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)

Sodium-dependent high-affinity uptake of glutamate is thought to play a major role in the maintenance of very low extracellular concentrations of excitatory amino acids (EAA), and may modulate the actions of released transmitter at G-protein-coupled receptors and extrasynaptic receptors that are activated over a longer distance and time course. We have examined the effects of the recently developed uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) on monosynaptically evoked excitatory postsynaptic currents (EPSCs) in very-low-density cultures of hippocampal neurons. L-Trans-PDC produced a decreased amplitude of both the non-NMDA and NMDA receptor-mediated components of monosynaptically evoked EPSCs. Examination of miniature EPSCs (mEPSCs) indicated that changes in the sensitivity of postsynaptic non-NMDA receptors did not underline the decrease in evoked EPSC amplitudes. The metabotropic receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) also depressed both components of the EPSC. The competitive metabotropic receptor antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) blocked the depression of EPSC amplitude induced by 1S,3R-ACPD and also blocked the effects of L-trans-PDC. Finally, low concentrations of L-glutamate (2 microM) mimicked the effects of L-trans-PDC on EPSC amplitude. From these results we conclude that the application of L-trans-PDC to cultured hippocampal neurons results in the activation of presynaptic metabotropic receptors, leading to a decrease in synaptic transmission. We propose that this effect is due to an increase in ambient glutamate concentrations following inhibition of glutamate uptake, resulting in presynaptic inhibition of excitatory synaptic transmission.
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PMID:The glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate depresses excitatory synaptic transmission via a presynaptic mechanism in cultured hippocampal neurons. 796 76

The effects of iontophoretically applied (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a metabotropic glutamate receptor (mGluR) agonist, were studied on extracellularly recorded neurons throughout the depth of the primary somatosensory cortex in the anaesthetized adult rat. Distinct excitatory effects were found almost exclusively in neurons recorded in layer V. Postsynaptic depressant effects dominated neurons recorded in layers I-IV. In layer VI, neurons were equally divided as to excitation and depression. Both the excitatory and postsynaptic depressant effects could be antagonized by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). Experiments using bicuculline and several lines of analysis suggested that the postsynaptic depressant effects were mediated directly, rather than through disfacilitation. In a proportion of neurons 1S,3R-ACPD selectively depressed synaptically evoked responses (produced by vibrissa deflections), with little or no effect on the postsynaptic level of firing. Comparing the depressant effects of 1S,3R-ACPD with those of GABA supported a presynaptic mGluR site. Responses to centre and surround receptive field stimulation were depressed to the same extent, suggesting that thalamocortical and intracortical axon terminals are equally endowed with presynaptic receptors. In contrast to previous studies, the actions of L-2-amino-4-phosphonobutyric acid (L-AP4) were shown to be qualitatively different to those of 1S,3R-ACPD, in particular suggesting that the presynaptic depression produced by 1S,3R-ACPD is not mediated by L-AP4-type receptors. The functional implications of different mGluR actions in the primary somatosensory cortex are discussed.
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PMID:Cortical layer-specific effects of the metabotropic glutamate receptor agonist 1S,3R-ACPD in rat primary somatosensory cortex in vivo. 800 May 74

In rat cerebellar slices, 500 microM (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) reversibly inhibited both dendritic and somatic increases in FLUO-3 fluorescence intensity induced by bath applications of 50-100 microM (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD). No effect of MCPG was observed on dendritically recorded excitatory postsynaptic potentials evoked by synaptic activation of either parallel or climbing fibres. Long-term depression of parallel fibre-Purkinje cell transmission, induced either by conjunctive activation of parallel and climbing fibres or by pairing parallel fibre stimulation with intradendritic injections of 8-BrcGMP, was not only prevented in the presence of MCPG but a robust long-term potentiation of responses consistently occurred. These data show that metabotropic glutamate receptor activation is necessary for the induction of LTD.
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PMID:Induction of cerebellar long-term depression requires activation of glutamate metabotropic receptors. 806 Dec 95

