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)

The pathophysiology of polydipsia in patients with schizophrenia is inadequately understood. This study aims to investigate the genetic influence on polydipsia in schizophrenia, and is comprised of a family study and an association study. First, we screened in-patients in 14 psychiatric hospitals and found a total of 36 pairs of a proband and his/her first-degree relative, both of whom were diagnosed with schizophrenia. Among these pairs, a significant familial concordance of polydipsia was found (Fisher's exact test, two-sided, P = 0.0014; odds ratio, 88.20; 95% confidence interval, 7.31-1064.34). These results indicate that genetic factors may underlie the pathophysiology of polydipsia in patients with schizophrenia. Subsequently, we examined the genetic association between polydipsia/water intoxication and the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism in patients with chronic schizophrenia (polydipsics: n = 65; non-polydipsics: n = 97) because several lines of evidence suggested that ACE might be involved in the development of polydipsia in schizophrenia. The D allele of ACE was found to be associated with a non-significant trend toward an increased risk of polydipsia (P = 0.086). Furthermore, a significant allelic association was found between the D allele of ACE and water intoxication (P = 0.0392). This significance remained after the data were adjusted for confounding variables by regression analysis. These results suggest that the ACE D allele may be a risk factor for polydipsia/water intoxication in patients with schizophrenia.
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PMID:Genetic approaches to polydipsia in schizophrenia: a preliminary report of a family study and an association study of an angiotensin-converting enzyme gene polymorphism. 1270 30

Neonatal ventral hippocampal (nVH) lesioned male rat has been used as a model to test the hypothesis that early neurodevelopmental abnormalities lead to behavioral changes putatively linked to schizophrenia. There are significant gender differences in schizophrenia with male and female individuals differing in the age of onset, course and outcome of the disorder. In order to assess whether the behavioral effects of nVH lesions extend to or are different in female rats, we investigated spontaneous locomotion, grooming, social interactions and spatial memory in male and female rats post-pubertally at postnatal day (P) 56 following bilateral ibotenic acid of the ventral hippocampus at P7. The spontaneous locomotor activity in a novel environment of both male and female nVH lesioned rats was significantly enhanced compared to their respective sham-operated controls. In tests of social interactions, the number of encounters was significantly decreased in female lesioned rats, whereas the male nVH lesioned rats showed a significantly reduced duration of active social interactions. Furthermore, Morris water maze test showed a deficit of spatial learning/memory in only male lesioned rats with significant decrease in the latency to find hidden platform. These results suggest that while nVH lesions affect post-pubertal behavior in both sexes of rats, the males appear to be affected to a greater extent than the females underscoring the influence of sex differences in the development of behaviors in the nVH lesioned animals.
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PMID:Comparative behavioral changes between male and female postpubertal rats following neonatal excitotoxic lesions of the ventral hippocampus. 1273 72

Alterations in brain high-energy phosphate metabolism, determined by in vivo magnetic resonance spectroscopy (MRS), have been reported in subjects with a number of brain disorders including major depression, schizophrenia, and substance abuse. It is not clear to what extent these changes can be modified by pharmacological or nutritional means. To address this possibility, we evaluated changes in brain chemistry that were associated with oral creatine (Cr) administration. We hypothesized that oral Cr supplementation, by increasing brain creatine and high-energy phosphate stored in phosphocreatine, would result in an increase in the creatine resonance, as measured using proton 1H-MRS, and a decrease in the beta-nucleoside triphosphate (NTP) peak and an increase in the phosphocreatine (PCr) peak, as measured by phosphorus 31P-MRS, in brain of healthy human subjects. Fifteen healthy male subjects (age=22.9+/-2.2; body mass index=22.9+/-1.7), who were without any axis I disorders or physical or neurological illness, were recruited. Ten subjects took creatine-monohydrate, 0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days (creatine group). Five comparison subjects took equivalent amounts of sucrose as placebo (placebo group). Both 1H- and 31P-MRS scans were acquired at baseline, as well as at day 7 and day 14 of oral supplementation. 1H-MRS: Water suppressed localized spectra were acquired using a single-voxel (1.5 cm x 2 cm x 2 cm) proton MRS PRESS sequence in the left frontal lobe. 31P-MRS: Phosphorus spectral data were recorded from a 5-cm-thick axial brain slice using a short-TE slice selective spin-echo pulse sequence. The creatine group had significantly increased brain creatine levels (8.1% and 9.3%, in creatine/N-acetyl aspartate and creatine/choline ratios, respectively) compared to the placebo group over the 2-week period. The creatine group had significantly decreased beta-NTP levels (7.8%) and marginally increased PCr (3.4%) over the same period. In addition, the brain inorganic phosphate level increased over the same period in the creatine group (9.8%). The current study is the first multinuclear (1H and 31P) MRS study to evaluate changes in brain high-energy phosphate metabolism following oral creatine supplementation in healthy human subjects. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including major depression, schizophrenia, cocaine and opiate abuse, where alterations in brain high-energy phosphate metabolism have been reported.
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PMID:Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. 1285 Feb 48

