Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

(1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a potent and selective metabotropic glutamate 2/3 (mGlu 2/3) receptor antagonist, exhibits antidepressant-like activities in some animal models. In the present study, we examined the effect of MGS0039 on extracellular dopamine levels in the rat nucleus accumbens (NAc) shell using in vivo microdialysis evaluation because accumbal dopamine has been implicated in depression. Local application of MGS0039 into the NAc shell at 10 microM significantly increased extracellular dopamine levels in the NAc shell in freely moving rats. In contrast, local application of 10 microM of LY354740, an mGlu 2/3 receptor agonist, significantly decreased extracellular dopamine levels in the same brain region. These findings suggest that dopamine release in the NAc shell is regulated by mGlu 2/3 receptors, and that the effect on dopamine levels in the NAc shell may partially explain the antidepressant-like properties of mGlu 2/3 receptor antagonists.
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PMID:A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell. 1623 56

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

Patch-clamp recording from hypoglossal motoneurons in neonatal Wistar rat brainstem slices was used to investigate the electrophysiological effects of bath-applied nicotine (10 microm). While nicotine consistently evoked membrane depolarization (or inward current under voltage clamp), it also induced electrical oscillations (3-13 Hz; lasting for >/= 8.5 min) on 40% of motoneurons. Oscillations required activation of nicotinic receptors sensitive to dihydro-beta-erythroidine (0.5 microm) or methyllycaconitine (5 nm), and were accompanied by enhanced frequency of spontaneous glutamatergic events. The slight voltage dependence of oscillations and their block by the gap junction blocker, carbenoxolone, suggest they originate from electrically coupled neurons. Network nicotinic receptors desensitized more slowly than motoneuron ones, demonstrating that network receptors remained active longer to support heightened release of the endogenous glutamate necessary for enhancing the network excitability. The ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and the group I metabotropic receptor antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), suppressed oscillations, while the NMDA receptor antagonist, d-amino-phosphonovaleriate (APV), produced minimal depression. Nicotine-evoked oscillations constrained spike firing at low rates, although motoneurons could still generate high-frequency trains of action potentials with unchanged gain for input depolarization. This is the first demonstration that persistent activation of nicotinic receptors could cause release of endogenous glutamate to evoke sustained oscillations in the theta frequency range. As this phenomenon likely represented a powerful process to coordinate motor output to tongue muscles, our results outline neuronal nicotinic acetylcholine receptors (nAChRs) as a novel target for pharmacological enhancement of motoneuron output in motor dysfunction.
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PMID:Persistent rhythmic oscillations induced by nicotine on neonatal rat hypoglossal motoneurons in vitro. 1710 Aug 42

Synaptic plasticity at corticostraital synapses is proposed to fine tune movment and improve motor skills. We found paired-pulse plasticity at corticostriatal synapses reflected variably expressed short-term facilitation blended with a consistent background of longer-lasting depression. Presynaptic modulation via neuotransmitter receptor activation was ruled out as a mechanism for long-lasting paired-pulse depression by examining the effect of selective receptor antagonists. EPSC amplitude and paired-pulse plasticity, however, was influenced by block of D2 dopamine receptors. Block of glutamate transport with l-transdicarboxylic acid (PDC) reduced EPSCs, possibly through a mechanism of AMPA receptor desensitization. Removal of AMPA receptor desensitization with cyclothiazide reduced the paired-pulse depression at long-duration interstimulus intervals (ISIs), indicating that AMPA receptor desensitization participates in corticostriatal paired-pulse plasticity. The low-affinity glutamate receptor antagonist cis-2,3-piperidine dicarboxylic acid (PDA) increased paired-pulse depression, suggesting that a presynaptic component also exists for long-lasting paired-pulse depression. Low Ca(2+)-high Mg(2+) or BAPTA-AM dramatically reduced the amplitude of corticostriatal EPSCs and both manipulations increased the expression of facilitation and, to a lesser extent, they reduced long-lasting paired-pulse depression. EGTA-AM produced a smaller reduction in EPSC amplitude and it did not alter paired-pulse facilitation, but in contrast to low Ca(2+) and BAPTA-AM, EGTA-AM increased long-lasting paired-pulse depression. These experiments suggest that facilitation and depression are sensitive to vesicle depletion, which is dependent upon changes in peak Ca(2+) (i.e. low Ca(2+)-high Mg(2+) or BAPTA-AM). In addition, the action of EGTA-AM suggests that basal Ca(2+) regulates the recovery from long-lasting paired-pulse depression, possibly thourgh a Ca(2+)-sensitive process of vesicle delivery.
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PMID:Reliable long-lasting depression interacts with variable short-term facilitation to determine corticostriatal paired-pulse plasticity in young rats. 1723 3

