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 group I specific metabotropic glutamate (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) (100 microM, 10 min) induced long-term depression (LTD) of synaptic transmission in the CA1 region of adult rat hippocampal slices, measured using a grease-gap recording technique. In "normal" (1 mM Mg2+-containing) medium, LTD (measured 30 min after washout of DHPG) was small (13+/-3%), but LTD was enhanced if DHPG was applied when the tissue was made hyperexcitable, either by omitting Mg2+ from the perfusate (35+/-3%) or by adding the GABA(A) receptor antagonist picrotoxin (29+/-2%). The N-methyl-D-aspartate (NMDA) receptor antagonist AP5 (100 microM) substantially reduced the generation of DHPG-induced LTD in Mg2+-free medium, but had little effect on LTD induced in the presence of picrotoxin. In Mg2+-free medium, the threshold concentration of DHPG required to induce LTD was between 1 and 3 microM. Neither agonists specific for group II (100 nM DCG-IV or 1 microM LY354740) or group III (10 microM L-AP4) mGlu receptors or a combined group I and II agonist (30-100 microM (1S,3R)-ACPD) induced LTD. However, an agonist (1 mM CHPG) which activates mGlu5 but not mGlu1 receptors did induce LTD. Surprisingly, DHPG-induced LTD was reversed by mGlu receptor antagonists, applied hours after washout of DHPG. DHPG-induced LTD did not occlude with LTD induced by synaptic activation (1200 stimuli delivered at 2 Hz), in Mg2+-free medium. These data show that activation of group I mGlu receptors (probably mGlu5) can induce LTD and that this mGlu receptor-mediated LTD may, or may not, require activation of NMDA receptors, depending on the experimental conditions.
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PMID:The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. 951 22

Understanding the roles of metabotropic glutamate (mGlu) receptors has been severely hampered by the lack of potent antagonists. LY341495 (2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l)propanoic acid) has been shown to block group II mGlu receptors in low nanomolar concentrations (Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D., 1998. LY341495 is a nanomolar potent and selective antagonist at group II metabotropic glutamate receptors. Neuropharmacology 37, 1-12) but can be used in higher concentrations to block all hippocampal mGlu receptors, identified so far by molecular cloning (mGlu1-5,7,8). Here we have further characterised the mGlu receptor antagonist activity of LY341495 and have used this compound to investigate roles of mGlu receptors in hippocampal long-term potentiation (LTP) and long-term depression (LTD). LY341495 competitively antagonised DHPG-stimulated PI hydrolysis in AV12-664 cells expressing either human mGlu1 or mGlu5 receptors with Ki-values of 7.0 and 7.6 microM, respectively. When tested against 10 microM L-glutamate-stimulated Ca2+ mobilisation in rat mGlu5 expressing CHO cells, it produced substantial or complete block at a concentration of 100 microM. In rat hippocampal slices, LY341495 eliminated 30 microM DHPG-stimulated PI hydrolysis and 100 microM (1S,3R)-ACPD-inhibition of forskolin-stimulated cAMP formation at concentrations of 100 and 0.03 microM, respectively. In area CA1, it antagonised DHPG-mediated potentiation of NMDA-induced depolarisations and DHPG-induced long-lasting depression of AMPA receptor-mediated synaptic transmission. LY341495 also blocked NMDA receptor-independent depotentiation and setting of a molecular switch involved in the induction of LTP; effects which have previously been shown to be blocked by the mGlu receptor antagonist (S)-MCPG. These effects may therefore be due to activation of cloned mGlu receptors. In contrast, LY341495 did not affect NMDA receptor-dependent homosynaptic LTD; an effect which may therefore be independent of cloned mGlu receptors. Finally, LY341495 failed to antagonise NMDA receptor-dependent LTP and, in area CA3, NMDA receptor-independent, mossy fibre LTP. Since in the same inputs these forms of LTP were blocked by (S)-MCPG, a novel type of mGlu receptor may be involved in their induction.
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PMID:The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity. 988 67

