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 principal brain synaptic vesicular monoamine transporter (VMAT2) is responsible for the reuptake of serotonin, dopamine, norepinephrine, epinephrine, and histamine from the cytoplasm into synaptic vesicles, thus contributing to determination of the size of releasable neurotransmitter vesicular pools. Potential involvement of VMAT2 gene variants in the etiology of schizophrenia and related disorders was tested using polymorphic VMAT2 gene markers in 156 subjects from 16 multiplex pedigrees with schizophrenia, schizophreniform, schizoaffective, and schizotypal disorders and mood incongruent psychotic depression. Assuming genetic homogeneity, complete (theta = 0.0) linkage to the schizophrenia spectrum was excluded under both dominant and recessive models. Allelic variants at the VMAT2 locus do not appear to provide major genetic contributions to the etiology of schizophrenia spectrum disorders in these pedigrees.
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PMID:Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders. 882 97

Given evidence for excessive striatal dopamine activity in schizophrenia, we sought to test the hypothesis that dopaminergic innervation in the striatum is abnormally elevated, and a secondary hypothesis that age-related loss is accelerated. Twelve schizophrenic subjects on stable doses of medications, along with 12 age and sex-matched healthy control subjects, underwent positron emission tomography (PET) studies with [11C]dihydrotetrabenazine (DTBZ), which binds to the vesicular monoamine transporter, type 2 (VMAT2). DTBZ binding reflects principally dopaminergic projections in the striatum and appears in animal models, over treatment periods as long as two weeks, not to be regulated by antipsychotic drugs. Using an equilibrium analysis, we obtained measurements of the binding potential (BP) of [11C]DTBZ, as well as a transport (K(1)) measure, corresponding to regional cerebral blood flow. BP in the striatum showed no difference between the patient and control groups, and no differential effect of age. We did not find evidence supporting the hypothesis that excessive dopamine activity in schizophrenia could be explained by increased density of striatal dopamine terminals.
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PMID:In vivo measurement of the vesicular monoamine transporter in schizophrenia. 1106 22

The synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Altered functions of SVMT have been implicated in the pathogensis of several neuropsychiatric diseases. We determined exon/intron boundaries of the human SVMT gene and performed mutational analysis for the exonic and neighboring intronic regions of the gene. Detected polymorphisms were subject to association analysis with schizophrenia in a family-based design. The human SVMT gene consists, of 16 exons and 15 introns, which is consistent with the murine SVMT gene. When mutational analysis was performed by the single strand conformational polymorphism (SSCP) analysis, we found two and four single nucleotide polymorphisms (SNPs) in exons and neighboring introns, respectively. Neither exonic SNP results in an amino acid change. In family-based association analyses in a sample of 50 Japanese schizophrenics and their parents, no significant association was found for the intronic polymorphisms. Our data suggest that there is no common polymorphism in the SVMT gene affecting the primary structure of the human SVMT protein. Furthermore, we obtained no evidence for the major effect of the novel polymorphisms on susceptibility to schizophrenia.
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PMID:Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene. 1144 33

We have created a transgenic mouse with a hypomorphic allele of the vesicular monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive into adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of the monoamine neurotransmitters below potentially toxic thresholds. Homozygous mice show large reductions in brain tissue monoamines, motor impairments, enhanced sensitivity to dopamine agonism, and changes in the chemical neuroanatomy of the striatum that are consistent with alterations in the balance of the striatonigral (direct) and striatopallidal (indirect) pathways. The VMAT2-deficient KA1 mice are also more vulnerable to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in terms of nigral dopamine cell death. We suggest that the mice may be of value in examining, long term, the insidious damaging consequences of abnormal intracellular handling of monoamines. On the basis of our current findings, the mice are likely to prove of immediate interest to aspects of the symptomatology of parkinsonism. They may also, however, be of use in probing other aspects of monoaminergic function and dysfunction in the brain, the latter making important contributions to the pathogenesis of schizophrenia and addiction.
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PMID:Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism. 1146 16

Transgenic technology, especially the use of homologous recombination to disrupt specific genes to produce knockout mice, has added considerably to the understanding of dopamine (DA) neuron develop, survival and function. The current review summarizes results from knockout mice with the target disruption of genes involved in the development of DA neurons (engrailed 1 and 2, lmx1b, and Nurr1), in maintaining DA neurotransmission (tyrosine hydroxylase, vesicular monoamine transporter, DA transporter, DA D2 and D3 receptors) and important for DA neuron survival (alpha-synuclein, glia cell line-derived neurotrophic factor and superoxide dismutase). As alterations in DA neurotransmission have been implicated in a number of human neuropathologies including Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder, understanding how specific genes are involved in the function of DA neurons and the compensatory changes that result from loss or reduction in gene expression could provide important insight for the treatment of these diseases.
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PMID:The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease. 1267 88

