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)

At most synapses, chemical signalling is terminated by a rapid reaccumulation of neurotransmitter into presynaptic terminals. Uptake systems for the biogenic amines are the initial site of action for therapeutic antidepressants and drugs such as cocaine and the amphetamines. We have isolated a complementary DNA clone encoding a human noradrenaline transporter. The cDNA sequence predicts a protein of 617 amino acids, with 12-13 highly hydrophobic regions compatible with membrane-spanning domains. Expression of the cDNA clone in transfected HeLa cells indicates that noradrenaline transport activity is sodium-dependent and sensitive to selective noradrenaline transport inhibitors. Transporter RNA is localized to the brainstem and the adrenal gland. The predicted protein sequence demonstrates significant amino-acid identity with the Na+/gamma-aminobutyric acid transporter, thus identifying a new gene family for neurotransmitter transporter proteins. Analysis of its structure and function may lead to structure-based drug design for the treatment of human depression and could help determine whether transporter abnormalities underlie affective disorders.
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PMID:Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. 200 12

Desipramine, a tricyclic antidepressant, inhibits the neuronal uptake of adrenaline and noradrenaline and, as a radioligand, labels the noradrenaline transporter in central and peripheral tissues of the rat. To study whether [3H]desipramine also labels the neuronal adrenaline transporter in vitro, its binding was evaluated in the frog heart, a tissue with a rich adrenergic innervation but virtually devoid of noradrenergic innervation. [3H]Desipramine binding to membranes from the frog heart was of high affinity (Kd = 1.94 nM) and was potently inhibited by nisoxetine and (+)oxaprotiline. Unexpectedly, [3H]desipramine binding to the transporter for adrenaline in the frog heart was also sensitive to inhibition by imipramine and the atypical antidepressants mianserin and iprindol. This is the first study to demonstrate radioligand binding to the neuronal transporter for adrenaline. The results indicate that the pharmacological profile of the transporter for adrenaline may be different from that of the noradrenergic transporter, if species differences can be excluded. It remains to be established if the affinity of imipramine, mianserin and iprindol for the adrenaline transporter contributes to their therapeutic efficacy in depression.
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PMID:[3H]desipramine labels with high affinity the neuronal transporter for adrenaline in the frog heart. 349 46

Noradrenaline has been implicated in the pathogenesis of depression and the noradrenaline transporter (NET) is a target for some antidepressants. Therefore, mice with disrupted NET gene expression (NET-KO) appear especially suitable for studying this behavioral disorder. We have examined the interaction between social stress (an etiological factor of depression) and the resulting depressive behaviors in NET-KO mice. Social stress was induced by daily defeats from larger resident mice while depression was assessed by the behavioral despair model. Animals subjected to repeated social stress showed reduced weight gain and a gradual shift from offensive to defensive behaviors. The latter may be considered a situation-specific depressive-like behavior. NET gene disruption did not prevent these changes that developed in a homotypic situation (i.e., during the repeated application of the same stressor). In contrast, stressed NET-KO mice showed more struggling in the behavioral despair model than stressed wild type (WT) animals. Thus, NET gene disruption inhibited depression-like behavior in chronically stressed animals tested in a situation heterotypic to the original cause of chronic stress. We suggest that the behavioral effects of NET gene disruption were overruled by experience and learning in the homotypic situation but manifested fully in the heterotypic situation. Tentatively, our data suggest that enhanced noradrenergic function does not prevent situation-specific social learning but impedes the generalization of depression to heterotypic circumstances.
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PMID:Behavioral responses to social stress in noradrenaline transporter knockout mice: effects on social behavior and depression. 1212 53

The reason for the high frequency of depression and anxiety in Parkinson's disease is poorly understood. Degeneration of neurotransmitter systems other than dopamine might play a specific role in the occurrence of these affective disorders. We used [11C]RTI-32 PET, an in vivo marker of both dopamine and noradrenaline transporter binding, to localize differences between depressed and non-depressed patients. We studied eight and 12 Parkinson's disease patients with and without a history of depression matched for age, disease duration and doses of antiparkinsonian medication. The depressed Parkinson's disease cohort had lower [11C]RTI-32 binding than non-depressed Parkinson's disease cases in the locus coeruleus and in several regions of the limbic system including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum. Exploratory analyses revealed that the severity of anxiety in the Parkinson's disease patients was inversely correlated with the [11C]RTI-32 binding in most of these regions and apathy was inversely correlated with [11C]RTI-32 binding in the ventral striatum. These results suggest that depression and anxiety in Parkinson's disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system.
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PMID:Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. 1571 2