SSR181507 ((3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at dopamine D(2) receptors and agonist activity at 5-HT(1A) receptors. SSR181507 antagonized apomorphine-induced climbing in mice and stereotypies in rats (ED(50) of 2 and 3.4 mg/kg i.p., respectively) and blocked D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice. SSR181507 did not induce catalepsy in rats (MED>60 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.) haloperidol-induced catalepsy. SSR181507 was also active in two models sensitive to antidepressant/anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a saccharin solution. Furthermore, SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with antidepressants. Coadministration of the selective 5-HT(1A) blocker SL88.0338 produced catalepsy and antagonized the effects of SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT(1A) receptors confers an atypical profile on SSR181507, and is responsible for its antidepressant/anxiolytic properties. Finally, SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of SSR181507 suggests that it should control the symptoms of schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of antidepressant/anxiolytic activities.
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PMID:SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. II: Behavioral profile predictive of an atypical antipsychotic activity. 1290 93

Schizophrenia unfolds during the late period of brain maturation, while myelination is still continuing. In the present study, we used MRI and T2 relaxation analysis to measure the myelin water fraction in schizophrenia. In schizophrenia (n=30) compared with healthy subjects (n=27), overall white matter showed 12% lower myelin water fraction (P=0.031), with the most prominent effects on the left genu of the corpus callosum (36% lower, P=0.002). The left anterior genu was affected in both first-episode (P=0.035) and chronic patients (P=0.011). In healthy subjects, myelin water fraction in total white matter and in frontal white matter increased with age, and with years of education, indicating ongoing maturation. In patients with schizophrenia, neither relation was statistically significant. Post-mortem studies of anterior frontal cortex demonstrated less immunoreactivity of two oligodendrocyte-associated proteins in schizophrenia (2',3'-cyclic nucleotide 3'-phosphodiesterase by 33%, P=0.05; myelin-associated glycoprotein by 27%, P=0.14). Impaired myelination in schizophrenia could contribute to abnormalities of neural connectivity and persistent functional impairment in the illness.
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PMID:Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. 1293 Dec 8

Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with (15)O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n=6) and normal volunteers (NVs) (n=12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1). Rest, (2). sensory motor control (SMC) task, and (3). decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n=5) and/or clozapine (n=5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol- and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidol-treated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.
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PMID:Clozapine but not haloperidol Re-establishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex. 1452 Mar 37

The dopamine 3 (D3) subtype receptor has been implicated in several neurological conditions, and potent and selective D3 ligands may have therapeutic potential for the treatment of drug addiction, Parkinson's disease, and schizophrenia. In this paper, we report computational homology modeling of the D3 receptor based upon the high-resolution X-ray structure of rhodopsin, extensive structural refinement in the presence of explicit lipid bilayer and water environment, and validation of the refined D3 structural models using experimental data. We further describe the development, validation, and application of a hybrid computational screening approach for the discovery of several classes of novel and potent D3 ligands. This computational approach employs stepwise pharmacophore and structure-based searching of a large three-dimensional chemical database for the identification of potential D3 ligands. The obtained hits are then subjected to structural novelty screening, and the most promising compounds are tested in a D3 binding assay. Using this approach we identified four compounds with K(i) values better than 100 nM and eight compounds with K(i) values better than 1 microM out of 20 compounds selected for testing in the D3 receptor binding assay. Our results suggest that the D3 structural models obtained from this study may be useful for the discovery and design of novel and potent D3 ligands. Furthermore, the employed hybrid approach may be more effective for lead discovery from a large chemical database than either pharmacophore-based or structure-based database screening alone.
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PMID:Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor: discovery of novel and potent D3 ligands through a hybrid pharmacophore- and structure-based database searching approach. 1452 3

