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)

Dopamine receptor dysfunction and altered tyrosine hydroxylase activity have both been implicated in the pathophysiology of schizophrenia. Schizophrenic patients and control subjects were examined for allele frequencies in the tyrosine hydroxylase and dopamine D2 and D4 receptor genes. No significant differences of allele or genotype frequencies were found between the two groups after adjustment for multiple comparisons. Neither were any significant relationships observed between allele frequencies and a number of clinical variables within the schizophrenic subsample. When no adjustment was made for multiple testing a few significant tendencies were obtained which warrant further research in extended patient and control materials. The results are compatible with the view that the tyrosine hydroxylase, dopamine receptor D2 and D4 gene polymorphisms examined are not of major importance in the aetiology or pathophysiology of schizophrenia.
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PMID:A search for association between schizophrenia and dopamine-related alleles. 890 11

Dopamine, a major neurotransmitter in the vertebrate retina, is released from interplexiform cells and a restricted subset of amacrine cells. Dopamine effects vary between different retinal cell types, most likely due to differences in cell-specific receptor subtype expression. Identification of cells expressing receptors of the D2-subfamily (D2R, D3R, D4R) on a light microscopical level has rendered equivocal results, and no information is as yet available concerning the subcellular distribution of receptor protein. In the present study, D2R and D2/3R subtype-specific antisera, and D2R-, D3R- and D4R-specific oligonucleotide probes were used for ultrastructural and in situ hybridization analyses of the receptor subtype distribution in the rat retina. Light and electron microscopy showed that in addition to the known localization of intense D2R-immunoreactivity in all dopaminergic cells immunoreactive for tyrosine hydroxylase (TH), homogeneous, less intense D2R-immunoreactivity was also seen throughout the inner plexiform layer (IPL). Ultrastructurally, many additional amacrine cell processes devoid of TH-immunoreactivity at all levels of the inner plexiform layer were immunoreactive. D2R-immunoreactivity was found mainly on intracellular vesicles, and immunoreactivity associated with the plasma membrane was always extrasynaptic. No D2R-immunoreactivity was found in amacrine cell somata postsynaptic to the so-called dopaminergic 'ring endings'. Many D2R-mRNA reactive cells were observed throughout the inner nuclear layer. Morphologically, labelled cells resemble amacrines and bipolars but not horizontal cells. Reactivity with splice variant-specific oligonucleotide probes suggested that the D2LR variant is the predominant if not the only D2R isoform in the rat retina. D2R-mRNA reactivity was not observed in other retinal layers, in particular not in photoreceptor inner segments, which displayed D4R-mRNA reactivity. D3R-mRNA reactivity was not detected. The results indicate that D2-like responses are mediated through the D2R subtype, by an autoreceptor mechanism in dopaminergic cells, and by volume transmission in non-dopaminergic cells of the inner retina. D2-like responses in photoreceptors probably represent D4R activation.
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PMID:The dopamine D2 receptor subfamily in rat retina: ultrastructural immunogold and in situ hybridization studies. 1010 34

Parkinsonism-inducing neurotoxicity of 1,2,3,4-tetrahydroisoquinoline (TIQ), as contrasted to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and parkinsonism-preventing effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) have been investigated in mice by measuring their effects on the in vivo binding of radioligand to pre-synaptic dopamine transporters (DATs) or to dopamine D(2) receptors (D2R) in the striatum. A significant reduction of the ligand-DATs binding was found in the mice treated with MPTP, but not with TIQ, under the dosage inducing behavioral abnormality and loss of tyrosine hydroxylase-positive cells in the substantia nigra. A slight decrease in the ligand-DATs binding was observed in the mice given a larger dose of TIQ. Compensatory up-regulation in the post-synaptic D2Rs was found in the MPTP-treated mice. Pre-treatment with (S)-enantiomer, but not (R)-enantiomer, of 1-MeTIQ prevented the degeneration of DATs to some extent. We concluded that the TIQ-induced parkinsonism model is different from the MPTP-induced model as evaluated by the radioligand-DATs binding and that (S)-1-MeTIQ has a preventing effect for the degeneration of the DATs to a certain extent.
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PMID:Evaluation of neurotoxicity of TIQ and MPTP and of parkinsonism-preventing effect of 1-MeTIQ by in vivo measurement of pre-synaptic dopamine transporters and post-synaptic dopamine D(2) receptors in the mouse striatum. 1172 79

