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)

Emotional and neutral word versions of the fused rhymed words dichotic listening test were administered to members of 18 pairs of monozygotic twins discordant for schizophrenia, 7 pairs concordant for schizophrenia, and 7 pairs of normal twins. In the discordant group, affected twins had smaller right ear advantages than did their unaffected cotwins for neutral words. The difference was completely attenuated with the presentation of emotional words or in less powerful between-group comparisons that included twins concordant for schizophrenia and normal twins. It is unlikely that this finding reflects an abnormality in the lateralized representation of language, both because we did not find a correlation between handedness scores and dichotic listening scores and because emotional stimuli normalized results. The finding may reflect abnormalities in the allocation of attention for priming language centers in the left hemisphere. 'At risk' subjects, i.e., the unaffected members of the discordant pairs, did not differ significantly from normal monozygotic twins on measures of dichotic listening.
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PMID:Dichotic listening in monozygotic twins discordant and concordant for schizophrenia. 151 79

The dopamine (DA) hypothesis of schizophrenia proposes hyperactivity of the mesocorticolimbic DA system, originating within the A10 DA cells of the ventral tegmental area (VTA), as a pathophysiological mechanism. Thus, reduction of activity in this system, including that produced by putative "autoreceptor-selective" DA agonists, may be of clinical utility. The present studies compared the ability of eight D2 DA receptor agonists to inhibit the firing of rat A10 DA neurons after i.v. administration. Both N-n-propyl-N-phenylethyl-p(3-hydorxyphenyl)ethylamine hydrochloride (RU 24213) and 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]- azepine dihydrochloride (B-HT 920) were potent, high-efficacy agonists which completely inhibited the firing of A10 DA cells. The putative autoreceptor-selective DA agonists 3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-(1)-butyl)-indole hydrochloride (EMD 23,448) and (+)-3-(3-hydroxy-phenyl)-N-n-propylpiperidine [(+)-3-PPP] were considerably weaker than RU 24213 and B-HT 920, but also exhibited "full" efficacy (i.e., they completely suppressed cell firing). The putative autoreceptor agonist preclamol [(-)-3-PPP] and its trans-fused congener (-)-HW 165 were weak partial agonists that failed to completely inhibit A10 DA cells. The new putative autoreceptor agonist N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,3]dimethylopropa namide (SDZ 208-911) was also a weak partial agonist that exhibited partial antagonist effects (reversed inhibition produced by the D2 agonist quinpirole), whereas its structural analog N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2-dimethylopropa namide (SDZ 208-912) was nearly inactive as an agonist, but was an effective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electrophysiological effects of putative autoreceptor-selective dopamine agonists on A10 dopamine neurons. 809 68

During gross anatomy dissections of the brain, a developmental abnormality of the septum pellucidum was found in a 31-year-old male cadaver. Other parts of the central nervous system in this cadaver were normal in every aspect. Histological samples were taken from the neighboring areas of this abnormality, and they were examined under light microscope and scanning electron microscope. In this abnormality of the septum pellucidum, the two laminae of the septum pellucidum were fused together and there was a hole located 1 cm anterior to its apex. The maximum diameter of the hole was 0.5 cm in the sagittal plane and 0.6 cm in the vertical plane. In the light microscopic and scanning electron microscopic examinations, the free margin of this foramen was regular, and the surrounding tissue was intact and histologically unique to the septum pellucidum. Ependymal cells were present at the free margin of the foramen. Cavum vergae, cavum septum pellucidum, and agenesis of the septum pellucidum are described in the literature. These three abnormalities are seen in cadavers usually with histories of schizophrenia and other psychiatric or neurologic disorders. In a retrospective study, the cadaver with this abnormality had a history of schizophrenia and no history or signs of any kind of brain or head operation. As far as we could ascertain, the abnormality described here has not been reported previously.
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PMID:Unreported anatomical variation of septum pellucidum. 921 41

