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)

Permanent verbal, visual scenic and coenaestetic hallucinations are the most prominent psychopathological symptoms aside from psychomotor disorders in speech-sluggish catatonia, a subtype of chronic catatonic schizophrenia according to Karl Leonhard. These continuous hallucinations serve as an excellent paradigm for the investigation of the assumed functional disturbances of cortical circuits in schizophrenia. Data from positron emission tomography (F-18-FDG-PET and F-18-DOPA-PET) from three patients with this rare phenotype were available (two cases of simple speech-sluggish catatonia, one case of a combined speech-prompt/speech-sluggish subtype) and were compared with a control collective. During their permanent hallucinations, all catatonic patients showed a clear bitemporal hypometabolism in the F-18-FDG-PET. Both patients with the simple speech-sluggish catatonia showed an additional bilateral thalamic hypermetabolism and an additional bilateral hypometabolism of the frontal cortex, especially on the left side. In contrast, the patient with the combined speech-prompt/speech-sluggish catatonia showed a bilateral thalamic hypometabolism combined with a bifrontal cortical hypermetabolism. However, the left/right ratio of the frontal cortex also showed a lateralisation effect with a clear relative hypometabolism of the left frontal cortex. The F-18-DOPA-PET of both schizophrenic patients with simple speech-sluggish catatonia showed a normal F-18-DOPA storage in the striatum, whereas in the right putamen of the patient with the combined form a higher right/left ratio in F-DOPA storage was discernible, indicating an additional lateralized influence of the dopaminergic system in this subtype of chronic catatonic schizophrenia. Most likely, the prominent bitemporal F-18-FDG- hypometabolism in these chronic schizophrenic patients with speech-sluggish catatonia suffering from permanent continuous hallucinations, reflects a deficit in sensoric gating following prenatal cortical neurodevelopmental disturbances. However, the functional disturbances underlying hallucinations in "the schizophrenias" seem to be more complex; in different subtypes of the schizophrenic spectrum disorder hallucinations seem to be based on alterations in additional cortical and subcortical brain regions.
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PMID:Disturbed neural circuits in a subtype of chronic catatonic schizophrenia demonstrated by F-18-FDG-PET and F-18-DOPA-PET. 1147 18

The dopamine (DA) D2 family of receptors consists of the D2, D3, and D4 receptors. The DA D4 receptor is of interest as a target for drugs to treat schizophrenia based upon its high affinity for the atypical antipsychotic clozapine and its localization to the limbic and cortical regions of the brain. As part of a program to identify novel DA D4 receptor antagonists, a high-volume screen using the Parke-Davis compound library was initiated. This led to the discovery of PD 89211 (benzenemethanol, 2-chloro-4-[4-[(1H-benzimidazol-2-yl)methyl]-1-piperzinyl]) that displaced [3H]spiperone binding to hD4.2 with an affinity (Ki) of 3.7 nM. PD 89211 exhibited high selectivity for the DA D4.2 receptor (> 800-fold) as compared to other hDA receptor subtypes, rat brain serotonin, and adrenergic receptors. In vitro, PD 89211 had D4 receptor antagonist activity reversing quinpirole-induced [3H]thymidine uptake in CHOpro5 cells (IC50 = 2.1 nM). Limited structure-activity relationship (SAR) studies indicated that compounds with a 4-chloro-, 4-methyl-, and 3-chloro- substituents on the phenyl ring retained high affinity for D4 receptors, while those with a 4-methoxy- and no substituent had less affinity. While all clinically effective antipsychotics increase DA synthesis (DOPA accumulation) in rodents, PD 89211 did not increase DA synthesis in the DA-enriched striatum, indicating no effect on DA turnover and low propensity for exhibiting motor side effects. However, it did increase catecholamine synthesis in rat hippocampus, as did clozapine. Moreover, PD 89211 selectivity increased catecholamine synthesis in the hippocampus of wild type but not in mice lacking D4 receptors, suggesting that one function of D4 receptors may be to modulate DA/norepinephrine (NE) turnover in this brain area known to possess D4 receptors. The discovery of compounds like PD 89211 provides a tool to help in understanding the function of DA D4 receptors in the CNS.
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PMID:The discovery of PD 89211 and related compounds: selective dopamine D4 receptor antagonists. 1181 97