The transmission of vestibular inputs to reticulospinal (RS) neurones of the posterior rhombencephalic nucleus (PRRN) has been shown to be depressed by the bath application of N-methyl-D-aspartate (NMDA). The aim of this study was to investigate the pharmacological mechanism involved using patch clamp recordings of reticulospinal neurones. It is demonstrated that the chemical component of vestibular inputs to the PRRN is mediated by glutamatergic synapses utilising alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors on the PRRN neurones. Monosynaptic excitatory postsynaptic currents (EPSCs) from octavomotorius relay cells to RS neurones are markedly depressed by the application of NMDA, a depression which was insensitive to competitive and non-competitive NMDA receptor antagonists. The effect of NMDA was eliminated by inactivation of G proteins. A similar depressive effect was observed following application of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) to the superfusate. It is concluded that NMDA acts at a metabotropic receptor located most likely presynaptically to reticulospinal neurones on terminals of octavomotorius relay cells.
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PMID:Glutamate metabotropic receptor mediated depression of synaptic inputs to lamprey reticulospinal neurones. 809 88

Long-term depression (LTD) is held relevant to memory and learning. Its induction is known to require postsynaptic calcium increases. However, the source of these calcium increases remains unclear. In visual cortex slices, LTD was induced by tetanization after blockade of N-methyl-D-aspartate (NMDA) and non-NMDA ionotropic glutamate receptors. LTD induced under this condition was prevented by an intracellular injection of each of the following drugs into the postsynaptic neuron: (i) guanosine 5'-[beta-thio]diphosphate, which competitively inhibits the binding of GTP to GTP-binding regulatory proteins; (ii) heparin, which antagonizes 1,4,5-inositol triphosphate binding; and (iii) calcium chelators. Moreover, LTD was induced without tetanization by applying quisqualate (10 microM), a metabotropic glutamate receptor agonist, but not another agonist, trans-aminocyclopentane-1,3-dicarboxylic acid (10 microM). Together, these results suggest that activation of 1,4,5-inositol trisphosphate-linked subtypes of metabotropic glutamate receptor is responsible for the increase in postsynaptic calcium concentration, which results in homosynaptic LTD.
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PMID:Dependence of long-term depression on postsynaptic metabotropic glutamate receptors in visual cortex. 809 20

Spreading depression (S.D.) can be reproducibly evoked in the retinas of 3- to 6-day-old chickens by K+ ions, N-methyl-D-aspartate (NMDA), kainate (KA), and quisqualate (QA). Specific NMDA antagonists inhibit S.D. evoked by all the above agents. The very selective non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) blocks QA- and KA-evoked S.D. but not NMDA- or K(+)-evoked S.D. These findings indicate that NMDA receptor activation is the vital event in the triggering of S.D. in this tissue, and that QA and KA trigger S.D. indirectly via excitation of NMDA receptors. Tetrodotoxin, cadmium chloride, conotoxin, baclofen and adenosine agonists are all ineffective in blocking K(+)-, NMDA-, QA- or KA-evoked S.D. L-trans-Pyrrolidine-2,4-dicarboxylic acid, a glutamate uptake blocker, does inhibit QA-evoked S.D. It is therefore argued that a presynaptic release of vesicular, glutamate 'neurotransmitter stores' is not the mechanism of action of QA and KA. A mechanism involving a reversal of the glutamate uptake carrier is suggested.
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PMID:The triggering of spreading depression in the chicken retina: a pharmacological study. 809 63

The perforant path is the major excitatory cortical projection to the hippocampal dentate gyrus. Field potentials from the medial perforant path exhibit paired-pulse depression when evoked at interstimulus intervals of 40 to 800 msec. We found that an early component of paired-pulse depression recorded at interstimulus intervals of 40 to 100 msec from slices of rat hippocampus was reduced by L-2-amino-4-phosphonobutanoic acid (L-AP4) (20 microM) without a change in the size of the first field potential in the pair. Paired-pulse depression evoked at intervals of 200 to 800 msec was not reduced. 1S,3R-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), DL-2-amino-3-phosphonopropionic acid and carbachol also reduced paired-pulse depression in a manner similar to L-AP4. Picrotoxin, phaclofen, theophylline or atropine did not reduce paired-pulse depression. Furthermore, paired-pulse depression (40-100 msec) does not appear to involve glutamate uptake or N-methyl-D-aspartate receptors as L-alpha-aminoadipate did not alter paired-pulse depression and neither trans-L-pyrrolidine-2,4-dicarboxylate and L-alpha-aminoadipate nor D-2-amino-5-phosphonopropionic acid blocked the effect of L-AP4 on paired-pulse depression. 4-Aminopyridine inhibits a potassium current that has a similar time course to the L-AP4-induced reduction of paired-pulse depression, however, paired-pulse depression was increased with exposure to 4-aminopyridine. These results indicate that the mechanism underlying paired-pulse depression consists of two components, the early component being reduced by L-AP4, 1S,3R-ACPD, DL-2-amino-3-phosphonopropionic acid and carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:L-2-amino-4-phosphonobutanoic acid and 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid reduce paired-pulse depression recorded from medial perforant path in the dentate gyrus of rat hippocampal slices. 810 Dec 17