Group II metabotropic (mGlu) receptors are known to play an important role in regulating the release of excitatory transmitter in a number of brain areas. Previous experiments demonstrated that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) depressed excitatory transmission in the adult rat barrel cortex. Here we show, using in vivo extracellular single unit recordings and iontophoretic application of drugs, that selective activation of Group II mGlu receptors depresses excitatory but not inhibitory transmission. The selective Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) had similar depressant effects to 1S,3R-ACPD on tactile evoked responses of rapidly adapting neurons. The depressant effects were seen on shorter latency (<12 ms) responses, were most pronounced in layers 3-4 (and 5b for 2R,4R-APDC only), and were reversibly antagonized by the Group II receptor antagonist (2S)-alpha-ethylglutamic acid (EGLU) relative to depressions produced by iontophoretic GABA. Where 1S,3R-ACPD and 2R,4R-APDC depressed excitatory transmission, there was little or no effect on postsynaptic excitations produced by iontophoretic AMPA--a result that supports a presynaptic location of Group II receptors on excitatory terminals. To assess the possible involvement of Group II mGlu receptors in the modulation of inhibition, we studied the effect of iontophoretic 1S,3R-ACPD in a condition-test protocol. The results contrasted markedly from those previously observed using the Group III agonist L(+)-2-amino-4-phosphonobutyric acid in that activation of Group II receptors using 1S,3R-ACPD did not modulate inhibition. Therefore our results show that Group II mGlu receptors play an important role in modulating excitatory, but not inhibitory, transmission. We propose that the Group II mGlu receptors are located on excitatory terminals, and act as autoreceptors. Their role appears to be important in the early stages of cortical processing, by keeping excitatory inputs within specified physiological limits, and possibly by mediating depression evidenced during synaptic plasticity.
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PMID:Group II metabotropic glutamate receptors reduce excitatory but not inhibitory neurotransmission in rat barrel cortex in vivo. 1734 94

Drug-induced neuroadaptations within the medial prefrontal cortex (mPFC) are thought to underlie the development of cocaine sensitization. Here, we report that repeated cocaine administration in vivo impaired the long-term depression (LTD) induced by bath application of group II metabotropic glutamate receptor (mGluR) agonists DCG-IV [2S, 2'R, 3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine] or LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid] at excitatory synapses onto layer V pyramidal neurons of rat mPFC. In contrast, this impairment was not found in slices from rats treated with saline or a single dose of cocaine. Such effect of cocaine was selectively prevented when cocaine was coadministered with the selective D1-like receptor antagonist SCH23390 [(R)-(+)-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine]. In slices from control rats, a brief application of either protein kinase C (PKC) activator phorbol-12,13-dibutyrate or adenosine A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5-N-methyluronamide mimicked the effect of repeated cocaine treatment to impair the induction of LTD. Bilateral intra-mPFC infusion of PKC inhibitor bisindolylmaleimide I or adenosine A3 receptor antagonist MRS1220 (N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide) before cocaine injection prevented cocaine-induced impairment of LTD induction. Furthermore, endogenous adenosine tone is greater in slices from cocaine-treated rats than from the saline-treated controls. When the metabolism of cAMP to adenosine was blocked, the extent of LTD in slices from saline and cocaine-treated rats was similar. These results suggest that cocaine-induced impairment of group II mGluR-mediated LTD is caused, at least in part, by an increase in adenosine subsequent to the rise in cAMP after D1-like receptor activation, which leads to an adenosine A3 receptor-mediated upregulation of PKC activity and thereby triggers an inhibition of group II metabotropic glutamate receptor function.
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PMID:Repeated cocaine administration impairs group II metabotropic glutamate receptor-mediated long-term depression in rat medial prefrontal cortex. 1736 Sep 19

Thalamocortical synapses provide a strong glutamatergic excitation to cortical neurons that is critical for processing sensory information. Unit recordings in vivo indicate that metabotropic glutamate receptors (mGluRs) reduce the effect of thalamocortical input on cortical circuits. However, it is not known whether this reduction is due to a reduction in glutamate release from thalamocortical terminals or from a decrease in cortical neuron excitability. To directly determine whether mGluRs act as autoreceptors on thalamocortical terminals, we examined the effect of mGluR agonists on thalamocortical synapses in slices. Thalamocortical excitatory postsynaptic currents (EPSCs) were recorded in layer IV cortical neurons in developing mouse brain slices. The activation of group II mGluRs with (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) reduced thalamocortical EPSCs in both excitatory and inhibitory neurons, while the stimulation of group I or group III mGluRs had no effect on thalamocortical EPSCs. Consistent with a reduction in glutamate release, DCG IV increased the paired pulse ratio and the coefficient of variation of the EPSCs. The reduction induced by DCG IV was reversed by the group II mGluR antagonist, LY341495, and mimicked by another selective group II agonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (APDC). The mGluR2 subtype appears to mediate the reduction of thalamocortical EPSCs, since the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), had no effect on the EPSCs. Consistent with this, we showed that mGluR2 is expressed in the barrels. Furthermore, blocking group II mGluRs with LY341495 reduced the synaptic depression induced by a short stimulus train, indicating that synaptically released glutamate activates these receptors. These results indicate that group II mGluRs modulate thalamocortical processing by inhibiting glutamate release from thalamocortical synapses. This inhibition provides a feedback mechanism for preventing excessive excitation of cortical neurons that could play a role in the plasticity and refinement of thalamocortical connections during this early developmental period.
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PMID:Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex. 1741 55

