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)

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg/kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.
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PMID:Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission. 898 31

A tetranucleotide repeat polymorphism in the first intron of the tyrosine hydroxylase (TH) locus was examined in a group of 118 adult suicide attempters and 78 control subjects. The suicide attempters were diagnosed according to DSM-III-R criteria at the index attempt and represented the following diagnoses: major depression (18), dysthymia (13), anxiety disorders (16), adjustment disorders (29), psychoactive substance abuse disorders (27) and psychotic disorders (15). A significant variation in the prevalence of carriers of the TH-K3 allele (high for suicide attempters with adjustment disorders, P = 0.0023) and a tendency toward a variation of the TH-K1 allele (low among all suicide attempters, P = 0.046) was observed. In light of other data the variation of TH-K1 and TH-K3 suggests that these alleles may reflect predisposition for a common phenotype with altered vulnerability for psychiatric disorders.
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PMID:Tyrosine hydroxylase allelic distribution in suicide attempters. 933 98

HPNS (high pressure neurological syndrome) is considered to be reversible condition of the nervous system caused by elevated (atmospheric) pressure. Clinical observations and experimental findings gave rise to the belief that this syndrome at least partly functions as a model of a dopamin dependent psychosis. Morphological alterations during or after HPNS in man and animals have not been reported so far. We treated rats for three hours with an increasing pressure of helium-oxygen mixture up to 61 ATA in a pressure chamber. This pressure was subsequently maintained for one hour and then released to zero within twenty seconds. The rats died within the first three seconds of pressure release due to complete deoxygenation. Brains were immediately removed and either cooled in liquid nitrogen or fixed in formalin. In both instances the central nervous tissue was excellently preserved. In paraffin embedded formalin fixed specimens, dark neurons in different brain regions were found, especially within parts of the dentate gyrus, the CA 4 subfield of the ammons horn, in dopaminergic brainstem nuclei and in some cortical pyramidal cells. In dopaminergic cells, tyrosine hydroxylase was found to be absent in cells transformed into dark neurons. These dark neurons which have long been recognized in neuropathology, probably represent reversibly damaged neurons transformed into the dark configuration by aldehyde fixation. They may correspond to early apoptosis or they may be the consequence of cytoskeletal disruption.
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PMID:Early morphological findings in experimental high pressure neurological syndrome. 949 42

This report describes linkage data presented at the Workshop on Chromosomes 11, 14, and 15 at the Sixth World Congress of Psychiatric Genetics in Bonn, Germany, together with relevant linkage data submitted to the chair and co-chair, and it is presented in the context of the previous literature concerning these chromosomes. We have attempted to collate current linkage data to provide a guide to potentially interesting findings on chromosomes 11, 14, and 15 for the phenotypes of bipolar disorder, schizophrenia, alcoholism, autism, and spelling and reading disability. We discuss methodological limitations and provide chromosome ideograms and tables summarizing findings to date. The most promising region currently appears to be 15q13-q15 in the region of the alpha 7 nicotinic receptor for the phenotype of schizophrenia (and, perhaps, more generally for functional psychosis). Additionally, 15q11-q13 in the region of GABRB3 holds interest as a potential site of a susceptibility gene for autism. Two regions on chromosome 11, 11p15 in the region of tyrosine hydroxylase gene and 11q22-q23 in the region of DRD2, continue to retain some interest for functional psychosis.
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PMID:Chromosome Workshop: chromosomes 11, 14, and 15. 1037 39

Based on a number of neuroanatomical and behavioural similarities, recent evidence suggests that heterozygous reeler mice, haploinsufficient for reelin expression, represent a useful model of psychosis vulnerability. As brain mesolimbic dopamine pathways have been proposed to be associated with the pathophysiology of psychotic disorders, we thought it would be of interest to examine whether these animals present disturbances in the mesolimbic dopamine system. To this end we studied by immunocytochemical, in situ hybridization procedures and receptor autoradiography, several markers of the mesotelencephalic dopamine pathway in heterozygous reeler mice and controls. We report that heterozygous reeler mice exhibit a reduction in the number of tyrosine hydroxylase-immunoreactive cell bodies and tyrosine hydroxylase mRNA levels in the ventral tegmental area, as well as a reduction of tyrosine hydroxylase and dopamine transporter immunoreactivity in the dopamine terminal fields of the limbic striatum. In these areas we also observed a reduction of dopamine D2 receptor mRNA. Finally, a marked increase in D3 receptor mRNA levels was observed concomitant with a significant increase in D3 binding sites. On the contrary, the nigrostriatal pathway did not show any significant alteration in heterozygous reeler mice with regards to the dopaminergic markers examined in substantia nigra cell bodies and dorsal striatum dopamine terminal fields. These results suggest a specific link between reelin-related neuronal pathology and dopamine involvement in the pathophysiology of psychotic disorders.
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PMID:Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia. 1198 30