As opiates increase dopamine transmission, we measured the effects of morphine on dopamine-related genes using a real-time optic PCR assay that reliably detects small differences in mRNA in discrete brain regions. Tissue from dopaminoceptive and dopaminergic brain regions was collected from rats injected twice daily for 7 days with saline or increasing doses of morphine. Tissues were assayed for D1, D2 and D3 dopamine receptor mRNAs (D1R, D2R and D3R), as well as for mRNAs for tyrosine hydroxylase (TH) and the dopamine transporter (DAT). The neuron-associated mRNAs for SNAP-25 and synaptophysin, as well as the glial-associated mRNA for S100-beta and three 'housekeeping' mRNAs, were also measured. As reported previously by others, there was no alteration in D1R mRNA and a 25% decrease in D2R mRNA in the caudate-putamen, 2 h after the final morphine injection. Importantly, in the same RNA extracts, D3R mRNA showed significant increases of 85% in the caudate-putamen and 165% in the ventral midbrain, including the substantia nigra and ventral tegmental area. There were no other significant morphine effects. Mapping of brain regions in saline control rats agreed with previous studies, including showing the presence of low abundance TH mRNA and the absence of DAT mRNA in the caudate-putamen. The finding that chronic, intermittent injections of morphine caused an increase in D3R mRNA extends our understanding of the ability of D3R agonists to reduce the effects of morphine.
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PMID:Elevated D3 dopamine receptor mRNA in dopaminergic and dopaminoceptive regions of the rat brain in response to morphine. 1265 7

We demonstrated synchronous oscillation of intracellular Ca2+ in cultured-mouse mid-brain neurons. This synchronous oscillation was thought to result from spontaneous and synchronous neural bursts in a synaptic neural network. We also examined the role of endogenous dopamine in neural networks showing synchronous oscillation. Immunocytochemical study revealed a few tyrosine hydroxylase (TH)-positive dopaminergic neurons, and that cultured neurons expressed synaptophysin and synapsin I. Western blot analyses comfirmed synaptophysin, TH, and 2 types of dopamine receptor (DR), D1R and D2R expression. The synchronous oscillation in midbrain neurons was abolished by the application of R(-)-2-amino-5-phosphonopentanoic acid (AP-5) as an N-methyl-D-aspartate receptor (NMDAR) antagonist. This result suggests that the synchronous oscillation in midbrain neurons requires glutamatergic transmissions, as was the case in previously reported cortical neurons. SCH-12679, a D1R antagonist, inhibited synchronous oscillation in midbrain neurons, while raclopride, a D2R antagonist, induced a transient increase of intracellular Ca2+ and inhibited synchronous oscillation. We consider that endogenous dopamine maintains synchronous oscillation of intracellular Ca2+ through D1R and D2R, and that these DRs regulate intracellular Ca2+in distinctly different ways. Synchronous oscillation of midbrain neurons would be a useful tool for in vitro researches into various neural disorders directly or indirectly caused by dopaminergic neurons.
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PMID:Endogenous dopamine maintains synchronous oscillation of intracellular calcium in primary cultured-mouse midbrain neurons. 1504 10

