UMLS:C0036341 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is considerable controversy regarding a putative association between schizophrenia and a biallelic BalI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3), although meta-analyses of published data suggest an association. If such an association exists, it may be detectable at markers physically close to DRD3. Accordingly, we conducted a case-control association study using D3S1310, a short tandem repeat polymorphism located approximately 700 kb telomeric to DRD3 on chromosome 3q13.3. The subjects were Swedish patients with schizophrenia (DSM III-R criteria, n = 110) and screened adult controls (n = 83). A trend for a negative association with the 141 bp allele was detected (chi2 = 7.6, d.f. = 1, P = 0.006; odds ratio 0.46, 95% confidence intervals 0.26, 0.81). However, following corrections for multiple comparisons using subgroups (n = 15) the difference was not significant. Also, due to the risk for population stratification in case-control association studies the results must be treated as tentative. If replicated the results may lend further support for the proposition of an association between schizophrenia and DRD3 or a gene in close proximity to DRD3 on chromosome 3q.
...
PMID:Trend for an association between schizophrenia and D3S1310, a marker in proximity to the dopamine D3 receptor gene. 1040 2

The association between schizophrenia and the Ser9Gly variant of the dopamine D3 receptor gene (DRD3) has been the subject of numerous studies. Under meta-analysis this site, or one or more in linkage disequilibrium with it, appears to contribute a small increase to the relative risk of schizophrenia. In this study, 768 bp of the 5'-leader region of DRD3 mRNA was screened for polymorphisms to assess their contribution to the association of DRD3 with schizophrenia. A cluster of three single nucleotide polymorphisms (SNPs) was identified in tight linkage disequilibrium with each other and with the Ser9Gly polymorphism. One of the 5'-leader SNPs encodes a Lys9Glu variant within a 36 amino acid residue stretch of an upstream open reading frame (uORF). Two common haplotypes are found in the population examined; one is linked to the Ser9 coding variant and the other to the Gly9 variant. A panel of 73 schizophrenic patients and 56 matched controls recruited from the East Anglia region of the United Kingdom was screened for disease association at these sites. Since the 5'-leader and coding sites are in tight disequilibrium, the combined genotype of all 4 sites was scored for each patient. A significant association was seen between disease and the frequency distribution of these genotypes (chi2 = 13.19, d.f. = 3, P = 0.0042; Cochran method for sparse cells applied). A 20% excess of one of the heterozygous genotypes, in which the sequences differ at three of the four SNPs, including Ser9/Gly9 in the receptor and Lys9/Glu9 in the uORF, was found in the patient group. An absence of association of disease with the Ser9Gly polymorphism had previously been reported for this panel. This suggests that these SNPs and the corresponding coding changes may exert a combined or synergistic effect on susceptibility to schizophrenia.
...
PMID:A cluster of single nucleotide polymorphisms in the 5'-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. 1067 Jul 76

In the search for genetic factors contributing to tardive dyskinesia, dopamine receptor genes are considered major candidates. The dopamine D3 receptor is of primary interest as dopamine D3 receptor knock-out mice show locomotor hyperactivation resembling extrapyramidal side-effects of neuroleptic treatment. Furthermore, Steen and colleagues (1997) recently reported an association between tardive dyskinesia and a dopamine D3 receptor gene variant. In the present study we tried to replicate this finding. We investigated 157 patients with schizophrenia or schizoaffective disorder receiving long-term neuroleptic medication who never or persistently displayed tardive dyskinesia. As advanced age is a main risk factor for tardive dyskinesia, we also compared older patients with a long duration of schizophrenia not displaying tardive dyskinesia to younger patients with a shorter duration of the illness displaying tardive dyskinesia. However, we found no evidence that the dopamine D3 receptor gene is likely to confer susceptibility to the development of tardive dyskinesia.
...
PMID:Dopamine D3 receptor variant and tardive dyskinesia. 1073 62