Positron emission tomography (PET) has been shown to be of great importance in elucidating the mechanism of action of antipsychotic drugs. In psychotic patients L-[11C]DOPA PET has been used to demonstrate some differences in dopaminergic activity compared with that in healthy volunteers. Ten healthy volunteers were investigated with PET and L-[11C]DOPA. Ten drug-free patients with psychosis, nine stable schizophrenics treated with clozapine, and nine stable patients treated with classical antipsychotics were also investigated with L-[11C]DOPA. Principal-component analysis was employed for the analysis of L-[11C]DOPA Ki values across a number of corticostriatal brain regions. These data revealed a significant three-component model with clear-cut separation between healthy controls and patients with unmedicated schizophrenia. Stable optimal treatment with either classical neuroleptics or clozapine partially, albeit differentially, reversed the aberrant patterns seen in drug-free schizophrenia. It can thus be concluded that schizophrenia is associated with abnormal patterns of L-[11C]DOPA utilization in corticostriatal systems. Treatment with clozapine or classical neuroleptics induces partial, albeit differential, normalization of the abnormal patterns seen in untreated schizophrenia.
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PMID:Different corticostriatal patterns of L-DOPA utilization in patients with untreated schizophrenia and patients treated with classical antipsychotics or clozapine. 1291 93

Catechol O-methyltransferase (COMT) inactivates catecholamines and catechol-containing drugs such as L-DOPA. The common genetic polymorphism Val158Met in the human COMT gene is suspected to be associated with "persistence" or risk for schizophrenia. In this study, we attempted to identify the canine COMT gene fragment and to find a similar polymorphism and to reveal its genetic distribution among five representative canine breeds. We found that the amplified gene consisted of 663 bp nucleotides and was 84% homologous with the human COMT gene. The single nucleotide polymorphisms, guanine adenine substitution, were observed at the 39th, 216th and 482nd nucleotides. From the genotyping of the 216th polymorphism among 266 dogs by the polymerase chain reaction-restriction fragment length polymorphism method with restriction enzyme EagI, and that of the 482nd polymorphism with restriction enzyme SfcI, we found inter-breed variations of genotypes as well as of allelic frequencies for both of these polymorphic regions. These results suggest that the identified polymorphisms will be useful tools in elucidating the genetic background of canine behavioral traits.
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PMID:Breed differences in genotype and allele frequency of catechol O-methyltransferase gene polymorphic regions in dogs. 1503 47

The etiology of Asperger syndrome is essentially unknown, but abnormality of the dopamine system has been shown in clinically overlapping disorders. The present study was designed to investigate the presynaptic dopamine function in Asperger syndrome. Eight healthy, drug-free males with Asperger syndrome and five healthy male controls were examined with positron emission tomography using 6-[18F]fluoro-L-DOPA ([18F]FDOPA) as a tracer. In the Asperger syndrome group, the [18F]FDOPA influx (Ki) values were increased in the striatum, i.e. in the putamen and caudate nucleus and in the frontal cortex. The results indicate that the dopamine system is affected in subjects with Asperger syndrome. Partially similar results have also been obtained in schizophrenia, suggesting an overlap not only of the clinical features but also of pathogenesis.
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PMID:Increased presynaptic dopamine function in Asperger syndrome. 1507 9

