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)

Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specific molecular targets. At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre- and postsynaptic receptors and transporters. Monoamines, 5-hydroxytryptamine or serotonin (5-HT), norepinephrine (NE), and dopamine (DA) play an important modulatory role in the CNS and are involved in numerous physiological functions and pathological conditions. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine. Monoamine transporters are the sites of action for widely used antidepressants and are high affinity molecular targets for drugs of abuse including cocaine, amphetamine, and 3,4-methylenedioxymetamphetamine (MDMA) "Ecstasy." Monoamine transporters also serve as molecular gateways for neurotoxins. Emerging evidence indicates that regulation of transporter function and surface expression can be rapidly modulated by "intrinsic" transporter activity itself, and antidepressant and psychostimulant drugs that block monoamine transport have a profound effect on transporter regulation. Therefore, disregulations in the functioning of monoamine transporters may underlie many disorders of transmitter imbalance such as depression, attention deficit hyperactivity disorder, and schizophrenia. This review integrates recent progress in understanding the molecular mechanisms of monoamine transporter regulation, in particular, posttranscriptional regulation by phosphorylation and trafficking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in influencing monoamine transport regulation.
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PMID:Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. 1635 49

CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) density. Thus, the development of compounds that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with additional heteroatoms at positions 3 and 6. The compounds were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [3H]WIN35,428 and [3H]citalopram as specific radioligands, respectively. Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50=1042 nM). These results suggest that 3-aryl-3-aza-6,8-dioxabicyclo[3.2.1]octanes may represent a new class of DAT ligands.
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PMID:3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter. 1667 30

A sample included 59 patients, 38 males and 21 females, mean age (M+/-SD) 33,4+/-10,2 years, age-at-onset 26+/-9,5 years, illness duration 7,8+/-6,1 years, with episodic progressive schizophrenia (ICD-10: schizophrenia, paranoid type, F20.0) with continuous course at the stage of exacerbation. Clinical symptoms were assessed using the PANSS. Platelet 5-HT content, 3H-serotonin uptake (Vmax), 3H-imipramine receptor density (Bmax), high- and low molecular weight human serotonin platelet transporter protein immunoreactivity (HMW-SERT and LMW-SERT values) were measured. The most frequent psychotic symptoms were delusions, conceptual disorganization and hallucinations, with the majority of patients experiencing from one to three symptoms. A significant increase of platelet 5-HT content and 3H-imipramine receptor density (Bmax) was found in male patients. In the male group, delusions, conceptual disorganization and hallucinations as well as PANSS psychotic cluster scores were correlated positively with 5-HT content and negatively with HMW-SERT and LMW-SERT values. Possible reasons of the differences in correlations of platelet 5-HT serotonin and serotonin transporter values with psychotic symptoms are discussed. The results are additional evidence for the involvement of serotonergic dysfunction in the pathogenesis of schizophrenic psychoses. They confirm the usefulness of testing of platelet 5-HT content and SERT immunoreactivity as biological markers of schizophrenic psychoses, in particular for male patents.
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PMID:[Platelet serotonergic parameters and clinical symptoms of psychosis in patients with episodic progressive schizophrenia]. 1837 99

Genetic factors are thought to contribute to schizotypal dimensions. Recently, a number of genetic variants associated with schizotypal traits in psychiatrically healthy people have been found. Authors reported earlier the association between the SERT 5-HTTLPR polymorphism and schizotypal traits measured with MMPI. The present study aimed at the replication of association on a larger sample using other questionnaires and methods of data analysis. The sample comprised 657 people from the Russian population. MMPI, SPQ-74 and TCI-125 were used to measure personality traits. Based on the results of psychological testing, the sample was divided into high risk and control groups. For MMPI, the high risk group included people with the elevation on scale Schizophrenia, for SPQ-74 - people with a total score more than 25 and for TCI-125 - people with lower scores on scale Cooperation and higher scores on Self-Transcendence. In all high-risk groups assessed by different psychological instruments, the frequency of the SS 5-HTTLPR genotype was significantly lower as compared to the corresponding control groups. MANCOVA also showed that individuals with the SS genotype had lower scores on scales related to schizotypal traits. Thus, we have confirmed our previous results on the association between the 5-HTTLPR polymorphism and schizotypal traits in psychiatrically healthy subjects.
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PMID:[Further evidence that the serotonin transporter gene is associated with schizotypal traits in a healthy Russian population]. 1949 18

We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.
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PMID:Genetic polymorphisms in dopamine- and serotonin-related genes and treatment responses to risperidone and perospirone. 2004 99

The monoamine systems have been suggested to play a role in the biological basis of attention-deficit hyperactivity disorder (ADHD) symptoms. Thus, polymorphisms, for example, in the monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) genes have been associated with ADHD-like phenotypes. Furthermore, platelet monoamine oxidase B (MAOB) activity has frequently been linked to impulsiveness-related traits. In this study, we have studied ADHD symptoms with regard to the combination of platelet MAOB activity and MAOA-variable number of tandem repeats (VNTR) or 5HTT-LPR genotype. The study group consisted of 156 adolescent twin pairs, that is, 312 individuals, who participated in a previous study. ADHD symptoms were scored with a structured clinical interview of both the twins and a parent using Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. The presence of a short 5HTT-LPR or short MAOA-VNTR allele, in combination with high levels of platelet MAOB enzyme activity was associated with higher scores of ADHD-like problems (P<0.001 and 0.01, respectively). This re-examination of ADHD scores in a nonclinical sample suggests that effects of MAOA-VNTR and 5HTT-LPR are moderated by platelet MAOB activity.
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PMID:Associations of MAOA-VNTR or 5HTT-LPR alleles with attention-deficit hyperactivity disorder symptoms are moderated by platelet monoamine oxidase B activity. 2161 May 56