The effects of iontophoretically applied (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), an agonist of metabotropic glutamate receptors, were examined in rat cerebellar Purkinje cells in vivo. Multibarrel electrodes were used for extracellular recordings of spontaneous single unit discharges and iontophoretic ejection of 1S,3R-ACPD. The effect of 1S,3R-ACPD depended on both the strength and the duration of the iontophoretic current. Application of the agonist with ejection currents at or slightly above the response threshold for up to 60 s resulted in an increased rate of action potential firing. With larger ejection currents of the same duration the initial increase in activity was followed by a depression and eventually a cessation of activity. In the transition phase between low frequency firing and firing arrest, Purkinje cells generated almost exclusively complex spikes. When the drug application was continued for longer durations (1-10 min) the initial response was followed by a characteristic cyclic firing pattern. These cycles consisted of alternating phases of mainly simple spike activity, predominantly complex spike activity and silent intervals. At the end of drug applications using large ejection currents, a prolonged period (on average 66 s) with almost no spiking activity was observed. This period ended with an abrupt onset of simple spike firing. These findings point to an important function of cerebellar metabotropic glutamate receptors in the regulation of Purkinje cell activity.
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PMID:Multiphasic responses of cerebellar Purkinje cells to 1S,3R-ACPD: an in vivo study. 812 70

Perfusion of the 1S,3R isomer of trans-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 50 microM), or arachidonic acid (10 microM), for 5 min produced only depression of the field excitatory postsynaptic potential recorded in the CA1 region of rat hippocampal slices from which the CA3 region had been removed. However, perfusion of t-ACPD and arachidonic acid in combination induced a rapid potentiation of the response which in 4/6 slices was maintained for at least 90 min.
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PMID:Co-administration of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid and arachidonic acid potentiates synaptic transmission in rat hippocampal slices. 824 50

In order to investigate the functional role of metabotropic glutamate receptors (mGluRs) in the striatum we performed extracellular and intracellular recordings from a corticostriatal brain slice preparation. The effects of L-2-amino-3-phosphopropionic acid (L-AP3), an antagonist of mGluRs, were studied both on long-term synaptic depression (LTD) and on presynaptic inhibition of excitatory postsynaptic potentials (EPSPs) induced by different agonists of mGluRs. L-AP3 produced a dose-dependent (3-30 microM) reduction of the LTD evoked in the striatum by the tetanic stimulation of the corticostriatal pathway. In contrast to this action, L-AP3 (10-100 microM) did not significantly affect the presynaptic inhibitory effect of 1-amino-cyclopentyl-trans-dicarboxylic acid (t-ACPD), an agonist of mGluRs, on corticostriatal transmission. Higher concentrations of L-AP3 (0.3-1 mM) reduced by themselves the EPSP amplitude. The inhibitory effect of t-ACPD on the cortically evoked EPSPs was mimicked either by the active stereoisomer 1S,3R-ACPD or by amino-4-phosphonobutyric acid (L-AP4), a glutamate autoreceptor agonist. In some neurons, these inhibitory actions were coupled with membrane depolarizations. The depression of synaptic transmission caused by t-ACPD, 1S,3R-ACPD and L-AP4 was not altered following the induction of LTD. Chronic lithium treatment of the animals (60-120 mg/kg i.p. for 10 days) blocked striatal LTD but not presynaptic inhibition mediated by mGluR agonists. The present findings show that the mechanisms underlying LTD and the presynaptic inhibition induced by different agonists of mGluRs exhibit functional and pharmacological differences. These data suggest heterogeneity of mGluRs in the striatum.
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PMID:Heterogeneity of metabotropic glutamate receptors in the striatum: electrophysiological evidence. 827 36


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