UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission and play a key role in synaptic plasticity in the mammalian central nervous system (CNS). In recent years several classes of AMPA receptor potentiators have been reported in the literature, including pyrrolidones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and biarylpropylsulfonamides (LY392098, LY404187, LY450108, LY451395 and LY503430). Clinical and preclinical data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. However, recent evidence has shown that in addition to modulating fast synaptic plasticity and memory processes, AMPA receptor potentiators alter downstream signalling pathways and may thereby have utility in other CNS disorders. The present review summarises studies into the effects of AMPA receptor potentiators (with a focus on the biarylpropylsulfonamides) in rodent models of depression and Parkinson's disease.
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PMID:AMPA receptor potentiators: application for depression and Parkinson's disease. 1750 4

Degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) plays an important role in the pathophysiology of neurodegenerative diseases like Parkinsonism and vascular dementia. SNc dopamine neurons both in vitro and in vivo show sensitivity to hypoxic/ischemic conditions and undergo degeneration. In acute brain slices, these dopamine neurons undergo hyperpolarization during hypoxia and hypoglycemia, which results in silencing of the neurons. However, the role that SNc excitatory synapses play in this process is poorly understood. Here we examined the effect of oxygen/glucose deprivation (OGD) on glutamatergic synaptic transmission in the SNc in a rat midbrain slice preparation. OGD for 5 min caused pre-synaptic ischemic long-term depression (iLTD) of glutamate transmission, as both alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and N-methyl-D-aspartate receptor-mediated synaptic currents in SNc dopamine neurons were depressed to a similar extent. This depression began immediately after exposure to OGD and was not recovered upon washout of OGD. Pharmacological studies revealed that the iLTD was triggered by a rise in post-synaptic intracellular calcium and mediated by activation of pre-synaptic adenosine A(1) receptors, which reduced glutamate-dependent synaptic transmission by activating ATP-dependent potassium channels. Furthermore, we observed that iLTD did not occlude tetanic long-term depression (LTD) at the SNc excitatory synapses, suggesting that these two forms of LTD involve different pathways. Taken together, our results showed that brief exposure to hypoxia and hypoglycemia results in LTD of synaptic activity at glutamatergic synapses onto SNc neurons and this phenomenon could represent a protective mechanism by reducing ischemia-induced excitotoxic injury to dopamine neurons.
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PMID:Brief ischemia causes long-term depression in midbrain dopamine neurons. 1788 Mar 89

Synaptic plasticity in the form of long-term potentiation (LTP) plays a critical role in the formation of a Pavlovian fear association. However, the role that synaptic plasticity plays in the suppression of a learned fear response remains to be clarified. Here, we assessed the role that long-term depression (LTD) plays in the acquisition, expression, and extinction of a conditioned fear response. We report that blockade of LTD with a GluR2-derived peptide (Tat-GluR2(3Y); 1.5 micromol/kg, i.v.) that blocks regulated alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor endocytosis during an initial extinction training session disrupted both the expression and recall of extinction learning. A similar impairment of extinction during training, but not recall, was observed when NMDA receptor-dependent LTD was inhibited through the selective blockade of NMDA NR2B receptors with Ro 25-6981. In contrast, blockade of LTD with Tat-GluR2(3Y) during fear conditioning or during a fear recall test did not effect the expression or recall of either contextual or cue-induced conditioned fear. Similarly, administration of Tat-GluR2(3Y) prior to an extinction recall test did not affect spontaneous recovery or rate of re-extinction in previously extinguished rats. These data demonstrate that AMPA receptor endocytosis does not mediate acquisition or expression of conditioned fear, but may play a role in the extinction of fear memories. Furthermore, these findings suggest that LTD may be a molecular mechanism that facilitates the selective modification of a learned association while leaving intact the ability to form a new memory.
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PMID:Disruption of AMPA receptor endocytosis impairs the extinction, but not acquisition of learned fear. 1804 3

Modifying the function of postsynaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) is one of the most important mechanisms by which the efficacy of synaptic transmission at excitatory glutamatergic synapses in the mammalian brain is regulated. Traditionally these types of modifications have been thought to be achieved mainly by altering the channel gating properties or conductance of the receptors. A large body of evidence accumulated from recent studies strongly suggests that AMPARs, like most integral plasma membrane proteins, are continuously recycled between the plasma membrane and the intracellular compartments via vesicle-mediated plasma membrane insertion and clathrin-dependent endocytosis. Regulation of either receptor insertion or endocytosis results in a rapid change in the number of these receptors expressed on the plasma membrane surface and in the receptor-mediated responses, thereby playing an important role in mediating certain forms of synaptic plasticity, such as long-term potentiation (LTP) and depression (LTD). These studies have significantly advanced our understanding of the molecular mechanisms underlying LTP and LTD, and their potential contributions to learning and memory-related behaviours. Here I provide a brief summary of the current state of knowledge concerning clathrin-mediated AMPAR endocytosis and its relationship to the expression of certain forms of LTD in several brain areas. The potential impact of recent advancements on our efforts to probe the roles of synaptic plasticity in learning and memory-related behaviours, and their relevance to some brain disorders, particularly drug addiction, are also discussed.
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PMID:Probing the role of AMPAR endocytosis and long-term depression in behavioural sensitization: relevance to treatment of brain disorders, including drug addiction. 1805 15

