Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase (TH) is the rate limiting enzyme in the synthesis of dopamine and norepinephrine. A polymorphic repeat of the tetranucleotide (TCAT) in the first intron of the TH gene may behave as a regulatory element for the gene expression. Allelic fragments of the tandem repeat were typed by a PCR-based process with a pair of primers specific for the polymorphic sequence. The association between the polymorphism and schizophrenia was examined in a Japanese sample. There was a statistically significant association between the polymorphism and schizophrenia in females (chi2 = 26.018, p = 0.010), but not in males (chi2 = 15.995, p = 0.305). The genotype heterozygous for the TH9 and TH6 was significantly decreased in female schizophrenics (chi2 = 5.125, p = 0.0236). These results suggest that TH could be considered as a minor gene contributing to the susceptibility of Japanese female schizophrenia.
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PMID:An association of the polymorphic repeat of tetranucleotide (TCAT) in the first intron of the human tyrosine hydroxylase gene with schizophrenia in a Japanese sample. 1147 15

In neurons, pituitary adenyl cyclase activating peptide (PACAP) stimulates signaling cascades, involving cAMP and calcium. PACAP appears to play a role in up-regulation of tyrosine hydroxylase and dopamine beta-hydroxylase via protein kinase C and/or protein kinase A. Furthermore, the PACAP gene (ADCYAP1) is located in chromosome 18p11, where linkage of bipolar disorders and schizophrenia has been reported. In this study, we scanned the coding region of the PACAP gene for mutations in 24 Japanese patients with schizophrenia and 24 Japanese patients with bipolar disorders. No variant in the coding region was found. One polymorphism, INV3-37A/T, in the third intron was detected. Case-control comparisons revealed no significant association between this polymorphism and schizophrenia or bipolar disorders. This study did not provide evidence for the contribution of the PACAP gene to the etiology of schizophrenia or bipolar disorders in the Japanese population.
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PMID:Association analysis of the pituitary adenyl cyclase activating peptide gene (PACAP) on chromosome 18p11 with schizophrenia and bipolar disorders. 1151 50

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT(2A) receptors. It is currently unknown if 5-HT(2A) receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT(2A) receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT(2A) receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT(2A) receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT(2A) immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT(2A) receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT(2A) receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT(2A) receptor activation may modulate reward-related behavior in rodents. 5-HT(2A) receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT(2A) receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.
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PMID:Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. 1195 20

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

Phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine, shares physical, structural and catalytic properties with tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) that catalyze the rate-limiting steps in the biosynthesis of the neurotransmitters dopamine, noradrenaline, and serotonin. Because these neurotransmitter systems have all been implicated in the pathophysiology of schizophrenia, the aromatic amino acid hydroxylases are among the likely candidates for genes associated with schizophrenia. A mutation in the functionally critical tetrahydrobiopterin cofactor binding domain of the PAH gene had been identified in African-American patients with the diagnosis of schizophrenia, and biochemical analyses suggested that this mutation has physiological consequences related to amine neurotransmitter function. DNA sequencing of the highly conserved cofactor binding domain of the PAH, TH, and TPH genes in African-American subjects with schizophrenia and unrelated, never mentally ill subjects from the NIMH Schizophrenia Genetics Initiative, was undertaken to assess the concordance of mutant genotype with psychiatric phenotype. The K274E mutation was observed in the PAH gene cofactor binding domain, and several polymorphisms were identified in adjacent intronic regions of the PAH, TH, and TPH genes. All of the genetic variants observed were represented in the schizophrenia group and in the never mentally ill group. Genetic evaluation of the family members of subjects with the PAH K274E mutation showed that all individuals with the K274E mutation also exhibited the PAH L321L polymorphism in the catalytic domain of the PAH enzyme.
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PMID:Aromatic amino acid hydroxylase genes and schizophrenia. 1221 Feb 76

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.
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PMID:[Human striatal D-neurons and their significance]. 1237 66

