Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of knockout (KO) mice have been evaluated as models of depression-related behavioral and neurobiological changes, and used to investigate molecular and cellular mechanisms underlying the activity of antidepressant drugs. Adult neurogenesis and brain 5-hydroxytryptamine (5-HT)/neurotrophic factor interactions have recently attracted great interest in relation to the mechanism of action of antidepressant drugs. The present review focuses primarily on genetic manipulation of the serotoninergic (5-HT) system. Basal neurochemical and behavioral changes occurring in mice lacking the 5-HT transporter (SERT), which is the main target of antidepressant drugs, as well as in those lacking G protein-coupled serotonin receptors (e.g. 5-HT1B, 5-HT1A, and 5-HT4 receptors) are described and evaluated. The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its high-affinity receptor (R-TrkB), is also addressed. Constitutive KO, tissue specific, or inducible KO mice targeting both 5-HT and brain-derived neurotrophic factor systems may potentially make an important contribution to knowledge of the pathophysiology and treatment of depression.
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PMID:Mutant mouse models and antidepressant drug research: focus on serotonin and brain-derived neurotrophic factor. 1917 48

Recently, the number of workers who suffer from job stress was increasing in Japan because of a prolonged recession, increasing number of elderly workers, and structural reorganization of companies. On the other hand, polymorphism associated with depression or alcoholism was detected. Relationship between job stress and these polymorphisms were investigated. Brief job stress questionnaire was assessed for 243 employees who worked at a manufacturing company and a local hospital in Japan (mean age 40.8 years). Alcohol consumption and smoking habit were assessed as lifestyle factors. DNA samples were prepared to detect polymorphisms of 5HTT, aldehyde dehydrogenase 2 (ALDH2), D2 dopamine receptor (DRD2), and cytochrome p450 2A6 (CYP2A6) genes. The level of depressed mood by job stress was significantly higher among carriers of two short alleles of the 5HTT regulatory region compared with carriers of one or two long alleles (Mann-Whitney U, p<0.05). In a logistic regression analysis, the s/s allele of the 5HTT had a tendency to be a risk of depressed mood. When subjects had high supervisor's support, depressed mood was significantly lower irrespective of 5HTT polymorphism. Job stress may elicit biological responses that contribute to depressed mood in relation to 5HTT polymorphism.
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PMID:5HTT polymorphisms are associated with job stress in Japanese workers. 1925 54

Depression and abdominal obesity often co-occur, predominantly in women, and are associated with an increased risk for the development of glucose intolerance and subsequently type 2 diabetes. The underlying mechanisms are poorly understood. We found that female, but not male, depression-prone serotonin transporter knockout (SERT(-/-)) rats had a strong increase (54%) in abdominal fat, whereas no increases in plasma concentrations of glucose and insulin were observed. Surprisingly, application of a high-fat, high-sucrose (HFHS)-choice diet, which results in increased abdominal fat deposition and increased plasma glucose levels in wild-type rats, did not result in elevated plasma glucose levels in female SERT(-/-) rats. Our results show that serotonin transporter deficiency affects abdominal fat deposition in a sex-dependent way, but protects against rises in glucose levels, and thereby potentially glucose intolerance. The increased abdominal fat formation could result from serotonin-mediated developmental changes and provides heuristic value for understanding the effects of the depression-associated serotonin transporter promoter polymorphism in humans.
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PMID:Serotonin transporter deficiency increases abdominal fat in female, but not male rats. 1944 35

The serotonin transporter knockout (SERT(-/-)) mouse, generated in 1998, was followed by the SERT(-/-) rat, developed in 2006. The availability of SERT(-/-) rodents creates the unique possibility to study the conservation of gene function across species. Here we summarize SERT(-/-) mouse and rat data, and discuss species (dis)similarities in neurobehavioral endophenotypes. Both SERT(-/-) rodent models show a disturbed serotonergic system, altered nociception, higher anxiety, decreased social behavior, as well as increased negative emotionality, behavioral inhibition and decision making. Used to model a wide range of psychiatric disorders, SERT(-/-) rodents may be particularly valuable in research on neurodevelopmental disorders such as depression, anxiety, and possibly autism. We conclude that SERT function is conserved across mice and rats and that their behavioral profile arises from common neurodevelopmental alterations. Because mice and rats have species-specific characteristics that confer differential research advantages, a comparison of the two models has heuristic value in understanding the mechanisms and behavioral outcome of SERT genetic variation in humans.
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PMID:Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes. 1969 44

