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)

Vesicular monoamine transporters are involved in the presynaptic packaging of norepinephrine, dopamine and serotonin into storage vesicles. The vesicles release their content upon arrival of an action potential into the synaptic cleft. Dysregulation of monoaminergic neurotransmission has been long postulated to play a relevant role in the etiology of neuropsychiatric disorders. The gene encoding the vesicular monoamine transporter 1 (VMAT1/SLC18A1) maps to chromosome 8p21, a region where several linkage peaks overlap between schizophrenia, bipolar disorder and anxiety-related personality traits. In this study, we tested the hypothesis that the missence variation Thr136Ile in the VMAT1/SLC18A1 gene is associated with anxiety-related personality traits. We tested a total of 337 unrelated subjects of German descent (167 male, 170 female). All participants were carefully screened for psychiatric disorders. The self-report State-Trait Anxiety Inventory (STAI) was completed by all subjects. Genotypes were obtained for the Thr136Ile (rs1390938) variation in the VMAT1 gene for all subjects. Genotype effects on personality variables were computed with MANOVA including age as a co-variant and gender as independent factor (MANCOVA). Results show that STAI scores were significantly affected by genotype (F=3.108; d.f.=4,331; p=0.015) and age (F=7.233; d.f.=2,331; p=0.001) but not by gender. A gender-by-genotype effect was observed for both the STAI state (p=0.052) and trait score (p=0.035). Dissection of the group by gender and subsequent contrast analysis of the genotype effects performed within the female group showed significant results (STAI state: Thr/Ile vs. Ile/Ile: T=4.408, p=0.0004; STAI trait: Thr/Ile vs. Ile/Ile: T=3.074, p=0.009) but not in the male group. Our findings support the hypothesis that anxiety-related personality traits are associated with variation in the VMAT1/SLC18A1 gene.
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PMID:Association between variation in the vesicular monoamine transporter 1 gene on chromosome 8p and anxiety-related personality traits. 1824 96

Linkage studies have suggested a susceptibility locus for schizophrenia (SZ) exists on chromosome 8p21-22. The vesicular monoamine transporter 1 gene (VMAT1), also known as SLC18A1, maps to this SZ susceptibility locus. Vesicular monoamine transporters are involved in the presynaptic vesicular packaging of monoamine neurotransmitters, which have been postulated to play a role in the etiology of SZ. Variations in the VMAT1 gene might affect transporter function and/or expression, and might be involved in the etiology of SZ. Genotypes of 62 patients with SZ and 188 control subjects were obtained for 4 missense single nucleotide polymorphisms (Thr4Pro, Thr98Ser, Thr136Ile, Val392Leu) and 2 noncoding single nucleotide polymorphisms (rs988713, rs2279709). All cases and controls were of European descent. The frequency of the minor allele of the Thr4Pro polymorphism was significantly increased in SZ patients when compared to controls (p = 0.0140; d.f. = 1; OR = 1.69; 95% CI = 1.11-2.57). Assuming a recessive mode of inheritance, the frequency of homozygote 4Pro carriers was significantly increased in the SZ patients when compared to controls (24 vs. 8%, respectively; p = 0.0006; d.f. = 1; OR = 3.74; 95% CI = 1.703-8.21). Haplotype analysis showed nominal significance for an individual risk haplotype (p = 0.013); however, after permutation correction, the global p value did not attain a statistically significant level (p = 0.07). Results suggest that variations in the VMAT1 gene may confer susceptibility to SZ in patients of European descent. Further studies are necessary to confirm this effect, and to elucidate the role of VMAT1 in central nervous system physiology and possible involvement in the genetic origins of SZ.
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PMID:Association between polymorphisms in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) on chromosome 8p and schizophrenia. 1845 39

Dopamine signaling is involved in a number of brain pathways, and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo- and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine-based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control.
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PMID:Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals. 1967 Mar 15