Second-generation antipsychotics (SGA) are multi-target agents widely used for the treatment of schizophrenia and bipolar disorder that also hold potential for the treatment of impaired emotional control, thanks to their diverse receptor profiles as well as their potential in modulating neuroadaptive changes in key brain regions. The aim of this study was thus to establish the ability of lurasidone, a novel SGA characterized by a multi-receptor signature, to modulate behavioural and molecular defects associated with a genetic model of impaired emotional control, namely serotonin transporter knockout (SERT KO) rats. At behavioural level, we found that chronic lurasidone treatment significantly increased fear extinction in SERT KO rats, but not in wild-type control animals. Moreover, at molecular level, lurasidone was able to normalize the reduced expression of the neurotrophin brain-derived neurotrophic factor in the prefrontal cortex of SERT KO rats, an effect that occurred through the regulation of specific neurotrophin transcripts (primarily exon VI). Furthermore, chronic lurasidone treatment was also able to restore the reduced expression of different GABAergic markers that is present in these animals. Our results show that lurasidone can improve emotional control in SERT KO rats, with a primary impact on the prefrontal cortex. The adaptive changes set in motion by repeated treatment with lurasidone may in fact contribute to the amelioration of functional capacities, closely associated with neuronal plasticity, which are deteriorated in patients with schizophrenia, bipolar disease and major depression.
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PMID:Behavioural and neuroplastic properties of chronic lurasidone treatment in serotonin transporter knockout rats. 2316 5

One fifth to one third of all patients diagnosed with schizophrenia are resistant to drug treatment, which makes it a major clinical challenge. Genetic studies have focused on the association between treatment resistant schizophrenia (TRS) and a number of candidate genes, including serotonin and dopamine system genes. We explored associations between carefully characterized TRS and DAT-VNTR, SERT-PR and SERT-in2 polymorphisms. There were 173 patients enrolled in the study that were clinically evaluated using Positive and Negative Syndrome Scale and Clinical Global Impressions Scales and divided into two groups based on treatment resistance (92 patients in TRS group). Patients with a combination of SERT-in2 ll and DAT 9/10, 9/11, 9/9 and 6/6 genotypes were more likely to have TRS, compared to those with 10/10 or 10/12 genotype (OR=5.1; 95% CI=1.6-16.8). In the group of patients with DAT 10/10 or 10/12 genotype, those who also shared SERT-in2 ls or ss genotype were more likely to have TRS, compared to ll genotype carriers (OR=2.7; 95% CI=1.0-7.0). The model in which interaction between SERT-in2 and DAT polymorphisms is linked to TRS can possibly explain contradictory previous results regarding role of DAT and SERT in TRS, but further research is needed.
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PMID:Treatment-resistant schizophrenia and DAT and SERT polymorphisms. 2468 Jul 25

A disruption of dopaminergic transmission in the amygdala of subjects with schizophrenia was proposed as a main contributor to pathophysiological and clinical manifestations of this disorder. We tested the hypothesis that the expression of the dopamine transporter (DAT) is decreased in the amygdala of subjects with schizophrenia. In normal control, schizophrenic subjects and bipolar disorder subjects, we measured numerical density of axon varicosities immunoreactive (IR) for DAT in the lateral (LN), basal, accessory basal (ABN), and cortical (CO) nuclei and intercalated cell masses (ITCM) of the amygdala. Tyrosine hydroxylase (TH)-IR and dopamine beta-hydroxylase (DBH)-IR varicosities were measured to test for potential loss of varicosities and serotonin transporter (5HTT)-IR for involvement of the serotoninergic system. Among several potential confounding variables tested, particular emphasis was placed on exposure to therapeutic drugs. In schizophrenic subjects, DAT-IR varicosities were decreased in LN (P = .0002), ABN (P = .013), and CO (P = .0001) in comparison with controls, and in comparison with bipolar disorder subjects in LN (P = .004) and CO (P = .002). DBH-IR varicosities were decreased in ABN (P = .008) and ITCM (P = .017), compared with controls. TH- and 5HTT-IR varicosities were not altered. No changes were detected in bipolar disorder. Taken together with TH and DBH findings, reductions of DAT-IR varicosities point to decreased DAT expression in dopaminergic terminals in the amygdala of subjects with schizophrenia. This DAT decrease may disrupt dopamine uptake, leading to increased dopaminergic synaptic transmission and spillage into the extracellular space with activation of extrasynaptic dopamine receptors. Concurrent decrease of noradrenaline in the ABN may disrupt memory consolidation.
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PMID:Reduced dopamine transporter expression in the amygdala of subjects diagnosed with schizophrenia. 2493 23

The aim of the present study was to analyze if the genetic polymorphisms might predict suicide attempts in mental disorder patients. The literature review and meta-analysis were conducted using the PubMed/Medline, Web of science and Scopus database using the terms: "5-HTT or SLC6A4 or 5-SERT and suicide, suicidal ideation or suicidal behavior or suicidal attempt". Thirty articles were analyzed. We found 17 articles that showed association and 13 articles that showed no association between LPR serotonin transporter polymorphism and suicide. A higher study of suicide identified the serotonin transporter polymorphism in patients with schizophrenia, mental disorder, major depression and bipolar disorder. There is an association between the serotonin-transporter-linked polymorphic region and suicidal behavior. The mental disorders with greater relationship with the suicide were the bipolar disorder, major depression and schizophrenia. The L allele had higher risk for suicide.
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PMID:Genetic Polymorphisms Might Predict Suicide Attempts in Mental Disorder Patients: A Systematic Review And Meta-Analysis. 2616 39


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