Dopamine neurotransmission influences those cognitive processes, which are generally regarded as prefrontal cortical functions. In previous positron-emission-tomography (PET) studies, net blood-brain clearance of [18F]-fluoro-l-DOPA (FDOPA) correlated with impaired cognitive performance in patients with Parkinson's disease or schizophrenia. We hypothesized that FDOPA influx also correlates with performance of cognitive tasks associated with prefrontal functioning in healthy volunteers. The net blood-brain clearance of FDOPA (K(in)(app)) was mapped in a group of 11 healthy volunteers and calculated in striatal volumes-of-interest. The Wisconsin-Card-Sorting-Test (WCST), Stroop-Test, Trail-Making-Test (TMT-A/B), and Continuous-Performance-Test (CPT-M) had been administered previously to the same subjects. No correlation of K(in) (app) with perseverative errors in WCST or age could be found. However, there were significant positive correlations between the magnitude of K(in)(app) in caudate nucleus, putamen, and midbrain with performance of the TMT-B, CPT-M, and the Stroop test. Highest correlations were found between the time needed to perform the Stroop interference task and the K(in)(app) of striatal areas (Caudate nucleus: -0.780, P = 0.005; putamen: -0.870, P < 0. 001). Thus, the present findings reveal a strong correlation between dopamine synthesis capacity in striatum of healthy volunteers and performance of cognitive tasks linked to the prefrontal cortex.
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PMID:'Prefrontal' cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation. 1713 2

The discovery of dopamine as a neurotransmitter in brain by Arvid Carlsson approximately 50 years ago, and the subsequent insight provided by Paul Greengard into the cellular signalling mechanisms triggered by dopamine, gained these researchers the Nobel Prize for Medicine in 2000. Dopamine research has had a greater impact on the development of biological psychiatry and psychopharmacology than work on any other neurotransmitter. Neuropsychological views of the role of dopamine in the CNS have evolved from that of a simple reward signal to a more complex situation in which dopamine encodes the importance or 'salience' of events in the external world. Hypofunctional dopamine states underlie Parkinson's disease and attention deficit hyperactivity disorder, and there is increasing evidence for dopamine hyperactivity in schizophrenia. Some of the medicines that are most widely used in psychiatry, such as L-DOPA, methylphenidate and neuroleptic drugs, act on dopaminergic mechanisms.
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PMID:Dopamine: 50 years in perspective. 1736 65

The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.
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PMID:Human D-amino acid oxidase: an update and review. 1792 43

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D(1) and D(2) receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [(11)C]SCH23390, [(11)C]raclopride, [(11)C]FLB457, [(11)C]PE2I, or L-[beta-(11)C]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D(1) and D(2) receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders.
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PMID:Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography. 1796 43

The relationship between limited tyrosine availability, DA (dopamine) synthesis and DA levels in the medial prefrontal cortex (MPFC) of the rat was examined by in vivo microdialysis. We administered a tyrosine- and phenylalanine-free mixture of large neutral amino acids (LNAA-) IP to lower brain tyrosine, and the norepinephrine transporter inhibitor desipramine (DMI) 10 mg/kg IP to raise MPFC DA levels without affecting DA synthesis. For examination of DOPA levels, NSD-1015 20 microM was included in perfusate. Neither NSD-1015 nor DMI affected tyrosine levels. LNAA- lowered tyrosine levels by 45%, and lowered DOPA levels as well; this was not additionally affected by concurrent DMI 10 mg/kg IP. In parallel studies DMI markedly increased extracellular levels of DA (420% baseline) and norepinephrine (NE) (864% baseline). LNAA- had no effect on baseline levels of DA or NE but robustly lowered DMI-induced DA (176% baseline) as well as NE (237% baseline) levels. Even when DMI (20 microM) was administered in perfusate, LNAA- still lowered DMI-induced DA and NE levels. We conclude that while baseline mesocortical DA synthesis is indeed dependent on tyrosine availability, the MPFC maintains normal extracellular DA and NA levels in the face of moderately lower DA synthesis. During other than baseline conditions, however, tyrosine depletion can lower ECF DA and NE levels in MPFC. These data offer a potential mechanism linking dysregulation of tyrosine transport and cognitive deficits in schizophrenia.
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PMID:Tyrosine depletion lowers dopamine synthesis and desipramine-induced prefrontal cortex catecholamine levels. 1808 73


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