In addition to its clinical antimanic effects, lithium also has efficacy in the treatment of depression. However, the mechanism by which lithium exerts its antidepressant effects is unclear. Our objective was to further characterize the effects of peripheral and central administration of lithium in mouse models of antidepressant efficacy as well as to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in these behaviors. We utilized the mouse forced swim test (FST) and tail suspension test (TST), intracerebroventricular (ICV) lithium administration, AMPA receptor inhibitors, and BS3 crosslinking followed by Western blot. Both short- and long-term administration of lithium resulted in robust antidepressant-like effects in the mouse FST and TST. Using ICV administration of lithium, we show that these effects are due to actions of lithium on the brain, rather than to peripheral effects of the drug. Both ICV and rodent chow (0.4% LiCl) administration paradigms resulted in brain lithium concentrations within the human therapeutic range. The antidepressant-like effects of lithium in the FST and TST were blocked by administration of AMPA receptor inhibitors. Additionally, administration of lithium increased the cell surface expression of GluR1 and GluR2 in the mouse hippocampus. Collectively, these data show that lithium exerts centrally mediated antidepressant-like effects in the mouse FST and TST that require AMPA receptor activation. Lithium may exert its antidepressant effects in humans through AMPA receptors, thus further supporting a role of targeting AMPA receptors as a therapeutic approach for the treatment of depression.
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PMID:Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test. 1809 91

Altered distribution of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 has been linked to stimulation-dependent changes in synaptic efficacy, including long-term potentiation and depression. The main olfactory bulb (OB) remains plastic throughout life; how GluR1 may be involved in this plasticity is unknown. We have previously shown that neonatal naris occlusion reduces numbers of interneuron cell bodies that are immunoreactive for GluR1 in the external plexiform layer (EPL) of the adult mouse OB. Here, we show that immunoreactivity of mouse EPL interneurons for GluR1 is also dramatically reduced following olfactory deafferentation in adulthood. We further show that expression of glutamic acid decarboxylase (GAD) 65, 1 of 2 GAD isoforms expressed by adult gamma-aminobutyric acidergic interneurons, is reduced, but to a much smaller extent, and that in double-labeled cells, immunoreactivity for the Ca(2+)-binding protein parvalbumin (PV) is also reduced. In addition, GluR1 expression is reduced in presumptive tufted cells and interneurons that are negative for GAD65 and PV. Consistent with previous reports, sensory deafferentation resulted in little neuronal degeneration in the adult EPL, indicating that these differences were not likely due to death of EPL neurons. Together, these results suggest that olfactory input regulates expression of the GluR1 AMPA receptor subunit by tufted cells that may in turn regulate GluR1 expression by interneurons within the OB EPL.
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PMID:Sensory deafferentation transsynaptically alters neuronal GluR1 expression in the external plexiform layer of the adult mouse main olfactory bulb. 1818 38

The induction of both long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 region is triggered by the activation of N-methyl-D-aspartate (NMDA) receptors and the subsequent postsynaptic intracellular Ca2+ increase. However, how NMDA receptor activation differs between LTP and LTD induction is unclear. In the present study, we examined the effects of the magnitude and duration of NMDA receptor activation on the induction of LTP and LTD. Partial blockage of NMDA receptors by a low concentration of aminophosphonovaleric acid (APV) (2 microM) prevented the induction of LTP, but not LTD. In contrast, a high concentration of APV (25 microM) blocked both LTP and LTD. Tetanus stimulation-induced LTP was impaired when hippocampal slices were given the tetanus stimulation for more than 5 min. Under partial blockage of NMDA receptors, the prolonged-tetanus stimulation induced LTD but not LTP. This phenomenon was mimicked by the application of glutamate to the slices. Finally, LTD induced by prolonged activation of NMDA receptors was not affected by inhibition of the desensitization of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. These results suggest that critical differences exist between the induction of LTP and that of LTD in terms of both the magnitude and the duration of NMDA receptor activation. The duration of the increase in intracellular Ca2+ concentration may be critical for determining whether LTP or LTD induction occurs.
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PMID:Critical differences in magnitude and duration of N-methyl D-aspartate(NMDA) receptor activation between long-term potentiation (LTP) and long-term depression (LTD) induction. 1832 68