Brain vesicular monoamine transporter 2 (VMAT2) has a critical role in the regulation of monoaminergic neurotransmission. In our previous study we have found decreased platelet VMAT2 density in healthy habitual smokers. Schizophrenia is associated with high rate of cigarette smoking. In the present study we assessed platelet VMAT2 pharmacodynamic characteristics in a population of medicated schizophrenia patients (n=36) comparing smokers (n=23) vs. non-smokers (n=13). A significant decrease in platelet VMAT2 density (24%, p=0.005) was found in the smokers compared to the non-smokers . This decrease was not ascribed to the pharmacotherapy. An inverse correlation was found in the smokers between the platelet VMAT2 density and the severity of schizophrenia as assessed by the positive and negative syndrome scale (PANSS). Our observation in schizophrenia patients is consistent with that found in healthy smokers. The complex relationship between VMAT2 expression, cigarette smoking and schizophrenia merits a further large scale study.
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PMID:Reduced platelet vesicular monoamine transporter density in smoking schizophrenia patients. 1613 73

Monoamine transporters such as the dopamine (DA) transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2) are critical regulators of DA disposition within the brain. Alterations in DA disposition can lead to conditions such as drug addiction, Parkinson's disease, and schizophrenia, a fact that underscores the importance of understanding DAergic signaling. Psychostimulants alter DAergic signaling by influencing both DAT and VMAT-2, and although the effects of these drugs result in increased levels of synaptic DA, the mechanisms by which this occurs and the effects that these drugs exert on DAT and VMAT-2 vary. Many psychostimulants can be classified as releasers (ie, amphetamine analogs) or uptake blockers (ie, cocaine-like drugs) based on the mechanism of their acute effects on neurotransmitter flux through the DAT. Releasers and uptake blockers differentially modulate the activity and subcellular distribution of monoamine transporters, a phenomenon likely related to the neurotoxic potential of these drugs to DAergic neurons. This article will review some of the recent findings whereby releasers and uptake blockers alter DAT and VMAT-2 activity and how these alterations may be involved in neurotoxicity, thus providing insight on the neurodegeneration observed in Parkinson's disease.
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PMID:Role of monoamine transporters in mediating psychostimulant effects. 1659 36

The vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) maps to the shared bipolar disorder (BPD)/schizophrenia (SZ) susceptibility locus on chromosome 8p21. Vesicular monoamine transporters are involved in transport of monoamine neurotransmitters which have been postulated to play a relevant role in the etiology of BPD and/or SZ. Variations in the VMAT1 gene might affect transporter function and/or expression and might be involved in the etiology of BPD and/or SZ. Genotypes of 585 patients with BPD type I and 563 control subjects were obtained for three missense single nucleotide polymorphisms (SNPs) (Thr4Pro, Thr98Ser, Thr136Ile) and four non-coding SNPs (rs988713, rs2279709, rs3735835, rs1497020). All cases and controls were of European descent. Allele frequencies differed significantly for the potential functional polymorphism Thr136Ser between BPD patients and controls (p=0.003; df=1; OR=1.34; 95% CI: 1.11-1.62). Polymorphisms in the promoter region (rs988713: p=0.005, df=1; OR=1.31; 95% CI: 1.09-1.59) and intron 8 (rs2279709: p=0.039, df=1; OR=0.84; 95% CI: 0.71-0.99) were also associated with disease. Expression analysis confirmed that VMAT1 is expressed in human brain at the mRNA and protein level. Results suggest that variations in the VMAT1 gene may confer susceptibility to BPD in patients of European descent. Additional studies are necessary to confirm this effect and to elucidate the role of VMAT1 in central nervous system physiology.
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PMID:Variations in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) are associated with bipolar i disorder. 1693 5

The synaptic vesicular monoamine transporter (SVMT) plays a key role in monoaminergic neurotransmission determining the size of neurotransmitter vesicular pools available for exocytotic release. Recently, several lines of evidence have suggested that altered functions of SVMT may be involved in the pathogenesis of certain neuropsychiatric diseases, including psychotic and mood disorders. In the present study, we tested the potential involvement of SVMT gene variants in the etiology of schizophrenia and bipolar disorder. Five different SNPs (T440G, C1368T, T2666C, A2683C, and A745G) were included in the analysis covering a region of about 35 kb along the SVMT gene. Analyses were performed in a case-control sample consisting of 88 bipolar patients, 107 subjects with schizophrenia, and 164 controls. Two risk haplotypes for both schizophrenia and bipolar disorder in SVMT gene were identified. Particularly, 2666T-2683A-745G (TAG) and 2666C-2683C-745A (CCA) combinations were significantly more frequent in both bipolar and schizophrenic patients than in controls. UNPHASED package estimated haplotype effects for all patients yielded relative risks of 4.1 (95%CI: 1.83-9.21) for TAG combination and 2.336 (95%CI: 1.28-4.26) for CCA haplotype. Conversely, 2666T-2683C-745A (TCA) and 2666C-2683A-745G (CAG) haplotypes seemed to protect against these mental disorders, since the estimated frequency in control chromosomes was 12% whilst such haplotypes were not observed in any bipolar or schizophrenic subject (P < 0.0000). Our results strongly suggest that SVMT gene or certain regions of it may constitute a genetic substrate of susceptibility for both schizophrenia and bipolar disorder.
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PMID:Identification of two risk haplotypes for schizophrenia and bipolar disorder in the synaptic vesicle monoamine transporter gene (SVMT). 1742 84

The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway.
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PMID:Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission. 2214 79


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