We have used extracellular microelectrode recording to characterise a form of long-term depression (LTD) of synaptic transmission that can be induced by metabotropic glutamate (mGlu) receptor activation in the CA1 region of the young (12-18 day old) rat hippocampus. Activation of group I mGlu receptors by the specific agonist 3,5-dihydroxyphenylglyine (DHPG) induced LTD of field excitatory postsynaptic potentials (fEPSPs). The mGlu5 selective agonist 2-chloro-5-hydroxyphenylglycine was also capable of inducing LTD. In contrast, the group II specific agonist DCG-IV had no effect on synaptic transmission, whilst the group III receptor agonist (S)-2-amino-4-phosphonobutyrate elicited a depression that reversed fully upon agonist washout. DHPG-induced LTD could still be generated after prior saturation of electrically-induced NMDA receptor-dependent LTD. DHPG-induced LTD was reversed by tetanic stimulation comprising 100 shocks delivered at 100 Hz. A novel mGlu receptor antagonist, (RS)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) that potently inhibits mGlu1 and mGlu5 receptors, prevented the induction of DHPG-induced LTD. Like other mGlu receptor antagonists, LY393053 also reversed pre-established DHPG-induced LTD. In contrast, a potent mGlu1 selective antagonist (S)-2-methyl-4-carboxyphenylglycine (LY367385) did not prevent the induction of DHPG-induced LTD. In conclusion, DHPG, probably via activation of mGlu5 receptors, is able to induce a robust form of LTD in the CA1 region of the young rat hippocampus that is mechanistically distinct from NMDA receptor-dependent homosynaptic LTD.
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PMID:DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists. 1053 Aug 19

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in the normal motor function, as well as in pathological conditions such as Parkinson's disease. Development of a complete understanding of the role of the STN in motor control will require a detailed understanding of the mechanisms involved in the regulation of excitatory and inhibitory synaptic transmission in this nucleus. Here, we report that activation of groups I or III metabotropic glutamate (mGlu) receptors, but not group II, causes a depression of excitatory transmission in the STN. In contrast, mGlu receptor activation has no effect on the inhibitory transmission in this nucleus. Further characterization of the group I mGlu receptor-induced effect on EPSCs suggests that this response is mediated by mGlu1 and not mGlu5. Further, paired pulse studies suggest that both the mGlu1 receptor and the group III mGlu receptor-mediated effects are due to a presynaptic mechanism. If these receptors are involved in endogenous synaptic transmission in the STN, these results raise the exciting possibility that selective agents targeting mGlu receptors may provide a novel approach for the treatment of motor disorders involving the STN.
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PMID:Activation of groups I or III metabotropic glutamate receptors inhibits excitatory transmission in the rat subthalamic nucleus. 1144 83

The actions of reportedly group-selective metabotropic glutamate (mGlu) receptor agonists and antagonists on neurotransmission at parallel fibre-Purkinje cell synapses in the rat cerebellum have been characterised using sharp microelectrode recording and an in vitro slice preparation. Application of the group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) or the group III selective agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depressed synaptic transmission in a reversible and concentration-dependent manner (EC(50)=18 and 5 microM, respectively). The depression produced by DHPG was unrelated to the depolarisation observed in some Purkinje cells. The group II agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV, 1 microM) had no effect. The effects of DHPG were inhibited by the group I-selective antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt), but not by the group II/III antagonist alpha-methyl-4-phosphonophenylglycine (MPPG). The effect of L-AP4 was inhibited by MPPG, but not by the group I/II antagonist (S)-alpha-methyl-4-carboxyphenylglycine (MCPG). By themselves, the antagonists did not affect the EPSPs, suggesting that neither receptor is activated during low frequency neurotransmission. It is concluded that, in addition to the excitatory role for group I receptors described previously, both group I and III (but not group II) mGlu receptors operate at this synapse to inhibit synaptic transmission. The specific receptor subtypes involved are likely to be mGlu1 and mGlu4.
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PMID:Metabotropic glutamate receptor subtypes modulating neurotransmission at parallel fibre-Purkinje cell synapses in rat cerebellum. 1144 84