The exact pathophysiology of schizophrenia is unknown despite intensive scientific studies using molecular biology, psychopharmacology, neuropathology, etc. It is thought that neurodevelopmental failures such as neuronal network incompetence and the inappropriate formation of neurons affect the neurotransmitters. Several animal models have been created to investigate the etiology of this disease. In this study, we investigated the expression of vesicle monoamine transporter 2 (VMAT2), which has a significant role in neurotransmission, in the hippocampal formation in 1-phenylcyclohexylpiperazine (PCP)-treated mice using immunohistochemical staining technique to clarify neuronal abnormalities. PCP-treated mice are thought to be one of novel animal models for schizophrenia. The expression of VMAT2 in the hippocampal formation was significantly reduced overall in the PCP-treated mice compared to that in control (saline-treated) mice, also these reductions were observed throughout the brain. These facts implied that the pathophysiology of this disease involves abnormal monoaminergic transmission through VMAT2, despite PCP was the N-methyl-d-aspartate (NMDA) receptor antagonist that might induce glutamatergic abnormality. Since insufficient or excess release of neurotransmitter might alter neurochemical function and neurotransmission, VMAT2 might be an important target for biological research in psychiatric disease including schizophrenia.
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PMID:Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal formation of PCP-treated mice. 2055 13

Recent research in the etiology of schizophrenia revealed that there may be some neurodevelopmental failures such as neuronal network incompetence in the brain of this disease, and neurotransmitters cannot function accurately or adequately. But, it is unknown precisely what kinds of deficit in neurotransmission may be existed histopathologically. We investigated the expression of vesicle monoamine transporter 2 (VMAT2), which has a significant role in neurotransmission, in the hippocampal formation of the animal model of schizophrenia, 14-3-3 epsilon hetero knockout (KO) mouse, using an immunohistochemical staining technique to clarify the neuronal abnormalities in the model animal. As a result, the expression of VMAT2 was increased significantly in the hippocampal formation of 14-3-3 epsilon hetero KO mice compared to that of the wild-type littermates. In conclusion, these findings might be related the pathophysiology of this disease includes a monoaminergic transmission abnormality, based on the investigation in a genetically-modified mouse as schizophrenic model.
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PMID:Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal region of genetic animal model of schizophrenia. 2081 37

In a former study, we reported decreased platelet vesicular monoamine transporter 2 (VMAT2) density (Bmax) in patients with ADHD. The current study aimed at measuring platelet VMAT2 in the disruptive behavior disorders (DBDs) to assess whether this finding is specific to ADHD or generalizable to the broader DBD concept. The study included 13 patients with DBDs aged 10-12 years and 16 healthy volunteers aged 8-17 years. All participants underwent a thorough clinical evaluation using Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version for diagnosis, the Nisonger Child Behavior Rating Form, the Clinical Global Impressions Scale-Severity version, and the DSM-IV ADHD Scale (DAS). The study group's DAS scores did not differ from those of the control group. There was no significant difference between the patients with DBDs and the control group either in VMAT2 density (Bmax) or affinity (Kd) as measured by high-affinity [(3)H]TBZOH binding. We conclude that the formerly reported decreased platelet VMAT2 Bmax in patients with ADHD may be specific to ADHD and not present in DBDs. Larger-scale replication is needed.
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PMID:Platelet vesicular monoamine transporter 2 density in the disruptive behavior disorders. 2185 Nov 91

Tetrabenazine (TBZ; Xenazine) is a potent, selective, reversible depletor of monoamines from nerve terminals. TBZ inhibits the vesicular monoamine transporter type 2 which, in humans, is expressed nearly exclusively in the brain. TBZ is rapidly metabolized in the liver by carbonyl reductase to stereoisomers of hydrotetrabenazine, some of which are potent inhibitors of vesicular monoamine transporter type 2. Initially developed in the 1950s for schizophrenia, since the 1970s several publications have reported on the efficacy of TBZ in the treatment of various hyperkinetic movement disorders. Although quite effective in controlling the involuntary movements, there were considerable inter-individual differences in the optimal dose, defined as the dose judged by the investigator to provide the greatest efficacy with minimal or tolerable adverse events. This variability is in part owing to differences in severity and mechanism of the target symptoms and to variable activity of the enzyme carbonyl reductase that metabolizes TBZ to its active metabolites. Dose-limiting adverse events, consisting mainly of sedation, parkinsonism, akathisia and depression, are usually rapidly reversible upon dosage reduction. In addition to its established antichorea efficacy in Huntington's disease, the drug has been reported to also be effective in a variety of other hyperkinetic movement disorders, including tardive dyskinesia and tics associated with Tourette's syndrome.
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PMID:Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders. 2201 29