Although the association between the Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia has been investigated by many research groups, it is not known whether the Ser9Gly polymorphism alone or a variation in linkage disequilibrium may effect susceptibility to schizophrenia. We searched the 5' region of the DRD3 gene and found three novel polymorphisms: -712G/C, -205A/G, and Ala38Thr. The Ala38Thr polymorphism is located in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients and 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association between the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0.02). Furthermore, there was a highly significant association between haplotypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia (P = 0.0007, corrected P = 0.007). These positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls (P = 0.04 and 0.0004, respectively). The most allelic differences of the Ser9Gly polymorphism between patient and control groups arose from the chromosome carrying specific alleles of the other three polymorphisms. This study indicates unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes associated with schizophrenia.
...
PMID:Mutation and association analysis of the 5' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia. 1088 55

Schizophrenia is a devastating mental disease that affects the human population worldwide with an incidence of about 1%. Over the last decades basic and clinical research has considerably increased our understanding of the pathophysiology of schizophrenia, as well as the mechanism of action of antipsychotic compounds (neuroleptics), and new atypical neuroleptics with equipotent or improved antipsychotic effects and fewer motoric side effects have been developed. However, the pharmacological intervention does not effectively treat all the symptoms of the disease, and there is still a need for new, more effective antipsychotic compounds. Studies of brain function have demonstrated a reduced activation of prefrontal cortical areas during cognitive tasks in schizophrenics. It is hypothesized, that this hypofrontality is associated with a reduced dopaminergic tonus in the prefrontal cortex, which subsequently causes the negative symptoms of schizophrenia, such as apathy and social withdraw. It has also been suggested, that increased dopaminergic activity in striatal areas is related to the wellknown positive schizophrenic symptoms, such as delusions and hallucinations. The present thesis addresses the regional effects of prototypical and atypical neuroleptics on nerve cell activity and dopaminergic tonus in three rat brain areas with special relevance for the pharmacological effects of neuroleptics. Finally, new pharmacological approaches to the medical treatment of schizophrenia are suggested based on our experimental results. Initially, the effects of the prototypical neuroleptic haloperidol and the atypical neuroleptic clozapine on nerve cell activity in the rat forebrain were investigated by measuring the regional expression of the Fos protein. The Fos protein is regarded as a marker of cellular activity and was measured by use of immunohistochemical techniques i) in the medial prefrontal cortex (PFC), probably involved in the negative symptoms of schizophrenia, ii) in the nucleus accumbens (NAc), probably involved in the positive symptoms of schizophrenia and iii) in the dorsolateral striatum (DLSt), most likely involved in the motoric side effects of neuroleptics. Clozapine increases Fos protein immunoreactivity in the PFC with no or minimal effects in the DLSt. In contrast, haloperidol increases Fos protein immunoreactivity in the DLSt with minor effect in the PFC. Other atypical neuroleptics (risperidone, sertindole and NNC 22-0031) induced a Fos protein expression pattern different from haloperidol: The atypical compounds exhibit a larger ratio between Fos protein expression in PFC and DLSt than measured for haloperidol. These results are in accordance with the reported beneficial effects of clozapine, risperidone and sertindole on negative symptoms of schizophrenia and their lower degree of motoric side effects compared to haloperidol. All neuroleptics induced Fos protein immunoreactivity in the NAc, in accordance with their ability to reduce positive psychotic symptoms in schizophrenics. The microdialysis technique was used to investigate the regional dopaminergic effects of the above mentioned antipsychotic compounds by measuring interstitial levels of the dopamine metabolite dihydroxyphenylacetic acid ([DOPAC]i) in PFC, NAc and DLSt. All antipsychotics tested increased [DOPAC]i in the NAc, whereas the atypical antipsychotics clozapine, risperidone, sertindole and NNC 22-0031--in contrast to haloperidol--preferentially increased [DOPAC]i in PFC compared to DLSt. Also these results are in concordance with the clinical effects of clozapine, risperidone, sertindole and haloperidol and support the hypothesis that reduced dopaminergic tone in the prefrontal cortex relates to the negative symptoms of schizophrenia. All clinically efficacious neuroleptics block central dopamine D2 receptors, which include the dopamine D2, D3 and D4 receptor subtypes. The present thesis characterizes a dopamine D3 receptor agonist, cis-OH-PBZI.
...
PMID:Novel pharmacological approaches to the treatment of schizophrenia. 1091 83

Schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia.
...
PMID:Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. 1103 92

Alterations in dopamine neurotransmission have been hypothesized to play a role in the etiology of schizophrenia. We considered the dopamine D3 receptor gene on chromosome 3 as a candidate gene for an association analysis. We compared PCR-based genotype markers for healthy controls (n=120) and patients (n=95) with schizophrenia and schizophrenia spectrum disorders as diagnosed by consensus according to DSM-III-R. Our results possibly indicate an association of schizoaffective disorder with DRD3 homozygosity (P=0.056).
...
PMID:Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special? 1106 91

1. Schizophrenia is a chronic, disabling brain disease that affects approximately 1% of the world's population. It is characterized by delusions, hallucinations and formal thought disorder, together with a decline in socio-occupational functioning. While the causes for schizophrenia remain unknown, evidence from family, twin and adoption studies clearly demonstrates that it aggregates in families, with this clustering largely attributable to genetic rather than cultural or environmental factors. Identifying the genes involved, however, has proven to be a difficult task because schizophrenia is a complex trait characterized by an imprecise phenotype, the existence of phenocopies and the presence of low disease penetrance. 2. The current working hypothesis for schizophrenia causation is that multiple genes of small to moderate effect confer compounding risk through interactions with each other and with non-genetic risk factors. The same genes may be commonly involved in conferring risk across populations or they may vary in number and strength between different populations. To search for evidence of such genetic loci, both candidate gene and genome-wide linkage studies have been used in clinical cohorts collected from a variety of populations. Collectively, these works provide some evidence for the involvement of a number of specific genes (e.g. the 5-hydroxytryptamine (5-HT) type 2a receptor (5-HT2a) gene and the dopamine D3 receptor gene) and as yet unidentified factors localized to specific chromosomal regions, including 6p, 6q, 8p, 13q and 22q. These data provide suggestive, but no conclusive, evidence for causative genes. 3. To enable further progress there is a need to: (i) collect fine-grained clinical datasets while searching the schizophrenia phenotype for subgroups or dimensions that may provide a more direct route to causative genes; and (ii) integrate recent refinements in molecular genetic technology, including modern composite marker maps, DNA expression assays and relevant animal models, while using the latest analytical techniques to extract maximum information in order to help distinguish a true result from a false-positive finding.
...
PMID:Molecular genetics of schizophrenia. 1115 40

Tardive dyskinesia (TD) is characterized by involuntary movements predominantly in the orofacial region and develops in approximately 20% of patients during long-term treatment with typical antipsychotics. The high prevalence of TD and its disabling and potentially irreversible clinical course is an important shortcoming for treatment with typical antipsychotics. The studies presented in this article evaluate the role of single nucleotide polymorphisms in dopamine D3 receptor (DRD3) and CYP1A2 genes for propensity to develop TD in patients with schizophrenia. In theory, a combined pharmacogenetic analysis of pharmacokinetic and pharmacodynamic targets for antipsychotics should improve our ability to identify subpopulations that differ in drug safety profile. This information may in turn contribute to the design of more efficient clinical trials and thus expedite the development and regulatory approval of newer antipsychotic compounds.
...
PMID:Pharmacogenetic assessment of antipsychotic-induced movement disorders: contribution of the dopamine D3 receptor and cytochrome P450 1A2 genes. 1117 71

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.
...
PMID:BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. 1133 82

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>