The presence of disorders of eye movements is today regarded as 'the strongest candidate for a genetically transmitted biological trait marker of schizophrenic disorders' (1). The present study is based on the experience, rather than the behaviour, of one patient in a search for a method of objectifying his visual problems. This method was found to be a simple test, which demonstrates a disturbance of fixation: while one eye accommodated on the figure without vergence, the other, vergent, eye fused with the image of the related background. The disorder had been misdiagnosed as 'exophoria' in conventional ophthalmological examinations, because prevailing ophthalmological theory accepts only one mode of vision; according to the most recent researches, however, it is necessary to distinguish two complementary modes of vision--one for panorama and one for detail--which differ in their coordination of vergence and accommodation. This new bimodal theory of vision--presented here for the first time--made it possible to understand the cause of the disorder as a substitution of sighting for fixation, due either to a disinhibition of panorama vision during fixation vision, or to an interchange of ipsilateral temporal and contralateral nasal projections from the retina, both associated with a fixation disparity. After correction of the patient's fixation disparity according to an unusual method, the dissociation of the visual goals was remedied and the mental disturbances of the patient vanished.
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PMID:The somatic component of schizophrenia: a dissociation of the goals of visual attention and bifoveal fixation? 1034 Feb 97

Tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, is predominantly expressed in several cell groups within the brain, including the dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, and the noradrenergic neurons of the locus coeruleus. To investigate the regulation of cell type-specific TH expression, we cloned and sequenced a 5.5kb fragment of human genomic DNA immediately 5(') of the TH coding region. This 5(')-flanking region does not contain either a CAAT box or a GC-rich region, but does contain a TATA box and consensus binding sequences for basal (TATA and CRE), and DA neuron-specific (NBRE, Gli, and BBE) transcription factors. Sequence analysis showed low overall homology with the rat and mouse TH promoter regions, with the exception of two high-homology domains, which encompassed -2384 to -2323 and -123 to -65, respectively. Interestingly, these distal and proximal domains contained NBRE, BBE, CRE, and TATA boxes, which are known to play important roles in DA neurogenesis. To further localize the TH promoter region responsible for transcriptional activity, we fused a 3301-bp human TH promoter fragment (-3174 to +127) to a luciferase reporter gene, and used this to assess promoter activity in neuronal and non-neuronal cell lines. Consistent with endogenous TH expression, this promoter construct was active in SH-SY5Y human neuroblastoma cells but not F3 human neural stem cells (NSCs). Deletion analysis of TH promoter/luciferase constructs revealed the presence of the repressor element in -1232 to -1210 upstream of transcription initiation site. While this region repressed 85% of promoter activity when transfected into F3 cells, it was not active in SH-SY5Y cells. These data suggest that the repressor element may play an important role in neuron cell-specific expression of the TH gene. Our results may provide insight into neuronal cell-specific expression of the human TH gene and allow a better understanding of catecholaminergic neuron disorders such as Parkinson's disease and schizophrenia.
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PMID:Cloning and cell type-specific regulation of the human tyrosine hydroxylase gene promoter. 1465 89

Neuregulin-1 (NRG-1) has been identified genetically as a schizophrenia susceptibility gene, but its function in the adult brain is unknown. Here, we show that NRG-1beta does not affect basal synaptic transmission but reverses long-term potentiation (LTP) at hippocampal Schaffer collateral-->CA1 synapses in an activity- and time-dependent manner. Depotentiation by NRG-1beta is blocked by two structurally distinct and selective ErbB receptor tyrosine kinase inhibitors. Moreover, ErbB receptor inhibition increases LTP at potentiated synapses and blocks LTP reversal by theta-pulse stimuli. NRG-1beta selectively reduces AMPA, not NMDA, receptor EPSCs and has no effect on paired-pulse facilitation ratios. Live imaging of hippocampal neurons transfected with receptors fused to superecliptic green fluorescent protein, as well as quantitative analysis of native receptors, show that NRG-1beta stimulates the internalization of surface glutamate receptor 1-containing AMPA receptors. This novel regulation of LTP by NRG-1 has important implications for the modulation of synaptic homeostasis and schizophrenia.
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PMID:Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. 1622 46