Schizophrenic patients with an onset before age 16 years (early-onset schizophrenia, EOS) would be a rare but attractive subpopulation for genetic studies. This study explored the relationship between the polymorphism of four dopamine-regulating-enzymes (tyrosine hydroxylase, dopamine-beta-hydroxylase, catechol-O-methyltransferase, monoamine oxidase-A) genes, four dopamine-receptors (dopamine D1, D2, D3, D4 receptors) genes and susceptibility to EOS in a Japanese sample. Subjects comprised 51 Japanese patients who met DSM-IV criteria for schizophrenia with an onset before age 16 (by age 15) and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was carried out by PCR-RELP using each restriction endonuclease. No significant difference was found in the allele frequencies or genotype distributions of any of the eight genes examined between EOS and the control groups. We did not find the relationship between the polymorphism of eight dopamine-related genes and susceptibility to EOS in a Japanese sample.
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PMID:Early-onset schizophrenia and dopamine-related gene polymorphism. 1249 8

Mesotelencephalic dopamine (DA) pathways are exquisitely vulnerable to ischemic-anoxic insult. These insults are known to produce long-term derangements in DA signaling and have been hypothesized to contribute, at least in part, to pathologic behaviors such as cerebral palsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Whether modest intermittent hypoxia, such as that encountered with repetitive apneas in premature infants, contributes to clinically significant impairments in DA signaling, and how these impairments manifest at a systems level, is unknown. To address these voids there is a need to develop animal models emulating features of a common disorder of prematurity, namely, apnea with hypoxia. Behavioral traits exhibited by such models include disturbed sleep-wake architecture, excessive locomotion, and impaired working memory persisting 1 to 2 months post-insult. Western-blot analysis of expression patterns of proteins involved in DA signaling (e.g., DA and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptors) are consistent with that which might be expected from hyper- or hypodopaminergic functioning in DA-responsive prefrontal cortex and striatal circuits, respectively. These novel observations suggest that intermittent hypoxia occurring during a period of critical brain development disrupts development of those mesotelencephalic pathways modulating the expression of sleep and wakefulness, locomotion, and executive functioning.
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PMID:Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning. 1252 74

It has recently been reported that the human corpus striatum, especially its ventral part, named as the nucleus accumbens, contains numerous non-monoaminergic aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme) neurons (D-neurons). D-neurons are the neurons immunoreactive for AADC but not immunoreactive for dopamine or serotonin. They lack the first-step monoamine synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. AADC is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons might 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 or noradrenaline, respectively. As the nucleus accumbens is one of the brain regions that are 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.
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PMID:[Localization of non-monoaminergic aromatic L-amino acid decarboxylase neurons (D-neurons) in the human striatum and their functional significance]. 1255 14

The rat prefrontal cortices participate in cognitive, affective and mnemonic functions. The importance of dopamine innervation for these computations is illustrated in studies showing that both supranormal levels and chemical lesions of prefrontal dopamine induce severe behavioral deficits. Observed hormone effects on some of these same behaviors suggest that the prefrontal cortices are also sensitive to gonadal steroids. These two influences seem to converge in recent evidence of increased dopamine axon density in representative prefrontal but not sensory or motor cortices in gonadectomized adult male rats. The seeming selectivity of these effects was further explored here using immunocytochemistry for tyrosine hydroxylase, dopamine-b-hydroxylase, serotonin and choline acetyltransferase to label neurochemically identified afferents in remaining, unstudied prefrontal fields of rat cortex in animals that were sham-operated or gonadectomized and given placebo, testosterone propionate, estradiol or dihydrotestosterone 28 days before being killed. Group comparisons revealed that across prefrontal zones, gonadectomy produced androgen-sensitive increases in presumed dopamine axon density, but did not affect the other afferents. These findings thus bolster evidence for a targeted gonadal steroid influence involving the prefrontal cortices and a neurotransmitter essential for their normal operations and implicated in their dysfunction in disorders such as schizophrenia as well.
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PMID:Long-term gonadectomy affects the density of tyrosine hydroxylase- but not dopamine-beta-hydroxylase-, choline acetyltransferase- or serotonin-immunoreactive axons in the medial prefrontal cortices of adult male rats. 1257 Nov 18


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