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)

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes.
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PMID:Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. 861 85

It has been hypothesized that glutamate receptor function is important in both the aetiology and treatment of schizophrenia. In order to understand how specific glutamate receptor genes are involved in the treatment of schizophrenia we have used a multiprobe oligonucleotide solution hybridization (MOSH) technique to examine the regulation of gene express of the NMDAR1, 2A, 2B, 2C, 2D receptor subunits in the left rat brain following treatment with the optical isomers of flupenthixol. cis- and trans-flupenthixol are both present in the commonly used oral and depot treatments for schizophrenia and a controlled trial showed that cis-flupenthixol had a significantly superior ability to ameliorate the positive symptoms of schizophrenia compared to its trans-isomer. At a dose of 0.2 mg/kg/day over a period of 1, 2, 4, 8, 12 and 24 weeks, we found that both isomers down regulated the expression of NMDAR1 mRNA in most regions of the brain. NMDAR2A, 2B and 2C receptor subunits showed a significantly decreased expression from 12 to 24 weeks but after 2 weeks NMDAR2B, 2C, 2D expression was increased in several brain regions. The NMDAR1 receptor subunit immunoreactivity in the right brain following 4 and 24 weeks of drug treatment was also examined by Western blotting. Both trans- and cis-flupenthixol significantly decreased the NR1 immunoreactivity in the right cerebellum after 24 weeks of treatment. These results suggest that NMDA receptor subunits may have a role in the action of antipsychotic drugs. If we assume that the NMDA receptor expression changes reflect a beneficial and significant mechanism in the treatment of schizophrenia, it could be argued that NMDA receptor changes are more related to the negative or non-specific symptoms of schizophrenia.
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PMID:Gene expression studies of mRNAs encoding the NMDA receptor subunits NMDAR1, NMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D following long-term treatment with cis-and trans-flupenthixol as a model for understanding the mode of action of schizophrenia drug treatment. 952 55

Phencyclidine (PCP) is a drug of abuse that produces schizophrenia-like symptoms in humans and increases locomotor activity and stereotypic behavior in rodents. PCP-induced alteration in rat locomotor activity is thought to be mediated by an inhibition of N-methyl-D-aspartate (NMDA) receptors in the striatum and other brain regions. In this study, rats treated chronically with PCP (20 mg/kg once per day for 5 days) showed a marked increase in locomotor activity following a PCP challenge (3.2 mg/kg) administered after either 3 or 8 days of withdrawal. In biochemical assays, the release of striatal [14C]GABA by NMDA was enhanced by about 77% by chronic PCP treatment, whereas [3H]ACh release was increased by about 31% in tissue from PCP-treated rats. Even though binding experiments with 1-[1-(2-thiethyl)cyclohexyl]piperidyl-3,4 3H(N) ([3H]TCP) showed no alteration in the Kd or Bmax in whole striatum, quantitative immunocytochemical experiments found an upregulation in the NR1 subunit in the cell bodies and neuropil of cortical and striatal regions of the forebrain following chronic PCP treatment. An increase in the size of NR1-immunoreactive cells in the forebrain was also observed following chronic PCP treatment. Together, these data may help in understanding the mechanisms underlying the adaptive response to chronic reduction in glutamatergic NMDA transmission that has been postulated to be involved in the etiology of schizophrenia.
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PMID:Augmentation of locomotor activity by chronic phencyclidine is associated with an increase in striatal NMDA receptor function and an upregulation of the NR1 receptor subunit. 1002 41

Saturation analyses of [3H]L-689,560, [3H]CGP 39653 and NMDA-specific [3H]ifenprodil binding revealed an equivalent increase (0.7 pmol/mg) in the number of [3H]L-689,560 and [3H]ifenprodil binding sites in superior temporal cortex (BA22) from drug-treated chronic schizophrenic patients and control subjects. No differences were observed between control and schizophrenic subjects for [3H]CGP 39653 binding in BA22, or for any of the radioligands binding to pre-motor cortex (BA6). Since [3H]L-689,560, [3H]CGP 39653 and [3H]ifenprodil label the glycine, glutamate and ifenprodil sites of the NMDA receptor complex, which are associated with NR1, NR1/NR2A and NR1/NR2B subunits respectively, our findings suggest that NR2B-containing receptors are selectively up-regulated in superior temporal cortex in schizophrenia.
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PMID:NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia. 1020 72

Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.
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PMID:Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia. 1110 7

Glutamatergic dysregulation has been hypothesized to play a role in schizophrenia. The N-methyl-D-aspartate (NMDA) type of glutamate receptor especially is of interest because, in addition to binding sites for glutamate and glycine, a necessary co-agonist, this receptor also contains noncompetitive binding sites for the psychotomimetics phencyclidine (PCP), MK-801, and ketamine. PCP-induced psychosis has been a useful disease model in that both the positive as well as the negative symptomatologies seen in schizophrenia are observed. Recently, a mouse deficient in expression of the NR1 subunit gene (NMDAR1) of the heteromeric receptor has been developed and shown to display aberrant behaviors, with reduced social and sexual interactions as well as increased stereotypic motor activity. In an extensive examination of the NMDAR1 gene in our laboratory in approximately 100 chronic schizophrenic patients, 28 unique sequence changes were identified, including eight single nucleotide polymorphisms (SNPs) in the 5' untranslated region (5'UTR), six SNPs in coding regions (cSNPs), eleven intronic SNPs, two intronic deletions of 7 and 30 bp, and an intronic microinsertion/deletion. With the exception of one previously reported cSNP, all of the identified changes were novel. The frequency of polymorphisms differed significantly by ethnicity and several appeared to be in linkage disequilibrium. None of the changes appeared likely to be of functional significance, thus suggesting that changes in the genomic NMDAR1 are unlikely to contribute to the etiology of schizophrenia. Estimates of nucleotide diversity are comparable to those observed in studies of other genes.
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PMID:Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients. 1132 95

Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7, 9 and 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X(L) proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy.
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PMID:Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. 1172 Jul 78

Regional cerebral blood flow (rCBF) data from two PET-15O water schizophrenia studies were analyzed using individually placed, magnetic resonance (MR)-guided hippocampal volumes of interest (VOI). In one study, normal (N = 10) and schizophrenic (N = 18) volunteers performed an overlearned auditory discrimination task in rest, control, and decision conditions. In the other study, schizophrenic and normal volunteers received the noncompetitive NMDA receptor antagonist ketamine and placebo and had sequential rCBF evaluations. Moreover, the schizophrenic volunteers were off drug in one study and on antipsychotic drug in the second study, allowing an additional comparison of medication status. VOIs were placed on anterior, middle, and posterior hippocampal areas in each PET image from both studies, redirected from an MR scan, and individually adjusted. While no hippocampal activation was apparent in either the normal or schizophrenic group in the task vs. condition comparison, rCBF was higher in the schizophrenic than in the normal hippocampus in both task and control conditions, independently. In addition, at rest rCBF was significantly higher in the unmedicated group of schizophrenics than in the group of medicated patient volunteers and higher than in the normal comparison group. This suggests that schizophrenia is associated with elevated rCBF in the hippocampus, which "normalizes" with antipsychotic drug treatment. Ketamine, the noncompetitive NMDA receptor antagonist, was more potent in reducing rCBF in the schizophrenic group compared to the normal volunteer group. These data are consistent with a previous report from our laboratory of reduced NMDA receptor NR1 subunit expression and possible abnormal NMDA receptor composition in schizophrenia. These data show an abnormality of hippocampal function in schizophrenia and suggest that this abnormality may be associated with the pathophysiology of the illness.
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PMID:Probing the human hippocampus using rCBF: contrasts in schizophrenia. 1173 7

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABA(A) receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABA(A) receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.
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PMID:Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA(A) synaptic receptors. 1212 79

Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population.
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PMID:Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia. 1236 94


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