In rat brainstem slices, we investigated the influence of the neurosteroids tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) on the synaptically driven and spontaneous activity of vestibular neurons, by analysing their effects on the amplitude of the field potentials evoked in the medial vestibular nuclei (MVN) by vestibular afferent stimulation and on the spontaneous firing rate of MVN neurons. Furthermore, the interaction with gamma-aminobutyric acid (GABA) and glutamate receptors was analysed by using specific antagonists for GABA(A) (bicuculline), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/ kainate [2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide disodium salt (NBQX)], N-methyl-D-aspartate (NMDA) [D-(-)-2-amino-5-phosphonopentanoic acid (AP-5)] and group I metabotropic glutamate receptors (mGlu-I) [(R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA)] receptors. THDOC and ALLO evoked two opposite long-lasting effects, consisting of either a potentiation or a reduction of field potential and firing rate, which showed early and late components, occurring in conjunction or separately after neurosteroid application. The depressions depended on GABA(A) receptors, as they were abolished by bicuculline, while early potentiation involved glutamate AMPA/kainate receptors, as NBQX markedly reduced the incidence of early firing rate enhancement and, in the case of ALLO, even provoked depression. This suggests that THDOC and ALLO enhance the GABA(A) inhibitory influence on the MVN neurons and facilitate the AMPA/kainate facilitatory one. Conversely, a late potentiation effect, which was still induced after glutamate and GABA(A) receptor blockade, might involve a different mechanism. We conclude that the modulation of neuronal activity in the MVN by THDOC and ALLO, through their actions on GABA(A) and AMPA/kainate receptors, may have a physiological role in regulating the vestibular system function under normal conditions and during the stress response that accompanies many forms of vestibular dysfunction.
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PMID:Neurosteroid modulation of neuronal excitability and synaptic transmission in the rat medial vestibular nuclei. 1759 93

In the hippocampus, synaptic depression of potentiated synapses in the form of depotentiation, or of naive synapses in the form of long-term depression (LTD) is mediated by distinct molecular mechanisms. Activation of group 1 metabotropic glutamate receptors (mGluRs) is critically required for both hippocampal long-term potentiation (LTP) and LTD in vivo, but their involvement in depotentiation is unclear. In this study, we investigated whether this class of mGluRs contributes to depotentiation in freely moving rats. Male adult Wistar rats underwent chronic implantation of stimulating and recording electrodes in the perforant path and dentate gyrus granule cell layer, respectively, as well as an injection cannula in the ipsilateral cerebral ventricle. Robust LTP which endured for over 24 h, was induced by high frequency tetanization (HFT, 200 Hz). Depotentiation was induced with LFS (5 Hz, 600 pulses) given 5 min after the LTP-inducing tetanus was applied. The selective group 1 mGluR antagonists, (S)-4-carboxyphenylglycine and (R,S)-1-aminoindan-1,5-dicarboxylic acid significantly inhibited both depotentiation and LTP. Activation of group I mGluRs leads to changes in postsynaptic intracellular calcium levels. These findings suggest that activation of group I mGluRs mediate thresholds for depotentiation and for persistent LTP. Effects may be linked to the intensity and duration of the calcium signal elicited by LFS and HFT.
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PMID:Modulation by group 1 metabotropic glutamate receptors of depotentiation in the dentate gyrus of freely moving rats. 1792 26

We have studied liquid/solid phase diagrams and water activities of the dicarboxylic acid/water binary systems for maleic, dl-malic, glutaric, and succinc acids using differential scanning calorimetry, infrared (IR) spectroscopy of thin films, and conductivity analysis of saturated solutions. For each binary system we report the measurements of the ice melting envelope, the acid dissolution envelope, and the ice/acid eutectic temperature and composition. Water activities have been determined by using the freezing point depression of ice. Additionally, an irreversible solid/solid phase transition for maleic acid was observed in both DSC and IR studies likely due to the conversion of a meta-stable crystal form of maleic acid to its most stable crystal form. In general we find good agreement with literature values for temperature-dependent acid solubilities.
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PMID:Phase diagrams and water activities of aqueous dicarboxylic acid systems of atmospheric importance. 1895 91


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