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)

1. Mature in vitro rat spinal cord preparations have been used to compare the depressant effects of 6-cyano-2,3-dihydroxy-7-nitroquinoxalinedione (CNQX) and kynurenate on transmission from low threshold myelinated primary afferents in dorsal roots. EC50 values +/- s.e.mean (number of preparations in parentheses) for depression of the monosynaptic ventral root reflex were respectively 1.0 +/- 0.3 microM (5) and 135 +/- 15 microM (3) for CNQX and kynurenate. Transmission through superior cervical ganglia was not significantly affected by concentrations of CNQX up to 100 microM or kynurenate up to 5 mM. 2. Immature in vitro rat spinal cord preparations were used to measure dose-ratios for antagonism of depolarizations induced by N-methyl-D-aspartate (NMDA), kainate or quisqualate by 4, 10 and 25 microM CNQX. In the presence of 0.75 mM Mg2+ pA2 values +/- s.e.mean were respectively 4.62 +/- 0.05 (16), 5.79 +/- 0.01 (4) and 5.59 +/- 0.05 (16) for each agonist. These values were not significantly altered in the absence of added Mg2+. The mean pA2 values for kainate were significantly higher than those for quisqualate (P less than 0.01). 3. Antagonism of NMDA-induced depolarizations was evident at 10 and 25 but not 4 microM CNQX. The antagonism of NMDA was reversed by D-serine (100 and 200 microM). 4. A similarity between the relative potencies of both CNQX and kynurenate for depression of synaptic transmission and antagonism of amino acid-induced depolarizations indicates that monosynaptic transmission from myelinated primary afferents to motoneurones is mediated by kainate and/or quisqualate sub-types of non-NMDA receptors.
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PMID:Effect of 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX) on dorsal root-, NMDA-, kainate- and quisqualate-mediated depolarization of rat motoneurones in vitro. 197 2

1. The effects of the glycine/NMDA receptor partial agonists, D-cycloserine and (+)-HA-966 and the full agonist, D-serine, on focal seizure threshold and behaviour have been determined in amygdala-kindled rats, i.e. a model of focal (partial) epilepsy. The uncompetitive NMDA receptor antagonist, MK-801, was used for comparison. 2. The high efficacy glycine partial agonist, D-cycloserine, did not alter the threshold for induction of amygdaloid afterdischarges (ADT) at doses of 20-80 mg kg-1 i.p., but significant ADT increases were determined after application of higher doses (160 and 320 mg kg-1). The ADT increases after these high doses were long-lasting; significant elevations were still observed 2 days after drug injection. Determination of D-cycloserine in plasma and brain tissue showed that it was rapidly eliminated from plasma. Compared to peak levels in plasma, only relatively low concentrations of D-cycloserine were measured in brain tissue. 3. The low efficacy glycine partial agonist, (+)-HA-966, 10-40 mg kg-1 i.p., did not alter the ADT or seizure recordings (seizure severity, seizure duration, afterdischarge duration) at ADT currents. However, the drug dose-dependently increased the duration of postictal behavioural and electroencephalographic depression in kindled rats. At the higher dose tested, postictal immobilization was dramatically increased from 3 min to about 120 min. This might indicate that glutamatergic activity is decreased postictally, which is potentiated or prolonged by (+)-HA-966. 4. Like D-cycloserine, the glycine receptor full agonist, D-serine, injected bilaterally into the lateral ventricles at a dose of 5 mumol, significantly increased the ADT, while no effect was seen at a lower dose (2.5 mumol). 5. The anticonvulsant effects observed with D-cycloserine were completely antagonized by combined treatment with (+)-HA-966, indicating that the effects of D-cycloserine were mediated by the glycine/NMDA receptor complex. 6. MK-801, 0.1 mg kg-1, did not alter the focal seizure threshold or seizure recordings at ADT current, but induced marked phencyclidine(PCP)-like behavioural alterations, such as hyperlocomotion, stereotypies and motor impairment. No PCP-like behaviours were observed after D-cycloserine, D-serine or (+)-HA-966. High doses of (+)-HA-966 induced moderate motor impairment in kindled rats. 7. The long lasting increases in seizure threshold observed after the high efficacy glycine partial agonist,D-cycloserine but not the low efficacy partial agonist, (+)-HA-966, may suggest that the effects of D-cycloserine are mediated by adaptive changes in the NMDA receptor complex in response to glycine receptor stimulation.8. Pharmacological intervention at the strychnine-insensitive glycine receptor by high-efficacy partial agonists with systemic bioavailability may be an effective means of increasing seizure-threshold without concomitantly inducing PCP-like adverse effects.
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PMID:Anticonvulsant effects of the glycine/NMDA receptor ligands D-cycloserine and D-serine but not R-(+)-HA-966 in amygdala-kindled rats. 803 69

