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Journal ArticleDOI

The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.

TL;DR: A model is presented of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis.
About: This article is published in Biological Psychiatry.The article was published on 2017-01-01 and is currently open access. It has received 410 citations till now. The article focuses on the topics: Dopaminergic & Dopamine receptor D3.
Citations
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Journal ArticleDOI
TL;DR: The aspects of dopamine as a catecholaminergic neurotransmitter and dopamine signaling pathways elicited through dopamine receptor activation in normal brain function are summarized and the potential involvement of these signaling pathways in evoking the onset and progression of some diseases in the nervous system are described.
Abstract: The dopaminergic system plays important roles in neuromodulation, such as motor control, motivation, reward, cognitive function, maternal, and reproductive behaviors. Dopamine is a neurotransmitter, synthesized in both central nervous system and the periphery, that exerts its actions upon binding to G protein-coupled receptors. Dopamine receptors are widely expressed in the body and function in both the peripheral and the central nervous systems. Dopaminergic signaling pathways are crucial to the maintenance of physiological processes and an unbalanced activity may lead to dysfunctions that are related to neurodegenerative diseases. Unveiling the neurobiology and the molecular mechanisms that underlie these illnesses may contribute to the development of new therapies that could promote a better quality of life for patients worldwide. In this review, we summarize the aspects of dopamine as a catecholaminergic neurotransmitter and discuss dopamine signaling pathways elicited through dopamine receptor activation in normal brain function. Furthermore, we describe the potential involvement of these signaling pathways in evoking the onset and progression of some diseases in the nervous system, such as Parkinson’s, Schizophrenia, Huntington’s, Attention Deficit and Hyperactivity Disorder, and Addiction. A brief description of new dopaminergic drugs recently approved and under development treatments for these ailments is also provided.

429 citations


Cites background from "The Role of Genes, Stress, and Dopa..."

  • ...Albeit the neurobiology of SZ remains to be elucidated, many hypotheses have been proposed to clarify the disease, including the neurodevelopmental hypothesis, the glutamate hypothesis, and the most accepted, dopamine hypothesis (Kambeitz et al. 2014; Hu et al. 2015; Schmidt and Mirnics 2015; Howes et al. 2017; Wang et al. 2017)....

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Journal ArticleDOI
TL;DR: The neurodevelopment hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis and integrated new evidence concerning dysregulated striatal dopamine as the final step on the pathway linking risk factors to psychotic symptoms.
Abstract: At its re-birth 30 years ago, the neurodevelopment hypothesis of schizophrenia focussed on aberrant genes and early neural hazards, but then it grew to include ideas concerning aberrant synaptic pruning in adolescence. The hypothesis had its own stormy development and it endured some difficult teenage years when a resurgence of interest in neurodegeneration threatened its survival. In early adult life, it over-reached itself with some reductionists claiming that schizophrenia was simply a neurodevelopmental disease. However, by age 30, the hypothesis has matured sufficiently to incorporated childhood and adult adversity, urban living and migration, as well as heavy cannabis use, as important risk factors. Thus, it morphed into the developmental risk factor model of psychosis and integrated new evidence concerning dysregulated striatal dopamine as the final step on the pathway linking risk factors to psychotic symptoms.

194 citations

Journal ArticleDOI
TL;DR: Findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.
Abstract: Importance The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. Objectives To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. Design, Setting, and Participants This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([ 18 F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. Main Outcomes and Measures Dopamine synthesis capacity (Ki cer ) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). Results The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Ki cer ) ( F 2,57 = 6.80, P = .002). Ki cer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10 −3 min −1 ; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10 −3 min −1 ; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10 −3 min −1 ). There was no significant difference in striatal Ki cer between the bipolar and schizophrenia groups. Ki cer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Ki cer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity. Conclusions and Relevance These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.

174 citations

Journal ArticleDOI
TL;DR: In individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum, which is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.
Abstract: Background Studies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum. Methods EMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed. Results Twenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges' g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003). Conclusion In individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.

164 citations


Cites methods from "The Role of Genes, Stress, and Dopa..."

  • ...For the meta-analysis of presynaptic dopamine function in schizophrenia the inclusion criteria were: (1) studies of patients with schizophrenia diagnosed in accordance with criteria specified in the Diagnostic and Statistical Manual for Mental Disorders (DSM), or the International Classification of Diseases (ICD)24,25 and a control group; (2) reporting molecular imaging measures of presynaptic dopaminergic function (see supplementary methods for further details) for both the patient and control groups; (3) providing data enabling the estimation of mean difference between control and clinical groups for the dopaminergic measure; and (4) For the subdivision analysis only studies reporting all 3 subdivisions (limbic, associative, and sensorimotor subdivisions) were included to enable comparisons across regions....

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Journal ArticleDOI
TL;DR: Overall the results of the present systematic review support a continuum view rather than a diagnostic model, but cannot distinguish between ‘quasi’ and ‘fully’ dimensional models.