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness.
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PMID:Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial. 2219 52

NR4A2 (nuclear receptor subfamily 4 group A member 2) or Nurr1 is a transcription factor implied in the differentiation, maturation, and survival of dopaminergic neurons. It also has a role in the expression of several proteins that are necessary for the synthesis and regulation of dopamine (DA), such as tyrosine hidroxilase, dopamine transporter, vesicular monoamine transporter 2, and cRET. DA is an important neurotransmitter in attentional pathways. Our aim was to evaluate the influence of NR4A2 gene in the performance of schizophrenia (SZ) patients and healthy subjects on a sustained attention task. For this study, we collected 188 SZ subjects (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 100 control individuals. We genotyped 5 tag SNPs in NR4A2 gene: rs1150143 (C/G), rs1150144 (A/G), rs834830 (A/G), rs1466408 (T/A), and rs707132 (A/G). We also analyzed the influence of its haplotypes (frequency>5%). To examine sustained attention, all the individuals completed the Degraded Stimulus Continuous Performance Test. We evaluated "hits," "reaction time," "sensibility a," and "false alarms." In the schizophrenic group, recessive genotypes of rs1150143, rs1150144, rs834830, and rs707132 were associated with a worse performance. SZ subjects who carried GGGTG haplotype showed less hits (P<.004), lower sensibility a scores (P<.009), and a higher reaction time (P=.013). We observed a sex effect of the gene: genotype and haplotype associations were only present in the male group. We conclude that NR4A2 gene is involved in attentional deficits of SZ patients, modifying hits, sensibility a, and reaction time.
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PMID:NR4A2: effects of an "orphan" receptor on sustained attention in a schizophrenic population. 2229 35

Adolescence coincides with symptomatic onset of several psychiatric illnesses including schizophrenia and addiction. Excess limbic dopamine activity has been implicated in these vulnerabilities. We combined molecular and dynamic indices of dopamine neurotransmission to assess dopamine function in adolescent rats in two functionally distinct striatal subregions: nucleus accumbens (NAc) and dorsal striatum (DS). In adolescents, we find an overall reduction in dopamine availability selective to the DS. Dopamine release in the DS, but not in the NAc, was less responsive to amphetamine in adolescents compared to adults. The dopamine transporter (DAT) inhibitor, nomifensine, similarly inhibited basal and amphetamine-induced dopamine release in either regions of both the age groups, suggesting that the reduced effectiveness of amphetamine is not due to differences in DAT function. Furthermore, DAT and vesicular monoamine transporter-2 expressions were similar in the DS and NAc of adolescent rats. In contrast, expression of tyrosine hydroxylase (TH) was reduced in the DS, but not in the NAc, of adolescents compared to adults. Behaviorally, adolescents were less sensitive to amphetamine but more sensitive to a TH inhibitor. These data indicate that, in contrast to the general notion that dopamine is hyperactive in adolescents, there is diminished presynaptic dopamine activity in adolescents that is selective to the DS and may result from attenuated TH activity. Given recent reports of altered dopamine activity in associative/dorsal striatum of individuals at a clinically high risk of psychosis, our data further support the idea that dorsal, as opposed to ventral, regions of the striatum are a locus of vulnerability for psychosis.
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PMID:Reduced presynaptic dopamine activity in adolescent dorsal striatum. 2335 39


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