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)

The induction of long-term depression (LTD) can be divided into two main forms, one dependent upon activation of postsynaptic NMDAR, and another independent of postsynaptic NMDAR. Non-postsynaptic NMDAR-LTD (non-NMDAR-LTD) occurs in many regions of the brain, and encompasses a wide variety of induction and expression mechanisms. In this article, the induction and expression mechanisms of such LTD in over 10 brain regions are described, with a number of common mechanisms compared across a large range of types of LTD. The article describes the involvement of different presynaptic or postsynaptic receptors in the induction of non-NMDAR-LTD, especially metabotropic glutamate receptors, cannabinoid receptors and dopamine receptors. An increase in presynaptic or postsynaptic intracellular Ca concentration is a key event in induction, commonly followed by activation of certain kinases, especially PKC, p38 MAPK and ERK. Expression mechanisms are either presynaptic via a reduction in release probability, or postsynaptic involving a decrease in AMPAR via phosphorylation of a glutamate receptor subunit, especially GluR2, followed by clathrin-mediated endocytosis. Retrograde signalling from postsynaptic to presynaptic occurs when induction is postsynaptic and expression is presynaptic.
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PMID:Induction and expression mechanisms of postsynaptic NMDA receptor-independent homosynaptic long-term depression. 1642 42

A 67-year-old woman was admitted with impaired general performance, suffering from fatigue, chest oppression on exertion, and paresthesia of the finger trips. The laboratory findings showed increased white blood cells with abnormal cells, and serum immunofixation test showed monoclonal IgM kappa paraprotein. On flow cytometric immunophenotyping with CD38 gating, most of the abnormal cells expressed surface CD20, CD138, cytoplasmic IgM, but neither surface CD56 nor surface IgM. Immunohistochemical staining of abnormal cells was positive for surface CD38, surface CD20 and cytoplasmic IgM. The final diagnosis was plasma cell leukemia IgM kappa type. Electrocardiography (ECG) on admission showed ST depression in II, III, aV(F), V4, V5, and V6. Coronary angiography (CAG) is invasive and difficult for patients with renal failure, therefore the patient underwent transthoracic Doppler echocardiography (TTDE), which revealed reduced coronary flow velocity reserve (CFVR). Two courses of VAD therapy were administered, then the condition improved, the serum IgM level decreased, abnormal cells were decreased in peripheral blood and bone marrow aspirates, and the creatinine levels improved. With the return of normal ECG findings and improved CFVR, the abnormal ECG and reduction in CFVR was thought to be associated with the hyperviscosity syndrome in PCL. Noninvasive assessment of CFVR by TTDE is significantly useful for the patients who have renal failure and need chemotherapy.
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PMID:[Effective measurement of coronary flow velocity reserve (CFVR) with transthoracic Doppler echocardiography (TTDE) for plasma cell leukemia with hyperviscosity syndrome]. 1647 78

The cognitive-behavioral, fear-avoidance (FA) model of chronic pain (Vlaeyen JWS, Kole-Snijders AMJ, Boeren RGB, van Eek H. Fear of movement/(re)injury in chronic low back pain and its relation to behavioral performance. Pain 1995a;62:363-72) has found broad empirical support, but its multivariate, predictive relationships have not been uniformly validated. Applicability of the model across age groups of chronic pain patients has also not been tested. Goals of this study were to validate the predictive relationships of the multivariate FA model using structural equation modeling and to evaluate the factor structure of the Tampa Scale of Kinesiophobia (TSK), levels of pain-related fear, and fit of the FA model across three age groups: young (< or =40), middle-aged (41-54), and older (> or =55) adults. A heterogeneous sample of 469 chronic pain patients provided ratings of catastrophizing, pain-related fear, depression, perceived disability, and pain severity. Using a confirmatory approach, a 2-factor, 13-item structure of the TSK provided the best fit and was invariant across age groups. Older participants were found to have lower TSK fear scores than middle-aged participants for both factors (FA, Harm). A modified version of the Vlaeyen JWS, Kole-Snijders AMJ, Boeren RGB, van Eek H (Fear of movement/(re)injury in chronic low back pain and its relation to behavioral performance. Pain 1995a;62:363-72.) FA model provided a close fit to the data (chi(2)(29)=42.0, p>0.05, GFI=0.98, AGFI=0.97, CFI=0.99, RMSEA=0.031 (90% CI 0.000-0.050), p close fit=0.95). Multigroup analyses revealed significant differences in structural weights for older vs. middle-aged participants. For older chronic pain patients, a stronger mediating role for pain-related fear was supported. Results are consistent with a FA model of chronic pain, while indicating some important age group differences in this model and in levels of pain-related fear. Longitudinal testing of the multivariate model is recommended.
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PMID:The fear-avoidance model of chronic pain: validation and age analysis using structural equation modeling. 1651 74