159 citations


Cites background from "The Role of Genes, Stress, and Dopa..."

  • ...Risk factors HVHs consistently report the presence ofwell-established latent risk factors for psychosis, i.e. genetic loading (Howes et al., 2016) and childhood trauma (Varese et al., 2012)....

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  • ...genetic loading (Howes et al., 2016) and childhood trauma (Varese et al....

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References
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Journal ArticleDOI
Stephan Ripke1, Stephan Ripke2, Benjamin M. Neale2, Benjamin M. Neale1  +351 moreInstitutions (102)
24 Jul 2014-Nature
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

6,809 citations


"The Role of Genes, Stress, and Dopa..." refers background in this paper

  • ...Akt3 was associated with schizophrenia in the GWAS described above (70), while Akt1 has been linked to schizophrenia in other studies (73,74)....

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  • ...Among the 108 loci associated with schizophrenia in the largest scale genomewide association study (GWAS) to date, one was for the D2 receptor (70)....

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Journal ArticleDOI
TL;DR: The KEGG GENES database now includes viruses, plasmids, and the addendum category for functionally characterized proteins that are not represented in complete genomes, and new automatic annotation servers, BlastKOalA and GhostKOALA, are made available utilizing the non-redundant pangenome data set generated from theGENES database.
Abstract: KEGG (http://www.kegg.jp/ or http://www.genome.jp/kegg/) is an integrated database resource for biological interpretation of genome sequences and other high-throughput data. Molecular functions of genes and proteins are associated with ortholog groups and stored in the KEGG Orthology (KO) database. The KEGG pathway maps, BRITE hierarchies and KEGG modules are developed as networks of KO nodes, representing high-level functions of the cell and the organism. Currently, more than 4000 complete genomes are annotated with KOs in the KEGG GENES database, which can be used as a reference data set for KO assignment and subsequent reconstruction of KEGG pathways and other molecular networks. As an annotation resource, the following improvements have been made. First, each KO record is re-examined and associated with protein sequence data used in experiments of functional characterization. Second, the GENES database now includes viruses, plasmids, and the addendum category for functionally characterized proteins that are not represented in complete genomes. Third, new automatic annotation servers, BlastKOALA and GhostKOALA, are made available utilizing the non-redundant pangenome data set generated from the GENES database. As a resource for translational bioinformatics, various data sets are created for antimicrobial resistance and drug interaction networks.

4,847 citations


"The Role of Genes, Stress, and Dopa..." refers background in this paper

  • ...Furthermore, a recent systematic pathway analysis of the Psychiatric Genomics Consortium’s enlarged sample (PGC2) GWAS findings identified the top pathway for genes associated with schizophrenia as being that for dopaminergic synapse (71) (Holmans P, Ph....

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Journal ArticleDOI
TL;DR: In this relatively brief study, the apparently increased comparative risk of agranulocytosis requires that the use of clozapine be limited to selected treatment-resistant patients.
Abstract: • The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics.DSM-IIIschizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.

3,842 citations

Journal ArticleDOI
TL;DR: A number of recent improvements to theNHGRI Catalog of Published Genome-Wide Association Studies are presented, including novel ways for users to interact with the Catalog and changes to the curation infrastructure.
Abstract: The National Human Genome Research Institute (NHGRI) Catalog of Published Genome-Wide Association Studies (GWAS) Catalog provides a publicly available manually curated collection of published GWAS assaying at least 100000 singlenucleotide polymorphisms (SNPs) and all SNP-trait associations with P <110 5 . The Catalog includes 1751 curated publications of 11912 SNPs. In addition to the SNP-trait association data, the Catalog also publishes a quarterly diagram of all SNP-trait associations mapped to the SNPs’ chromosomal locations. The Catalog can be accessed via a tabular web interface, via a dynamic visualization on the human karyotype, as a downloadable tab-delimited file and as an OWL knowledge base. This article presents a number of recent improvements to the Catalog, including novel ways for users to interact with the Catalog and changes to the curation infrastructure.

2,755 citations

Journal ArticleDOI
Amy F.T. Arnsten1
TL;DR: Recent research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.
Abstract: Stress affects cognition and increases noradrenaline and dopamine levels in the prefrontal cortex (PFC). Amy Arnsten discusses the intracellular signalling pathways that mediate the effects of these catecholamines on PFC function during acute and chronic stress, focusing on working memory. An interview with Amy Arnsten for Neuropod is available for download . The prefrontal cortex (PFC) — the most evolved brain region — subserves our highest-order cognitive abilities. However, it is also the brain region that is most sensitive to the detrimental effects of stress exposure. Even quite mild acute uncontrollable stress can cause a rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposure causes architectural changes in prefrontal dendrites. Recent research has begun to reveal the intracellular signalling pathways that mediate the effects of stress on the PFC. This research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.

2,320 citations


"The Role of Genes, Stress, and Dopa..." refers background in this paper

  • ...Stress-induced catecholamine release can impair working memory (90)....

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