Serotonin transporter (SERT, 5-HTT) is a key element in the serotonergic system which is probably involved in the psychiatric disorders commonly observed in people living with HIV/AIDS. However, no information is available about the effects of HIV infection on SERT expression. In this study, a TaqMan real-time RT-PCR method was established, levels of SERT mRNA in the peripheral blood mononuclear cells (PBMCs) and various tissues from normal Chinese rhesus macaques, in PBMCs from 32 SHIV-sf162p4 infected rhesus macaques and from 8 rhesus macaques before and 7, 14, 21, 28 and 196 days after SHIV-sf162p4 infection, and in PBMCs before and after in vitro phytohemagglutinin (PHA) stimulation were examined. It was found that SERT mRNA was widely distributed in lymphoid tissues; the level of SERT mRNA was significantly reduced in PBMCs from SHIV infected rhesus macaques and in PBMCs stimulated with PHA. The most evident decrease (to about one-tenth) in SERT mRNA level was observed at day 7 after SHIV infection. Difference in PBMC SERT mRNA level between 5-HTTLPR genotypes was not statistically significant. These data indicated that, in addition to previously observed abnormality in serotonin metabolism, SERT expression might be affected in HIV/AIDS, which might be associated with depression and other psychiatric disorders in HIV/AIDS. Besides, this study provided a basis for quantitative analysis of SERT gene expression under effects of host and environmental factors, such as 5-HTTLPR genotypes, SERT targeting drugs or other infectious agents.
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PMID:Alteration of serotonin transporter messenger RNA level in the peripheral blood mononuclear cells from simian/human immunodeficiency virus infected Chinese rhesus macaques (Macaca mulatta). 1985 62

The 5-hydroxytryptamine system is thought to play a crucial role in the pathophysiology of depression and represents the target for selective 5-HT reuptake inhibitors (SSRIs). Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats were bred from Sprague-Dawley (SPD) rats to produce strains with increased (FSL) or decreased (FRL) sensitivity to the cholinesterase inhibitor. The FSL rats have been identified as a good model of depression. Many studies in normal rats showed that chronic treatments with SSRIs reduce the densities of SERT. The objective of the present investigation was to assess the influence of chronic fluoxetine treatment on SERT density (Bmax; fmol/mg) in the FSL rat model of depression, relative to that in the FRL rats and SPD rats. FSL, FRL and SPD rats were randomly assigned into groups receiving the vehicle or 10 mg/kg of fluoxetine i.p. for 14 days. Binding was assessed by incubating the brain sections in a buffer containing 20 pM of [(125)I]-RTI-55 [[(125)I](-)-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane and 200 nM of GBR12935 [1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine]. The fluoxetine treatment reduced B(max) in all three rat strains when the saline and respective fluoxetine groups were compared (e.g., the FSL-SAL relative to FSL-FLX groups). Chronic fluoxetine treatment reduces the densities of SERT in the FSL rats to a larger extent than in the normal SPD control rats.
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PMID:Chronic fluoxetine treatment has a larger effect on the density of a serotonin transporter in the Flinders Sensitive Line (FSL) rat model of depression than in normal rats. 1992 93

Cohort studies have considerable prima facie value for investigating epigenetic processes in psychological disorder; however, the future prospects for such studies will depend on valid peripheral markers. The purpose of this pilot study was to investigate association between buccal cell methylation and risk for depression. Epigenotyping was limited to promoter methylation of the serotonin transporter gene (5HTT). A transcription limiting VNTR in the 5HTT promoter (5HTTLPR) was also genotyped. A nested sample of 25 depressed and 125 non-depressed adolescents was drawn from an established longitudinal study of adolescent health. There was no association between depressive symptoms and either buccal cell 5HTT methylation or 5HTTLPR. However, depressive symptoms were more common among those with elevated buccal cell 5HTT methylation who carried 5HTTLPR short-allele (OR 4.9, CI 1.9-13, p=0.001). Both complete and partial (as little as 10%) methylation of a 5HTT reporter gene in an expressing cell line reduced 5HTT activity. Replication is needed.
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PMID:Prospects for epigenetic research within cohort studies of psychological disorder: a pilot investigation of a peripheral cell marker of epigenetic risk for depression. 2001 25