In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABA(B) receptor (where GABA is gamma-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders.
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PMID:Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. 1167 21

Metabotropic glutamate (mGlu) receptors are located pre- and postsynaptically at central synapses. Activation of the receptors by exogenous agonists usually results in a reversible depression of fast glutamatergic neurotransmission. Evidence that synaptically released glutamate has such an action, however, is scarce. Sharp microelectrode recordings were used to investigate the modulatory role of mGlu receptors at a well-studied glutamatergic synapse, the one between parallel fibres and Purkinje cells in rat cerebellar slices. Brief, tetanic stimulation of the parallel fibres caused a depression of subsequent fast EPSPs. This post-tetanic depression (PTD) reached its maximum 4.5 s after the tetanus. Measured at this point, PTD was frequency-dependent; 10 stimuli at 20 Hz produced no significant depression, whereas, at 100 Hz the same number of stimuli was maximally effective (approximately 50% depression). The nonselective mGlu antagonist, (S)-alpha-methyl-4-carboxyphenylglycine 1 mm or the GABAB antagonist, CGP35348 (1 mm), both decreased the magnitude of the PTD. In the presence of CGP35348 the mGlu1 antagonist, 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (300 microm), inhibited PTD further. A group II/III mGlu antagonist had no effect. These observations indicate that synaptically activated mGlu1 receptors not only generate a slow EPSP and induce Ca2+ mobilization in Purkinje cells, as reported previously, but also produce a transient depression of fast synaptic transmission. This short-term plasticity may be important for shaping the output of cerebellar circuits and/or it could provide a substrate for long-term depression when additional mechanisms are superimposed.
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PMID:mGlu1 receptors mediate a post-tetanic depression at parallel fibre-Purkinje cell synapses in rat cerebellum. 1170 60

We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 microM), but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 microM) decreased Glu-induced [35S]guanosine 5'-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 microM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.
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PMID:Suppression of neuronal network excitability and seizure-like events by 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine in juvenile rat hippocampus: involvement of a metabotropic glutamate receptor. 1649 Feb 84

Plasticity at synapses between parallel fiber (PF) and Purkinje neurons (PN) is widely accepted as a cellular model for certain forms of cerebellar learning. Although PF-PN synapses are known to express bidirectional long-term plasticity at the postsynaptic site, long-term plasticity at the presynaptic site is currently limited to potentiation of the synapses. In this paper, we report on presynaptically expressed PF long-term depression (preLTD) that is observed when presynaptically expressed PF long-term potentiation (preLTP) is pharmacologically prevented. PF preLTD is most efficiently induced by 4 Hz PF stimulation and requires activation of cannabinoid CB1 receptors. Our results indicate that, during preLTD induction, endocannabinoids are released in an NMDA receptor-dependent, but not mGlu1 receptor-dependent, fashion. We conclude that bidirectional plasticity mechanisms exist for both presynaptic and postsynaptic components of cerebellar learning.
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PMID:Presynaptically expressed long-term depression at cerebellar parallel fiber synapses. 1866 69

The metabotropic glutamate receptor family comprises eight subtypes (mGlu1-8) of G-protein coupled receptors. mGlu receptors have a large extracellular domain which acts as recognition domain for the natural agonist glutamate. In contrast to the ionotropic glutamate receptors which mediate the fast excitatory neurotransmission, mGlu receptors have been shown to play a more modulatory role and have been proposed as alternative targets for pharmacological interventions. The potential use of mGluRs as drug targets for various nervous system pathologies such as anxiety, depression, schizophrenia, pain or Parkinson's disease has triggered an intense search for subtype selective modulators and resulted in the identification of numerous novel pharmacological agents capable to modulate the receptor activity through an interaction at an allosteric site located in the transmembrane domain. The present review presents the most recent developments in the identification and the characterization of allosteric modulators for the mGlu receptors.
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PMID:Allosteric modulators for mGlu receptors. 1930 1


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