Antipsychotic drugs (APD) are used in the treatment of schizophrenia and other psychotic disorders and exert their effects, in part, through dopamine receptor blockade. APD treatment causes many changes in the brains of humans and experimental animals including therapeutic, pathologic, or changes associated with motor side effects. Typical APD given chronically to animals induce behavioral sequelae that mimic tardive dyskinesia in several ways. Our previous work has shown that chronic treatment with haloperidol decreases striatal synaptic density but that symmetric synapses are lost only in rats that develop oral dyskinesias. The goals of this study were to determine if the density of dopaminergic terminals was affected by chronic haloperidol treatment and/or correlated with dyskinesias. Rats were given haloperidol (1.5 mg/kg/rat) or water, as a control. After 6 months of treatment, rats were divided into nondyskinetic or dyskinetic groups according to the behavior scores determined in the last month. Striatal volume was similar between controls and drug-treated rats. Synaptic density, calculated using stereological methods, was obtained from the matrix of the ventrolateral striatum. The density of symmetric synapses (mean +/- SD, per 100/microm(3)) formed by tyrosine hydroxylase (TH) containing terminals in haloperidol treated rats (3.58 +/- 1.64) was not significantly different from that of controls (3.06 +/- 1.00). The density of TH-labeled terminals forming symmetric synapses in the nondyskinetic group (3.65 +/- 1.67) vs. the dyskinetic group (3.54 +/- 1.73) was similar and neither was different from that of the controls. These data indicate that terminals other than dopaminergic ones form fewer symmetric synapses in dyskinetic rats. Moreover, these data have implications for interpreting results obtained in humans treated with typical antipsychotic drugs.
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PMID:Dopaminergic synapses in the matrix of the ventrolateral striatum after chronic haloperidol treatment. 1211

A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. The COMT valine allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis.
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PMID:Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. 1265 58

Dopamine (DA) neurons degenerate in Parkinson's disease and dopamine neurotransmission may be affected in psychotic states seen in schizophrenia. Understanding the regulation of enzymes involved in DA metabolism may therefore lead to new treatment strategies for these severe conditions. We investigated mRNA expression of the cytosolic aldehyde dehydrogenase (ALDH1), presumably involved in DA degradation, by in situ hybridization in DA neurons of human postmortem material. Parallel labeling for GAPDH, neuron-specific enolase, tyrosine hydroxylase, dopamine transporter, and dopamine beta-hydroxylase was used to ensure suitability of tissue specimen and to identify all dopamine neurons. ALDH1 was found to be expressed highly and specifically in DA cells of both substantia nigra (SN) and the ventral tegmental area (VTA) of controls. A marked reduction of ALDH1 expression was seen in surviving neurons of SN pars compacta but not of those in the VTA in Parkinson's disease. In patients suffering from schizophrenia we found ALDH1 expression at normal levels in DA cells of SN but at significantly reduced levels in those of the VTA. We conclude that ALDH1 is strongly and specifically expressed in human mesencephalic dopamine neurons and that low levels of ALDH1 expression correlate with DA neuron dysfunction in the two investigated human conditions.
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PMID:ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia. 1467 78

Immunohistochemical staining with non-specific IgG reliably labels a subset of neurons in both rat and human brain, overlapping the distribution of cortico-limbic D2 receptors (D2R). We used haloperidol to up-regulate rat D2R to observe any associated changes in IgG immunostaining. Rats were treated with haloperidol or vehicle for 30 d. Some rats were assessed for D2R up-regulation with apomorphine. The remaining rats were processed immunohistochemically and IgG-stained cells counted and statistically analysed in three cortico-limbic areas. Other brain regions were surveyed qualitatively. Positive (anti-glial fibrillary acidic protein or anti-tyrosine hydroxylase staining) and negative (antisera omitted) controls were performed on adjacent sections. Haloperidol dramatically the IgG staining areas quantified with all surveyed regions significantly decreased. Positive control staining was robust, ruling out generalized immunoreactivity reduction. These observations raise the possibility of an immunological effect of haloperidol in the brain. The identification and function of these IgG-labelled sites may have useful implications for psychosis.
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PMID:Haloperidol reduces IgG immunoreactivity in the rat brain. 1471 Jul 22

Dopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine beta-hydroxylase), Drd4 receptors, Gprk6 (G protein-coupled receptor kinase 6), Comt (catechol-O-methyltransferase), or Th-/-, DbhTh/+ (tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2High), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40-900%) for D2High were found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted.
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PMID:Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. 1571 60


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