Lymphocytes possess transporters of serotonin and dopamine, and also contain monoamines. The objective of this work was to determine the presence of noradrenaline transporters, the turnover rate of noradrenaline and serotonin in lymphocytes of major depression patients, and to correlate the biochemical parameters with the severity of the disorder. Lymphocytes from peripheral blood were isolated by Ficoll/Hypaque, and noradrenaline transporter was studied by binding of [3H]nisoxetine: control group (29, age 31.52+/-1.08, 7 men) and major depression patients (35, age 36.68+/-1.69, 6 men), Hospital Vargas de Caracas. Diagnostic was done by criteria of the American Psychiatric Association and severity by Hamilton Scale for Depression. Levels of noradrenaline, serotonin, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid were determined by HPLC. Turnover rate was evaluated by the ratios of monoamines and metabolites. Correlations were done between the biochemical parameters and the severity of depression. The score of Hamilton for Depression was 22.77+/-0.51. There was a reduction in the number of transporters in lymphocytes of patients, 0.95+/-0.27 versus 4.06+/-1.67 fmol/10(6) cells. Levels of monoamines and metabolites did not significantly differ between patients and controls. However, there was a higher monoamine/metabolite ratio in lymphocytes of patients, indicating a reduction of metabolic turnover rate. Also there was a relative greater concentration of noradrenaline than serotonin in the lymphocytes of the patients, as indicated by the ratio noradrenaline/serotonin. Noradrenergic and serotonergic turnover is decreased in blood peripheral lymphocytes of major depression patients; the reduction in noradrenaline transporter could be related to changes in intracellular levels, and these modifications could result in functional changes of the immune system.
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PMID:Noradrenaline transporter and its turnover rate are decreased in blood lymphocytes of patients with major depression. 1624 84

The protopine isolated from a Chinese herb Dactylicapnos scandens Hutch was identified as an inhibitor of both serotonin transporter and noradrenaline transporter in vitro assays. 5-hydroxy-DL-tryptophan(5-HTP)-induced head twitch response (HTR) and tail suspension test were adopted to study whether protopine has anti-depression effect in mice using reference antidepressant fluoxetine and desipramine as positive controls. In HTR test, protopine at doses of 5, 10, 20 mg/kg dose dependently increase the number of 5-HTP-induced HTR. Protopine at doses of 3.75 mg/kg, 7.5 mg/kg and 30 mg/kg also produces a dose-dependent reduction in immobility in the tail suspension test. The present results open up new possibilities for the use of protopine in the treatment of mood disorders, such as mild and moderate states of depression.
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PMID:Protopine inhibits serotonin transporter and noradrenaline transporter and has the antidepressant-like effect in mice models. 1653 Feb 30

Pathological immunoactivation is thought to play an important role in the etiology of depression; however, the effect of novel antidepressant drugs on immunity has been poorly recognized. Mirtazapine, an antidepressant drug, enhances noradrenergic and serotonergic neurotransmissions, which are crucially involved in the regulation of immune system activity. In the present study we examined the effect of acute and seven-day repeated administration of mirtazapine (20 mg/kg, i.p.) on immunoreactivity in noradrenaline transporter knockout (NET-KO) and wild-type male C57BL/6J mice subjected to the forced swimming test (FST). Mirtazapine decreased immobility time in the FST after acute, but not seven-day repeated, administration to C57BL/6J mice. Lack of the antidepressant effect of mirtazapine was observed, after acute and repeated administration to NET-KO mice, although those mice showed a significantly shorter immobility time in the FST than did wild-type animals. Seven-day repeated mirtazapine administration to wild-type mice suppressed the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines, whereas production of IL-4 was stimulated. Acute mirtazapine administration did not change immune parameters in C57BL/6J mice. In NET-KO mice, acute and seven-day repeated mirtazapine administration reduced the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines. This study indicates that, in comparison with wild-type C57BL/6J mice, NET-KO mice show enhanced mobility, which is not further potentiated by mirtazapine treatment. Furthermore, the NET-KO mice display higher susceptibility to the immunosuppressive effects of mirtazapine than do the wild-type animals. The present paper postulates an essential role of noradrenergic system in the immunological and behavioral effects of mirtazapine.
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PMID:Effect of acute and repeated treatment with mirtazapine on the immunity of noradrenaline transporter knockout C57BL/6J mice. 1719 39