Brain monoamines, and serotonin in particular, have repeatedly been shown to be linked to different psychiatric conditions such as depression, anxiety, antisocial behaviour, and dependence. Many studies have implicated genetic variability in the genes encoding monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) in modulating susceptibility to these conditions. Paradoxically, the risk variants of these genes have been shown, in vitro, to increase levels of serotonin, although many of the conditions are associated with decreased levels of serotonin. Furthermore, in adult humans, and monkeys with orthologous genetic polymorphisms, there is no observable correlation between these functional genetic variants and the amount or activity of the corresponding proteins in the brain. These seemingly contradictory data might be explained if the association between serotonin and these behavioural and psychiatric conditions were mainly a consequence of events taking place during foetal and neonatal brain development. In this review we explore, based on recent research, the hypothesis that the dual role of serotonin as a neurotransmitter and a neurotrophic factor has a significant impact on behaviour and risk for neuropsychiatric disorders through altered development of limbic neurocircuitry involved in emotional processing, and development of the serotonergic neurons, during early brain development.
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PMID:Serotonin, genetic variability, behaviour, and psychiatric disorders--a review. 2018 45

The aim of the study is to compare the expression level of candidate genes between patients suffering from a severe major depressive episode (MDE) and controls, and also among patients during MDE evolution. After a comprehensive review of the biological data related to mood disorders, we initiated a hypothesis-driven exploration of candidate mRNAs. Using RT-qPCR, we analyzed peripheral blood mononuclear cells (PBMCs) mRNA obtained from a homogeneous population of 11 patients who suffered from severe melancholic MDE. To assess the evolution of MDE, we analyzed PBMC mRNAs that were collected on Day 1 and 8 weeks later. Data from these patient samples were analyzed in comparison to age- and sex-matched healthy controls. Among 40 candidate genes consistently transcribed in PBMCs, 10 were differentially expressed in at least one comparison. We found that variations of mRNA levels for NRG1, SORT1 and TPH1 were interesting state-dependent biological markers of the disease. We also observed that variations in other mRNA expression were associated with treatment efficacy or clinical improvement (CREB1, HDAC5, HSPA2, HTR1B, HTR2A, and SLC6A4/5HTT). Significantly, 5HTT exhibited a strong correlation with clinical score evolution. We also found a state-independent marker, IL10. Moreover, the analysis of 2 separate MDEs concerning a same patient revealed comparable results for the expression of CREB1, HSPA2, HTR1B, NRG1 and TPH1. Overall, our results indicate that PBMCs obtained at different time points during MDE progression represent a promising avenue to discover biological markers for depression.
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PMID:Clinical variations modulate patterns of gene expression and define blood biomarkers in major depression. 2047 Oct 34

Trazodone is an antidepressant which behaves as a selective 5-HT(2) antagonist and 5-HT reuptake inhibitor. The lack of information on its effects in vivo prompted us to evaluate alpha(2)-adrenoceptors by means of the specific binding of [(3)H]-rauwolscine, and the 5-HT transporter (SERT) by means of the binding of [(3)H]-paroxetine ([(3)H]-Par), in platelets of depressed patients, before and after one month of treatment with trazodone (75-300 mg/day). Twenty-five outpatients of both sexes with a diagnosis of major depression, as assessed by the Structured Clinical Interview for DSM IV, were included in the study. Depressive symptoms were evaluated by means of the Hamilton Rating Scale for Depression: the total score (mean +/- SD) was 20 +/- 6 at baseline (t(0)) and 7 +/- 4 after one month of treatment (t(1)). Platelet membranes, [(3)H]- rauwolscine and [(3)H]-Par bindings were carried out according to standardized protocols. The results showed that the B(max) values of [(3)H]-Par were statistically lower at t(1) than at t(0) (733 +/- 30 vs 1471 +/- 99, P < 0.001), while the K(d) and the [(3)H]-rauwolscine binding parameters remained unchanged. The findings of this study suggest that in vivo trazodone modifies the number of the SERT proteins and that, perhaps, most of its antidepressant properties are related to this activity.
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PMID:Trazodone effects on [H]-paroxetine and alpha(2)-adrenoreceptors in platelets of patients with major depression. 2052 Jul 89


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