1. The shift in d.c. potential in dorsal roots (EC50 8.0 microM +/- 0.9 s.e. mean, n = 5) or depression of the C elevation of the compound action potential (EC50 3.0 microM +/- 0.3, n = 7) have been used to measure the depolarizing action of kainate on dorsal root C fibres of immature (3 to 5 day old) rats. Depolarization of motoneurones was measured from the shift in d.c. potential in ventral roots. 2. 6-Cyano-7-nitroquinoxaline,2-3,dione (CNQX) (pA2 5.78 +/- 0.06, n = 8) and 6-nitro-7-suplhamobenzo(f)quinoxaline-2,3-dione (NBQX) (pA2 5.75 +/- 0.04, n = 7) had similar potencies as antagonists of kainate at dorsal root fibres. The potency of NBQX as a kainate antagonist was similar also at motoneurones (pA2 5.72 +/- 0.07, n = 3). At motoneurones, NBQX was less potent as an antagonist of domoate (pA2 5.29 +/- 0.05) and more potent as an antagonist of S-alpha-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (pA2 6.80 +/- 0.09) than as an antagonist of kainate. 3. Application of L-glutamate, quisqualate and RS-AMPA to dorsal roots produced only short lasting depolarizations but kainate concentration-effect plots were shifted to the right in the presence of these three agonists (pA2 5.08 +/- 0.08, (n = 3), 5.59 +/- 0.04, (n = 4) and 4.46 +/- 0.04 (n = 4) respectively). Slopes of dose-ratio against concentration were significantly less than one for the latter antagonism. 4. The amplitude of depolarizations induced by L-glutamate, AMPA and quisqualate were increased up to ten fold and those induced by kainate up to two fold following treatment of dorsal roots with concanavalin A. The duration of the responses was increased also by the latter treatment. Folowing 85 s applications of glutamate, quisqualate, AMPA and kainate the mean respective times (s +/- s.e.mean (n))taken for responses to decay to half the peak amplitude were increased from 63 +/- 7 (10), 86 +/- 17 (4),95 +/- 19 (4) and 135 +/- 3 (12) to 202 +/- 49 (10), 147 +/- 7 (4), 160 +/- 13 (6) and 163 +/- 10 (10). Under similar conditions the mean decay time of y-aminobutyric acid-induced responses was 145 +/- 7 (10). This was not significantly altered by concanavalin A treatment.5. Application to dorsal roots of L-aspartate at concentrations up to 5 mm (with or without concanavalin A treatment), the selective metabotropic agonist 1S,3R-trans-1-aminocyclopentane-1,3-dicarboxylate (1 mM,) and D-serine (20 pM) in the presence or absence of N-methyl-D-aspartate (NMDA,500 pM) neither depolarized the preparations nor shifted the kainate concentration-effect plot.6. It is concluded that primary afferent C fibres possess only one type of non-NMDA receptor which is activated strongly by domoate or kainate but only weakly by AMPA. This receptor is readily desensitized by glutamate, quisqualate or AMPA and it is less readily desensitized by kainate.
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PMID:A comparison of the actions of agonists and antagonists at non-NMDA receptors of C fibres and motoneurones of the immature rat spinal cord in vitro. 809 24

1. The effects of N-methyl-D-aspartate (NMDA) receptor glycine-binding site antagonists 7-chlorokynurenate (7-Clkyn) and (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) on spinal reflexes in an isolated spinal cord that was maintained in Mg(2+)-free medium in vitro were examined. The actions of 7-Clkyn and HA-966 were compared with those of the channel-site antagonist (i.e., dizocilpine) and NMDA-binding site antagonists--that is, 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) and DL-2-amino-5-phosphonovalerate (APV). 2. 7-Clkyn and HA-966 produced a selective depression of the polysynaptic reflex (PSR) while negligibly affecting the activity of the monosynaptic reflex (MSR). The PSR was also differentially suppressed by dizocilpine, CPP and APV. The PSR inhibitory activity of the NMDA antagonists was in the following order: dizocilpine > CPP > APV = 7-Clkyn > HA-966. 3. The inhibitory effects of 7-Clkyn on PSR were markedly antagonized by the simultaneous application of D-serine, an agonist for the NMDA receptor glycine-binding sites. However, PSR inhibition by dizocilpine and CPP was unaffected. 4. Inhibition of the PSR by 7-Clkyn persisted in the presence of strychnine, which markedly increased the PSR activity by itself. 5. These findings suggest that the NMDA receptor glycine-binding sites play a role in generating the NMDA receptor-mediated PSR in the spinal cord in vitro.
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PMID:Selective depression of the spinal polysynaptic reflex by the NMDA receptor antagonists in an isolated spinal cord in vitro. 935 16