Diffusion tensor imaging (DTI) can non-invasively examine the molecular diffusion of water in vivo and directly reflects the anatomical integrity of neural fibers in white matter. Fractional anisotropy (FA) can be calculated from DTI data, and utilized to evaluate white matter integrity. DTI was performed on 30 patients with schizophrenia and 19 healthy controls, and their FA values were subsequently measured in multiple brain regions. Statistical analyses revealed that FA values were decreased in the anterior cingulum of schizophrenia subjects. There were no significant differences between patients and controls in any other regions. This study supports the hypothesis that schizophrenia is associated with abnormal white matter integrity of the anterior cingulum.
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PMID:Abnormal anterior cingulum in patients with schizophrenia: a diffusion tensor imaging study. 1453 30

Prior exposure to the psychotomimetic drug phencyclidine (PCP) produces a number of schizophrenia-like behaviors in animals. The goal of the present study was to determine whether prior exposure to PCP produces decreased reward function, thereby modeling one aspect of negative schizophrenic symptomatology. To this aim, the consequences of prior exposure to PCP were assessed on two types of appetitive consumptive behavior. In the first set of experiments, the effects of PCP (15 mg/kg, 20 h before testing) on sucrose consumption were tested for three consecutive days under conditions of deprivation and nondeprivation. In the deprivation condition, animals were water deprived for 4 h prior to injection of PCP or saline (SAL). Twenty hours following the injection (24 h after the onset of water deprivation), animals were allowed access to either 5% sucrose or water for 30 min. In the nondeprivation condition, 5% sucrose consumption was measured for 30 min, 20 h after PCP or SAL injection and water consumption was measured during the 23.5 h preceding sucrose consumption. PCP decreased both sucrose and water consumption under deprivation conditions on the second and third day of testing but selectively decreased sucrose consumption under nondeprivation conditions on all three testing days. LiCl (50 mg/kg, 20 h before testing) did not significantly reduce sucrose consumption in the nondeprivation paradigm, indicating that the effect of PCP was not due to conditioned taste aversion. In the second experiment, PCP (15 mg/kg, 20 h before testing) decreased operant performance when animals were switched from a continuous reinforcement schedule of food delivery to a fixed ratio (FR4) schedule. Apomorphine (APO, 30 microg/kg, 30 min before testing), a positive control, induced a similar performance deficit. However, the PCP-induced deficit was not apparent until the third day of FR4 testing while the APO deficit was apparent on the first day. The effects of PCP on sucrose consumption demonstrate PCP-induced decreases in reward function. However, the delayed appearance of the PCP-induced decrease in operant performance suggests that these results may be better explained by a PCP-induced attentional deficit, also characteristic of schizophrenic psychopathology.
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PMID:Prior exposure to phencyclidine decreases voluntary sucrose consumption and operant performance for food reward. 1464 37

It has been suggested that perinatal treatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) induces transient neurodegeneration in the limbic and cortical structures of rats. Since dysfunction of these structures is associated with cognitive deficits in patients with schizophrenia, we studied the effects of subchronic treatment with PCP in perinatal rats with respect to spatial reference, reversal, and spatial working memories using the Morris water maze task in adulthood. In addition, we investigated the effect of D-serine, which has clinical relevance for the treatment of cognitive deficits in patients with schizophrenia. Our goal was to develop a neurodevelopmental model with predictive validity for the cognitive dysfunction described in patients with schizophrenia. Male and female Sprague-Dawley rats were treated with either saline or PCP (8.7 mg/kg s.c.) on days 7, 9, and 11, postnatal, and the long-term behavioral effects were investigated in adulthood. Male PCP-treated rats were slightly impaired during the spatial reference memory task, but strongly impaired during the reversal and spatial working memory tasks. Female rats were not significantly affected by this treatment. This cognitive deficit was reversed by chronic treatment with D-serine. We suggest that this model mimics some of the cognitive deficits of patients with schizophrenia and might be appropriate for the screening of putative antipsychotic agents for the treatment of these cognitive deficits.
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PMID:Spatial memory deficits induced by perinatal treatment of rats with PCP and reversal effect of D-serine. 1497 Aug 28


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