The dopamine D3 receptor (D3R) has been implicated in schizophrenia, drug addiction, depression and Parkinson's disease. The D3R is localized post-synaptically on nucleus accumbens neurons, but is also an autoreceptor on dopaminergic neurons in the mesencephalon. Its functional role as autoreceptor is highly debated, but supported by the elevated basal extracellular dopamine levels found in D3R-deficient mice. To investigate the functional role of the D3R in vivo, we used mice with a targeted disruption of the D3R gene. We found a higher basal level of grooming in D3R-deficient mice, compared to their wild-type littermates. This behavior, which is under the control of D1R stimulation, may be related to an increased dopaminergic tone, since no changes in the gene expression of dopamine D1 and D2 receptors were noticed in the striatum of these mice. D3R-deficient mice displayed other neuroadaptive changes, including decreased tyrosine hydroxylase, increased dopamine transporter mRNAs and increased dopamine reuptake in striatum. The level of tyrosine hydroxylase protein was unchanged in the striatum, as preprodynorphin and preproenkephalin gene expressions. All the changes identified in D3R-deficient mice cannot explain hyperdopaminergia, but, on the contrary, tend to attenuate this phenotype. These results support a distinct role for D2R and D3R as autoreceptors: the D2R is the release-regulating and firing rate-regulating autoreceptor, whereas the D3R may control basal dopamine levels in the striatum, by an unknown mechanism, which does not involve regulation of dopamine transporters or tyrosine hydroxylase. This hyperdopaminergia phenotype of D3R-deficient mice may explain their hyperactivity to drug-paired environmental cues.
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PMID:Neuroadaptations to hyperdopaminergia in dopamine D3 receptor-deficient mice. 1564 98

This study was designed to investigate the postnatal developmental plasticity of the mesostriatal and mesolimbic dopamine systems that occurs following perinatal asphyxia. The time course and patterning of the changes in levels of tyrosine hydroxylase (TH), and D1 and D2 dopamine receptor (R) mRNA in the cell body region, substantia nigra and ventral tegmental area (SN/VTA), and projection fields, striatum and limbic regions at the age of 6 and 24 h, and 1 week after asphyxia were studied with a quantitative reverse transcription polymerase chain reaction method with appropriate internal cRNA standard. In Caesarean-delivered control rats (Sprague-Dawley), TH, D2R and D1R mRNA levels showed regional and temporal specificity in both absolute levels and developmental kinetics during the first week of life. TH mRNA levels were >10-fold higher in SN/VTA than in striatum and limbic regions. Compared to Caesarean delivered controls, severe asphyxia (15-20 min) induced an increase of TH and D2R mRNA in SN/VTA 6 h and 1 week after birth. In addition, asphyxia induced an increase of TH mRNA in the projection fields, striatum and limbic regions, at 1 week. Perinatal asphyxia did not appear to exert any effect on D1R mRNA levels. No differences in any of the parameters were observed between spontaneous- and Caesarean-delivered animals. The present results indicate that perinatal asphyxia triggers coordinated changes in the expression of TH, and dopamine receptor mRNA in SN/VTA, striatum and limbic regions. These changes may affect differently dopamine D2R and D1R expression along development, contributing to long-term neurocircuitry imbalances.
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PMID:Effect of perinatal asphyxia on tyrosine hydroxylase and D2 and D1 dopamine receptor mRNA levels expressed during early postnatal development in rat brain. 1583 23

Because the dopaminergic pathways in the midbrain have been closely associated with serious neuropsychiatric disorders, the elucidation of the mechanisms underlying dopaminergic neuronal development should provide some important clues for related disorders. In mice lacking the dopamine D2 receptor (D2R-/-), stereological cell counting analysis showed that the number of mesencephalic tyrosine hydroxylase (TH) cells was significantly low during ontogeny, compared with that observed in wild-type (WT) mice, thereby indicating an alteration in dopaminergic neuronal development in the absence of D2R. The results of immunohistochemical and reverse transcription-PCR analyses revealed that the expression of Nurr1, an orphan nuclear receptor, as well as Ptx3 expression, was selectively reduced in D2R-/- mice during the embryonic stage. A reporter gene assay using the Nur response element linked to the luciferase reporter gene indicated that the stimulation of D2R results in the activation of the Nurr1-mediated reporter gene. This D2R-mediated Nur response element-dependent transcriptional activity was regulated via the activation of extracellular signal-regulated kinase (ERK). Furthermore, quinpirole treatment was shown to elicit an increase in the number of TH-positive neurons, as well as the neuritic extension of TH neurons, coupled with ERK activation and Nurr1 activation in the TH-positive neurons in primary mesencephalic cultures from WT mice. However, this regulation was not detected in the D2R-/- mice. These results suggest that signaling through D2R in association with Nurr1 using ERK, plays a critical role in mesencephalic dopaminergic neuronal development.
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PMID:The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation. 1664 Dec 36