Investigations of the basic pathological, cellular, and molecular mechanisms of traumatic brain injury (TBI) over the past two decades have been carried out primarily in rodents. Unfortunately, these studies have not translated into improved outcome in patients with TBI. To better model human TBI, a swine model of controlled cortical impact (CCI) was developed. A CCI device was used to generate a focal lesion in 23 anesthetized male Yorkshire swine. In 10 swine, CCI parameters of velocity and dwell time were varied to achieve a consistent injury (3.5 m/sec, 400 msec, respectively). In 13 swine, depth of depression was varied from 9 to 12 mm. Physiological data, including heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP), were collected for 10 h after injury. Following injury, ICP and HR increased above baseline values in all swine, with a more pronounced elevation in animals impacted to a depth of depression of 12 mm. An 11-mm depth of depression was found to most closely mimic pathological features of human TBI with edema, infiltration of inflammatory cells, pericapillary hemorrhage, and petechial hemorrhages in the white matter. Injury to a depth of depression of 12 mm resulted in cortical laceration obscuring these features. Immunohistological staining with Neu-N, MAP-2, and Fluoro Jade B revealed evidence of degenerating neurons, axonal disruption, and impending cell death. These results indicate that the swine model of CCI results in a defined and reproducible injury with pathological features similar to human TBI. Physiological parameters after injury are readily monitored in a setting mimicking conditions of an intensive care unit, establishing a more clinically relevant experimental model for future investigations.
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PMID:Controlled cortical impact in swine: pathophysiology and biomechanics. 1650 97

The aim of the study was to examine an alexithymia score and depression among people smoking cigarettes and also to examine association between alexithymia, depression and smoking index, nicotine addiction, the motivation to quit smoking. The study comprised 46 people from Warsaw and its environs, without pulmonary, cardiovascular or neoplastic diseases, with at least medium education. The subjects were qualified into two groups: group I (n = 22) - subjects who had never smoked cigarettes, and group II - currently smoking (n=24). The total alexithymia score and scores of alexithymia subscales: difficulty in identifying feelings (TIE), b) difficulty in communicating feelings (TOU), c) externally oriented thinking (OSM) were assessed with Toronto Alexi. thymia Scale 20 (TAS-20). Beck Depression Inventory (Scale) (BDI) was used to evaluate presence and intensification of depression symptoms. The tobacco addiction rate was assessed with the Fagestrom questionnaire, and the motivation to quit smoking with the Schneider test. All data were obtained during individual exami. nations. The mean alexithymia score in the nonsmokers group was 38.6+/-8.8, in the smokers group: 46.6+/-13.0. The differences between the groups were statistically significant (p=0.02). Both difficulty in identifying feelings (TIE) and difficulty in communicating feelings (TOU) scores were significantly higher in the smokers (TIE p=0.01; TOU p=0.03). There were no differences in externally oriented thinking. It was found that people smoking cigarettes had a significantly higher level of intensification of depression symptoms than the controls. There was not any correlation between the total alexithymia score and depression symptoms or smoking index, the degree of nicotine addiction, the motivation to quit smoking.
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PMID:[Alexithymia and depression: relationship to cigarette smoking, nicotine dependence and motivation to quit smoking]. 1652 40