Transmission through the thalamus activates circuits involving the GABAergic neurons of the thalamic reticular nucleus (TRN). TRN cells receive excitatory inputs from thalamocortical and corticothalamic cells and send inhibitory projections to thalamocortical cells. The inhibitory output of TRN neurons largely depends on the level of excitatory drive to these cells but may also be partly under the control of mechanisms intrinsic to the TRN. We examined two such possible mechanisms, short-term plasticity at glutamatergic synapses in the TRN and intra-TRN inhibition. In rat brain slices, responses of TRN neurons to brief trains of stimuli applied to glutamatergic inputs were recorded in voltage- or current-clamp mode. In voltage clamp, TRN cells showed no change in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory postsynaptic current amplitudes to stimulation at non-gamma frequencies (< 30 Hz), simulating background activity, but exhibited short-term depression in these amplitudes to stimulation at gamma frequencies (> 30 Hz), simulating sensory transmission. In current clamp, TRN cells increased their spike outputs in burst and tonic firing modes to increasing stimulus-train frequencies. These increases in spike output were most likely due to temporal summation of excitatory postsynaptic potentials. However, the frequency-dependent increase in tonic firing was attenuated at gamma stimulus frequencies, indicating that the synaptic depression selectively observed in this frequency range acts to suppress TRN cell output. In contrast, intra-TRN inhibition reduced spike output selectively at non-gamma stimulus frequencies. Thus, our data indicate that two intrinsic mechanisms play a role in controlling the tonic spike output of TRN neurons and these mechanisms are differentially related to two physiologically meaningful stimulus frequency ranges.
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PMID:Two differential frequency-dependent mechanisms regulating tonic firing of thalamic reticular neurons. 1854 48

Preclinical research findings in laboratory animals indicate that the glutamatergic system is critically involved in nicotine dependence. In animals, compounds that decrease glutamatergic neurotransmission, such as antagonists at postsynaptic NMDA receptors, antagonists at excitatory postsynaptic metabotropic glutamate (mGlu) 5 receptors, or agonists at inhibitory presynaptic mGlu(2) and mGlu(3) receptors, decreased nicotine self-administration or reinstatement of nicotine-seeking behaviour. These findings suggest that medications that decrease glutamatergic transmission overall may reduce the reinforcing effects of tobacco smoking and prevent relapse to tobacco smoking in humans. Furthermore, compounds that increase glutamate release, such as antagonists at mGlu(2) and mGlu(3) receptors, ameliorated reward deficits associated with nicotine withdrawal in animals, and thus may alleviate the depression-like symptoms associated with nicotine withdrawal in humans. Animal studies also showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors did not appear to be involved in mediating the primary reinforcing effects of nicotine but that they may be involved in the development of nicotine dependence and withdrawal.Taken together, the preclinical data indicate that different glutamatergic receptors are involved in the mediation of different aspects of nicotine dependence. These findings have implications for the discovery and development of new pharmacotherapies that target the glutamatergic system to aid in smoking cessation. At present, very few clinical studies have addressed the effects of glutamatergic compounds on cigarette smoking. Clinical studies involving compounds that have actions at ionotropic glutamate receptors are briefly discussed in this review and suggest the potential of glutamatergic compounds as pharmacotherapies to aid in smoking cessation. Medications that target mGlu receptors have recently been tested in human phase II trials for various indications; however, the potential of these mGlu compounds as medications for nicotine dependence remains to be evaluated in humans. The preclinical data evaluated in this review indicate that such clinical trials for smoking cessation with mGlu compounds are clearly warranted and may reveal novel treatments for nicotine dependence.
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PMID:Role of the glutamatergic system in nicotine dependence : implications for the discovery and development of new pharmacological smoking cessation therapies. 1869 72

The classic example of experience-dependent cortical plasticity is the ocular dominance (OD) shift in visual cortex after monocular deprivation (MD). The experimental model of homosynaptic long-term depression (LTD) was originally introduced to study the mechanisms that could account for deprivation-induced loss of visual responsiveness. One established LTD mechanism is a loss of sensitivity to the neurotransmitter glutamate caused by internalization of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Although it has been shown that MD similarly causes a loss of AMPARs from visual cortical synapses, the contribution of this change to the OD shift has not been established. Using an herpes simplex virus (HSV) vector, we expressed in visual cortical neurons a peptide (G2CT) designed to block AMPAR internalization by hindering the association of the C-terminal tail of the AMPAR GluR2 subunit with the AP2 clathrin adaptor complex. We found that G2CT expression interferes with NMDA receptor (NMDAR)-dependent AMPAR endocytosis and LTD, without affecting baseline synaptic transmission. When expressed in vivo, G2CT completely blocked the OD shift and depression of deprived-eye responses after MD without affecting baseline visual responsiveness or experience-dependent response potentiation in layer 4 of visual cortex. These data suggest that AMPAR internalization is essential for the loss of synaptic strength caused by sensory deprivation in visual cortex.
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PMID:Essential role for a long-term depression mechanism in ocular dominance plasticity. 1947 Apr 83

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