Previously, we have shown that chronic exposure to environmental and social stimuli (ESS) during adolescence prevents the development of behavioral sensitization to amphetamine in adult rats. At the onset of the peripubertal-juvenile period (28-d) male rats were subjected to a 28-d long intermittent ESS protocol or handled as controls (NO-ESS). Twenty-four hours after the last session of ESS or NO-ESS, all rats started a regimen of behavioral sensitization to amphetamine (1mg/kg, i.p.), in which rats were injected every third day with amphetamine or saline on four occasions. Then following one week abstinence all rats were challenged with a lower dose of amphetamine (0.5mg/kg, i.p.) and their locomotor activity monitored for 2h. Our results showed that while NO-ESS rats developed behavioral sensitization to amphetamine, ESS rats did not develop this behavior. All rats were then sacrificed 3 days following the challenge to allow for amphetamine clearance. Since mesolimbic dopamine has been implicated in behavioral sensitization to amphetamine we compared messenger RNA (mRNA) expression of key dopamine-related molecules in the mesolimbic circuitry in ESS and NO-ESS rats. A decrease in dopaminergic D1 receptor (D1R) gene expression in the caudate-putamen (CPu) was associated with amphetamine sensitization in the controls, possibly as a result of a chronic increase in DA release. In contrast, amphetamine treatment did not modulate D1R mRNA levels in ESS rats. No change has been detected in any other dopaminergic markers [D2R, D3R, tyrosine hydroxylase (TH) or dopamine transporter (DAT) mRNAs]. Consequently, we conclude that ESS may inhibit the development of behavioral sensitization to amphetamine through preventing the decrease in CPu D1R mRNA levels.
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PMID:Effects of chronic environmental and social stimuli during adolescence on mesolimbic dopaminergic circuitry markers. 1759 May 8

Projections from the prefrontal cortex (PFC) to the amygdala (AMG) regulate affective behaviors in a manner that is modulated by dopamine (DA). Although PFC and DA inputs overlap within the basolateral nucleus (BLA) and intercalated cell masses (ICMs), the spatial relationship between these afferents has not been investigated, nor is it known how DA D1 (D1R) and D2 (D2R) receptors are localized in relationship to PFC terminals. We therefore combined tract-tracing from the rat PFC to the AMG with immunocytochemical labeling of tyrosine hydroxylase (TH) to identify presumed DA axons or D1R and D2R. In both the ICMs and BLA, PFC terminals formed asymmetric synapses onto spines that typically did not receive secondary synaptic inputs. TH-immunoreactive (-ir) fibers in the adjacent neuropil typically contacted different structures. Although PFC and TH-ir axons were sometimes apposed to the same dendrites or to each other, PFC terminals only rarely synapsed onto dendrites that also received synapses from TH-ir axons. D1R-ir spines and dendrites were observed commonly within the ICMs but less frequently within the BLA, and PFC axons in the ICMs occasionally synapsed onto D1R-ir spines. Within both regions, D2R-ir spines, dendrites, and axons were observed. PFC terminals occasionally contained presynaptic labeling for D2R but were not observed to synapse onto D2R-ir targets. The infrequent observation of synaptic convergence between PFC and presumed DA terminals within the AMG suggests that DA modulates PFC inputs primarily via extrasynaptic mechanisms, a conclusion supported by the localization of D2R within and D1R postsynaptic to PFC terminals.
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PMID:Ultrastructural analysis of prefrontal cortical inputs to the rat amygdala: spatial relationships to presumed dopamine axons and D1 and D2 receptors. 1834 Apr 60


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