A petroleum ether extract (FP) from Fructus Psoraleae, seeds of Psoralea corylifolia L. (Leguminosae), was found to strongly inhibit dopamine (DA) uptake by dopamine transporter (DAT) heterogeneously expressed cells (D8 cells) and noradrenaline (NE) uptake by noradrenaline transporter (NET) heterogeneously expressed cells, which, however, had no effect on gamma-aminobutyric acid transporter heterogeneously expressed cells and serotonin transporter heterogeneously expressed cells at the concentration up to 100 microg/ml. These inhibitory effects were also confirmed by experiments on SK-N-SH cell line and synaptosomes from rats' brains. In addition, FP showed a significantly mitigating effect on 1-methyl-4-pyridinium induced injury of D8 cells. Meanwhile, FP dose-dependently reduced the binding of tritium-labeled cocaine analog (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane to DAT of D8 cells, which suggests that FP may inhibit DAT activity in the same way as cocaine does. Behavioral study showed FP had a long-lasting stimulant effects on the activity of intact mice and reserpinized mice. So FP is proposed as a kind of DAT and NET inhibitor and may be involved in the process of regulating the DA and NE system, and FP or its unknown bioactive compounds may be developed into new medicines for disorders such as Parkinson's disease, depression, Attention Deficit Hyperactivity Disorder (ADHD) or cocaine addiction.
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PMID:Inhibitive effects of Fructus Psoraleae extract on dopamine transporter and noradrenaline transporter. 1755 97

Although effective treatment for mood and anxiety disorders have been available for more than 40 years, 30-50% of depressed patients and 25% of patients with anxiety disorder do not respond sufficiently to first-line treatment with antidepressants. Genetic factors are supposed to play a major role in both variation of treatment response and incidence of adverse effects to medication. So far, candidate genes of pharmacokinetic and pharmacodynamic pathways of antidepressants have been investigated, and associations between several candidate genes and response to antidepressants are reported. Two functional polymorphisms of the serotonin transporter gene, 5-HTTLPR and STin2 have been investigated in a large number of pharmacogenetic studies of depression; other candidate genes include serotonin receptor genes, brain-derived neurotrophic factor, P-glycoprotein (located in the blood-brain barrier), G-proteins, TPH1 and TPH2, MAOA, the noradrenaline transporter gene, FKBP5, or cytochrome P450 (CYP450) genes. CYP450 genes play a major role in the metabolism of a substantial part of psychotropics, including antidepressants, and the first estimates of dosage adjustments for antidepressants have been provided based on metabolizer status. Genome-wide association studies that use large numbers of single-nucleotide polymorphisms to screen the entire genome for alleles that influence a trait are now feasible, and the results of the first genome-wide association studies of antidepressant treatment outcome will soon be available. The current review not only updates pharmacogenetic research in depression but also focuses on antidepressant treatment response in anxiety disorders.
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PMID:The role of pharmacogenetics in the treatment of depression and anxiety disorders. 1973 81

Major depressive disorder (MDD) which is supposed to result from a complex interaction of genetic and epigenetic, environmental and developmental factors is one of the most common debilitating public health problems. The molecular mechanisms underlying this disease are still largely unclear. Identifying common pathways for diverse antidepressants (ADs) as well as new drug targets and thereby developing more effective treatments are primary goals of research in this field. Major targets of ADs are the serotonin transporter (SERT), the noradrenaline transporter (NAT) and also the dopamine transporter (DAT) located in the plasma membrane of corresponding neurons. These monoamine transporters (MATs) are important regulators of the extracellular neurotransmitter concentration. Among the clinically important ADs are tricyclic ADs (e.g. imipramine), selective serotonin re-uptake inhibitors (SSRIs, e.g. fluoxetine), selective noradrenaline (NA) re-uptake inhibitors (SNRIs, e.g. reboxetine) and NAT/DAT inhibitors like bupropion. This review is focussing on brain changes in monoamine neurotransmitter systems, downstream targets of monoaminergic neurotransmission as well as of behaviours of mice with a conventional knockout (KO) of either the SERT, DAT or NAT. MAT knockout induces changes in behaviour and brain neurochemistry. Although at least NATKO and SERTKO mice were expected to show a phenotype like AD-treated wild-type mice, this holds true only for the NATKO mice whereas SERTKO mice show an anxiety-like phenotype. Chronic social or restraint stress-induced depression-like behaviour and concomitant changes in brain neurotrophins are prevented by pharmacologically diverse ADs and by NATKO. Thus, NATKO mice are an interesting tool to investigate the mechanisms beyond monoamines responsible for depression as well as for AD actions.
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PMID:Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. 2114 64


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