Silent synapses, or excitatory synapses that lack functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), are thought to be critical for regulation of neuronal circuits and synaptic plasticity. Here, we report that SynGAP, an excitatory synapse-specific RasGAP, regulates AMPAR trafficking, silent synapse number, and excitatory synaptic transmission in hippocampal and cortical cultured neurons. Overexpression of SynGAP in neurons results in a remarkable depression of AMPAR-mediated miniature excitatory postsynaptic currents, a significant reduction in synaptic AMPAR surface expression, and a decrease in the insertion of AMPARs into the plasma membrane. This change is specific for AMPARs because no change is observed in synaptic NMDA receptor expression or total synapse density. In contrast to these results, synaptic transmission is increased in neurons from SynGAP knockout mice as well as in neuronal cultures treated with SynGAP small interfering RNA. In addition, activation of the extracellular signal-regulated kinase, ERK, is significantly decreased in SynGAP-overexpressing neurons, whereas P38 mitogen-activated protein kinase (MAPK) signaling is potentiated. Furthermore, ERK activation is up-regulated in neurons from SynGAP knockout mice, whereas P38 MAPK function is depressed. Taken together, these data suggest that SynGAP plays a critical role in the regulation of neuronal MAPK signaling, AMPAR membrane trafficking, and excitatory synaptic transmission.
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PMID:SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. 1653 64

One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET-/-) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET-/- mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the beta-adrenergic ligand [3H]CGP12177 in the cerebral cortex of NET-/- mice, indicating the changes at the level of beta-adrenergic receptors similar to those obtained with ADs treatment. The binding of [3H]prazosin to alpha1-adrenergic receptors in the cerebral cortex of NET-/- mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET-/- mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET-/- mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.
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PMID:Effect of antidepressant drugs in mice lacking the norepinephrine transporter. 1655 43

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.
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PMID:Fibromyalgia--new concepts of pathogenesis and treatment. 1656 42

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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PMID:Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677. 1663 98

Cotransporters use energy stored in Na+ or H+ gradients to transport neurotransmitters or other substrates against their own gradient. Cotransport is rapid and efficient, and at synapses it helps terminate signaling. Cotransport in norepinephrine (NET), epinephrine (EpiT), dopamine (DAT), and serotonin (SERT) transporters couples downhill Na+ flux to uphill transmitter flux. NETs, for example, attenuate signaling at adrenergic synapses by efficiently clearing NE from the synaptic cleft, thus preparing the synapse for the next signal. Transport inhibition with tricyclic antidepressants prolongs neurotransmitter presence in the synaptic cleft, potentially alleviating symptoms of depression. Transport inhibition with cocaine or amphetamine, which respectively block or replace normal transport, may result in hyperactivity. Little is known about the kinetic interactions of substrates or drugs with transporters, largely because the techniques that have been successful in discovering trans- porter agonists and antagonists do not yield detailed kinetic information. Mechanistic data are for the most part restricted to global parameters, such as Km and Vmax, measured from large populations of transporter molecules averaged over thousands of cells. Three relatively new techniques used in transporter research are electrophysiology, amperometry, and microfluorometry. This review focuses on fluorescence-based methodologies, which--unlike any other technique-permit the simultaneous measurement of binding and transport. Microfluorometry provides unique insights into binding kinetics and transport mechanisms from a quantitative analysis of fluorescence data. Here we demonstrate how to quantify the number of bound substrate molecules, the number of transported substrate molecules, and the kinetics of substrate binding to individual transporters. Although we describe experiments on a specific neurotransmitter transporter, these methods are applicable to other membrane proteins.
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PMID:Molecular microfluorometry: converting arbitrary fluorescence units into absolute molecular concentrations to study binding kinetics and stoichiometry in transporters. 1672 29


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