The effects of Ptychodiscus brevis toxin (PbTx) on the Ia-alpha motoneuron synaptic transmission in neonatal rat spinal cord in vitro was examined. The stimulation of a dorsal root evoked monosynaptic (MSR) and polysynaptic reflex (PSR) potentials in the segmental ventral root in Mg2+-free medium. Superfusion with PbTx (2.8-84 microM) depressed the MSR and the PSR in a concentration-dependent manner. At 2.8 microM of PbTx, the depression of MSR and PSR was 24+/-8.3% and 37+/-9.7%, respectively. The maximal depression was seen at 84 microM of the toxin (78% for MSR and 96% for PSR). The concentration of toxin required to produce 50% depression was 28.3+/-6.4 microM for MSR and 5.5+/-1.1 microM for PSR. The PbTx (28 microM) did not alter the magnitude of the dorsal root or the ventral root potentials. Addition of MgSO4 (1.3 mM) or DL-2-amino-5-phosphonovaleric acid (APV; 10 microM) to the physiological solution abolished the PSR totally and decreased the MSR by about 30%. In both the conditions, the PbTx-induced depression of the MSR was attenuated significantly. The PbTx-induced depression was blocked completely in the presence of APV+6-cyano-7-nitroquinoxaline-2,3-dione (0.1 microM). NMDA (1 microM) by itself did not alter the magnitude of MSR or PSR but enhanced the PbTx-induced depression (28 microM) of PSR significantly. 7-Chlorokynurenic acid (3 microM; glycine(B) antagonist) did not block the PbTx-induced depression of MSR. D-serine (glycine(B) agonist) did not reverse the PbTx-induced depression of reflexes although it reversed the 7-chlorokynurenic acid-induced depression of PSR. The results indicate that the PbTx depressed the spinal reflexes without altering the magnitude of dorsal root or ventral root activity. The depression of the PSR involved NMDA receptors while that of the MSR involved NMDA and non-NMDA receptors. The PbTx actions did not involve the glycine(B) site of the NMDA receptor.
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PMID:Involvement of N-methyl-D-aspartate receptors for the Ptychodiscus brevis toxin-induced depression of monosynaptic and polysynaptic reflexes in neonatal rat spinal cord in vitro. 1245 90

Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD.
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PMID:Glutamate as a therapeutic target in psychiatric disorders. 1527 97

In the hippocampal CA1 region of the rat, activity-dependent plasticity requires substantial postsynaptic depolarization and activation of the N-methyl-D-aspartate glutamate receptor subtype (NMDAR). Exogenous and endogenous compounds selectively modulate NMDAR function by acting at the glycine coagonist site. Here we investigate the modulatory role of the glycine site in the induction of bidirectional synaptic plasticity. Plasticity was induced by pairing low-frequency afferent pulses with different levels of postsynaptic depolarization in the absence and presence of glycine site compounds. We found strong dependence of glycine site agonist modulation on membrane voltage during induction. Thus, D-serine and glycine were more effective in enhancing long-term potentiation (LTP) during pairing of small depolarization (-60 or -50 mV) with subthreshold EPSCs than during pairing of stronger depolarization (-40 mV) with suprathreshold synaptic responses. The glycine site role in bidirectional synaptic plasticity was studied with the selective antagonist 7-chlorokynurenic acid. Blockade of the glycine site during the pairing reversed the direction of plasticity from LTP towards long-term depression. The magnitude of depression was dependent on antagonist concentration and the level of depolarization during the pairing. Thus, these experiments demonstrate the role of the glycine site in the induction of bidirectional synaptic plasticity.
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PMID:Role of the glycine site of the N-methyl-D-aspartate receptor in synaptic plasticity induced by pairing. 1592 25

Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.
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PMID:A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. 1715 77

The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM). The NMDA receptor co-agonist D-serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-serine likely saturates during LTP induction because exogenous D-serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-serine affinity. Thus, D-serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.
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PMID:D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. 1762 4

Synaptic plasticity underlies higher brain functions such as learning and memory. At glutamatergic synapses in the vertebrate central nervous system, plasticity usually requires changes in the number of postsynaptic AMPA receptors. Recently, several studies have revealed that glial cells play an important role in regulating postsynaptic AMPA receptor density. This is accomplished through the release of gliotransmitters such as D-serine, ATP and TNF-alpha. More specifically, the availability of D-serine, the endogenous co-agonist of N-methyl-D-aspartate receptors in many brain areas, governs the induction of long-term potentiation and long-term depression. Meanwhile, ATP and TNF-alpha trigger long-lasting increases in synaptic strength at glutamatergic hypothalamic and hippocampal inputs, respectively, through mechanisms that promote AMPA receptor insertion in the absence of coincident presynaptic and postsynaptic activity. These data clearly demonstrate a vital role for glia in plasticity and argue that their contributions to brain function extend well beyond their outdated role as cellular 'glue'.
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PMID:Glia: they make your memories stick! 1763 72


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