The dopaminergic and glutamatergic systems interact to initiate and organize normal behavior, a communication that may be perturbed in many neuropsychiatric diseases, including schizophrenia. We show here that NMDA, by allosterically modifying NMDA receptors, can act as a scaffold to recruit laterally diffusing dopamine D1 receptors (D1R) to neuronal spines. Using organotypic culture from rat striatum transfected with D1R fused to a fluorescent protein, we show that the majority of dendritic D1R are in lateral diffusion and that their mobility is confined by interaction with NMDA receptors. Exposure to NMDA reduces the diffusion coefficient for D1R and causes an increase in the number of D1R-positive spines. Unexpectedly, the action of NMDA in potentiating D1R recruitment was independent of calcium flow via the NMDA receptor channel. Thus, a highly energy-efficient, diffusion-trap mechanism can account for intraneuronal interaction between the glutamatergic and dopaminergic systems and for regulation of the number of D1R-positive spines. This diffusion trap system represents a molecular mechanism for brain plasticity and offers a promising target for development of antipsychotic therapy.
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PMID:Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines. 1640 51

A chiral procedure based on EKC was developed and validated for determination of the enantiomeric purity of PHA-543613, a drug candidate that was under development for treatment of the cognitive deficits of Alzheimer's disease and schizophrenia. Separation of enantiomers is accomplished via differential, enantiospecific complexation with a single-isomer, precisely sulfated beta-CD and heptakis-6-sulfato-beta-CD (HpS-beta-CD). Both neutral and sulfated CDs were screened before selecting HpS-beta-CD as the chiral selector. The separation is conducted in a 61 cm x 50 microm uncoated fused silica capillary with 25 mM HpS-beta-CD in pH 2.50, 25 mM lithium phosphate as the separation buffer with detection at 220 nm. Application of reverse polarity at -30 kV results in an elution time of about 12 min for PHA-543613 and 13 min for the undesired S-enantiomer. Quantification is versus an authentic reference S-enantiomer as an external standard in combination with an internal standard. The procedure was validated over the range 0.1-2.0% w/w. The detection limit is 0.01-0.02%. The amount of distomer intrinsic to the drug substance is about 0.1% or less. The developed method was used to generate stability data on multiple lots: in one case for up to 3 years.
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PMID:Method for enantiomeric purity of a quinuclidine candidate drug by capillary electrophoresis. 1701 19

Dichotic listening (DL) has been used as a tool to investigate possible left cerebral dysfunction in schizophrenia. However, the wide range of DL tests (e.g., words, emotions, sentences) as well as patient groups ("heterogeneity") has introduced several confounders. Assessing relatives of patients with schizophrenia may overcome some of these problems, and may be more useful in determining if loss of functional cerebral laterality in schizophrenia is a state or a trait phenomenon. The fused consonant-vowel DL test was administered to 114 subjects: 20 individuals with familial schizophrenia, 42 of their healthy relatives, and 52 healthy volunteers. We did this to investigate whether the normal language processing asymmetry-a right ear advantage (REA)-is present, and whether it could serve as a marker for genetic liability. General performance accuracy level was lower in schizophrenia patients and their relatives but the expected REA was present in all groups. Adjusting for age, accuracy, and obligate status made no difference. In conclusion, familial schizophrenic patients and their relatives have normal REA and hearing laterality on the fused DL test.
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PMID:Evidence of normal hearing laterality in familial schizophrenic patients and their relatives. 1772 25

The acquisition of multiple brain imaging types for a given study is a very common practice. However these data are typically examined in separate analyses, rather than in a combined model. We propose a novel methodology to perform joint independent component analysis across image modalities, including structural MRI data, functional MRI activation data and EEG data, and to visualize the results via a joint histogram visualization technique. Evaluation of which combination of fused data is most useful is determined by using the Kullback-Leibler divergence. We demonstrate our method on a data set composed of functional MRI data from two tasks, structural MRI data, and EEG data collected on patients with schizophrenia and healthy controls. We show that combining data types can improve our ability to distinguish differences between groups.
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PMID:A feature-based approach to combine functional MRI, structural MRI and EEG brain imaging data. 1794 95


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