody. With both antibodies, cytoarchitectonically identified subdivisions of monkey ERC (Amaral et al., 1987) differed in both the density and laminar distribution of labeled fibers. Immunoreactive processes exhibited a substantial rostral-to-caudal gradient of decreasing density across subdivisions of ERC, and the density of labeled fibers also decreased from medial to lateral in the rostral but not in the caudal subdivisions of ERC. The laminar distribution of labeled fibers differed both between and within subdivisions. For example, in the olfactory and rostral subdivisions of ERC, the superficial layers contained a very high density of immunoreactive processes, whereas in the intermediate region, three bands of labeled fibers were seen in layers I, III-IV, and VI. In addition, radial columns of fibers interdigitated with areas of decreased density were present between layers I and III. Although the overall density of labeled fibers was greater in lateral than in the caudal subdivisions of ERC, these regions had similar laminar distribution patterns. In these areas of monkey ERC, labeled processes were highest in density in deep layer I, and homogeneously distributed in the other cortical layers. These findings demonstrate that the DA innervation of monkey ERC is complex, and follows laminar- and subdivision-specific patterns. These patterns of distribution suggest the possible interactions that DA axons may have with other elements of ERC circuitry, and may provide insight into the possible functional roles of dopamine in ERC in both normal and disease states.
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PMID:The dopaminergic innervation of monkey entorhinal cortex. 790 2

A microtransplantation approach has been used in order to achieve more complete reinnervation of the dopamine denervated rat striatum by fetal nigral cell suspensions injected into multiple striatal sites. A total of 450,000 cells, obtained from the ventral mesencephalon of embryonic day 14 rat fetuses, were implanted either in the conventional way as two 1.8-microliters deposits centrally in the head of the caudate-putamen ('Macro grafts'), or as eighteen 0.2-microliter deposits disseminated over six needle penetrations in the same area using a 50-70 microns glass capillary tip ('Micro grafts'). Non-grafted lesioned rats served as controls. Dopamine neuron survival (as assessed by tyrosine hydroxylase immunohistochemistry at 4 months after transplantation) was 2.8-fold greater in the Micro grafts as compared to the Macro grafts. Striatal dopamine tissue levels (determined in a separate group of rats) was increased 2.5-fold in the head of the caudate-putamen (from 12.5% of normal in the Macro graft group to 30% of normal in the Micro graft group). Consistent with this, the overall graft-derived tyrosine hydroxylase positive fiber outgrowth was more extensive in the Micro graft group and covered larger areas of the previously denervated caudate-putamen. The results show that distribution of the fetal nigral tissue in multiple small deposits provides for increased dopamine neuron survival, probably because of a closer contact between the implanted cells and the surrounding host striatal tissue in the small-sized graft deposits. Less bleeding and necrosis at the implantation site may also have contributed to this effect. The present microtransplantation procedure is an efficient means to increase overall dopamine neuron survival and to achieve more complete reinnervation of the denervated striatum in the rat Parkinson model. It also substantially increased the reproducibility of DA graft survival between animals.
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PMID:Improved graft survival and striatal reinnervation by microtransplantation of fetal nigral cell suspensions in the rat Parkinson model. 790 29

The mechanisms that lead ultimately to neuronal death in pathological ageing of the brain remain mostly unknown as in the case of Parkinson's disease where there is a progressive and selective loss of dopaminergic neurons within the substantia nigra. Dopamine-expressing PC12 cells that were neuronally differentiated by nerve growth factor treatment were chosen as a culture model in which to study some of the changes that may occur during the course of the degenerative process. They were exposed to the calcium ionophore A23187 in order to produce a sustained rise in cytoplasmic calcium, a phenomenon related to various pathological conditions. The degenerative effects of the ionophore were dose- and time-dependent. They were characterized by early fragmentation of the neurites followed ultimately by a loss in cell viability. Biochemical changes, such as a decrease in [3H]dopamine uptake and modulations of the tyrosine hydroxylase gene, were detected before macroscopic evidence of cell suffering (e.g. neurite fragmentation) could be observed. Although an ongoing degenerative process was occurring in cell somata, PC12 cells were able to recover upon ionophore withdrawal. Characteristics of apoptosis such as chromatin condensation and DNA fragmentation were detectable in a small population of dying cells. DNA fragmentation could be prevented by the endonuclease inhibitor aurintricarboxylic acid. New protein synthesis was not required, as cycloheximide failed to prevent degeneration. Taken together, these results suggest that differentiated PC12 cells react to calcium stress through a sequence of regulatory processes which appears to be independent of the apoptotic pathway.
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PMID:Morphological and molecular characterization of the response of differentiated PC12 cells to calcium stress. 791 84

The main focus of the present study was to define the rotational response of 6-hydroxydopamine-lesioned rats to dopaminergic agonists to separate the partially lesioned rats from those having complete substantia nigra (SN) and ventral tegmental area (VTA) lesions. Animals were challenged by amphetamine and L-DOPA for 10 consecutive weeks. There was a correlation between rotational behavior and extent of midbrain cell loss. Rats with complete SN and < 40% VTA lesion turned more than 5 times/min after amphetamine administration, but not after L-DOPA; animals with complete SN and 40-80% VTA lesions turned vigorously following amphetamine and began turning after L-DOPA administration. Rats with complete SN and VTA lesions turned less after amphetamine than the other two groups, while their turning after L-DOPA administration increased. Extracellular dopamine (DA) measured by microdialysis, intracellular DA measured by postmortem tissue punches, and tyrosine hydroxylase-immunoreactive cell count in SN and VTA were also evaluated. It appears that the dopaminergic cells in the lateral VTA affect DA concentration in the medial caudate nucleus. In the nucleus accumbens of the lesioned side, DA release and metabolism substantially increased with the larger VTA lesion. Dopamine turnover rate in the caudate was also higher in the group with < 40% VTA lesion.
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PMID:A 6-hydroxydopamine-induced selective parkinsonian rat model: further biochemical and behavioral characterization. 792 17


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