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)

Hypoxia induces depression of excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) in CA1 neurons of the hippocampus. The effect of antagonists that act at the A1 adenosine receptor on hypoxia-induced depression of EPSCs and IPSCs were examined in hippocampal slices with the patch clamp technique (whole-cell configuration). The A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (200 nM) and 8-phenyltheophilline (8-PT) (10 microM) significantly prevented depression of EPSCs by hypoxia but failed to protect IPSCs. This result suggests that the hypoxia-induced depression of the EPSC involves the activation of adenosine receptors (possibly of the A1 subtype), whereas depression of the IPSC results from a different mechanism.
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PMID:Adenosine antagonists prevent hypoxia-induced depression of excitatory but not inhibitory synaptic currents. 826 52

The effect of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) on N-methyl-D-aspartate (NMDA)-evoked seizures was studied in C57BL/6 mice (20/group). Animals were injected i.p. either with CPA (0.5, 1, 2 mg/kg) or CPX (1, 2 mg/kg) 15 min prior to administration of NMDA (30, 60, 125 mg/kg). Administration of NMDA alone resulted in a complete locomotor arrest at 30 mg/kg, while clonic/tonic seizures and progressively increasing mortality were seen at higher doses. Prior administration of CPA resulted either in a delay of seizure onset and unchanged mortality (0.5 mg/kg CPA, 60 mg/kg NMDA) or in elimination of tonic episodes and a significant reduction in postictal mortality (1, 2 mg/kg CPA; 60, 125 mg/kg NMDA). Pretreatment with CPX at either 1 or 2 mg/kg eliminated locomotor depression in animals injected with NMDA at 30 mg/kg. At 60 mg/kg NMDA, the effect of CPX administration resulted in mortality equivalent to that seen with 125 mg/kg NMDA administered alone. The results indicate that A1 receptor agonists may protect against NMDA-evoked seizures and that the adenosine A1 receptor may be directly involved in these actions.
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PMID:Effects of N6-cyclopentyl adenosine and 8-cyclopentyl-1,3-dipropylxanthine on N-methyl-D-aspartate induced seizures in mice. 828 13

Relationships between caffeine dose, methylxanthine tissue concentrations, adenosine receptor binding and locomotor activity were examined in CD-1 mice. A method of caffeine infusion via s.c. pumps provided constant steady-state methylxanthine concentrations. Mice receiving caffeine doses of 97 mg/kg/day (with mean plasma concentration of 2.7 micrograms/ml) demonstrated motor activity depression for 6 days after pump implantation (vs. vehicle-treated controls). Mice receiving caffeine doses of 194 mg/kg/day (mean plasma concentration of 7.1 micrograms/ml) demonstrated motor stimulation 4 and 24 hr after implantation. Mice receiving this dose for 6 days developed motor depression. A reduction in the stimulant effects of acute caffeine (20 mg/kg i.p.) was found in mice receiving caffeine infusions (194 mg/kg/day for 6 days) as compared to those receiving vehicle infusions, suggestive of drug tolerance. These dose- and time-dependent behavioral effects during caffeine-infusion were associated with decreases between 20 and 69% in specific binding of A1 adenosine radioligand 1,3-[3H]dipropyl-8-cyclopentylxanthine in vivo. Behavioral alterations during caffeine infusion appear to be mediated by A1 adenosine receptor occupancy. Increasing motor depression developed on days 1 and 2 after pump removal with values returning to control levels by days 4 and 6. Behavioral alterations were associated with in vivo binding increases of 98 and 324%, respectively, and a return to control values on days 4 and 6. In vivo binding alterations were not associated with ex vivo A1 receptor binding changes. Caffeine tolerance and withdrawal effects in this animal model appear to be mediated by chronic occupancy of A1 adenosine receptors. The behavioral and in vivo receptor binding alterations observed after caffeine discontinuation follow a time course similar to caffeine withdrawal in humans.
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PMID:Caffeine treatment and withdrawal in mice: relationships between dosage, concentrations, locomotor activity and A1 adenosine receptor binding. 837 Nov 58

Endogenous interstitial adenosine may protect the hypoxic heart by attenuating beta-adrenergic-induced contractile and metabolic responses, thereby reducing energy utilization. Constant-flow perfused rat hearts were used to study: 1) the effect of hypoxia on isoproterenol (ISO)-induced increase in interstitial adenosine, as estimated with epicardial surface transudates, and 2) the role of endogenous adenosine in hypoxic depression of ISO-induced contractile responses. ISO (1 nM for 10 minutes) in the normoxic heart increased transudate adenosine 114% from a pre-ISO normoxic value of 343 pmol/ml. ISO administered to the hypoxic heart increased transudate adenosine 357% from a pre-ISO hypoxic value of 797 pmol/ml. The absolute magnitude of the ISO-induced increase in transudate adenosine was 625% greater during hypoxia than during normoxia. This was associated with a reduction in the ISO-induced contractile response during hypoxia. In other experiments, with normoxia ISO (10 nM for 10 seconds) increased developed left ventricular pressure by 140 mm Hg, and the maximum rates of left ventricular pressure development and relaxation by 5,860 and 2,771 mm Hg/sec, respectively, above control values of 90 mm Hg, 2,250 mm Hg/sec, and 1,875 mm Hg/sec. Hypoxia reduced the three ISO-induced contractile responses by 50%, 56%, and 36%. However, 1,3-dipropyl-8-cyclopentylxanthine (5 x 10(-7) M), an adenosine A1-receptor antagonist, added to the hypoxic hearts resulted in only a 31%, 39%, and 9% reduction in the ISO-induced responses in developed left ventricular pressure and the maximum rates of left ventricular pressure development and relaxation, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypoxia enhances isoproterenol-induced increase in heart interstitial adenosine, depressing beta-adrenergic contractile responses. 838 22

Adenosine has recently been shown to play a potentially important role in the regulation of synaptic excitability during experimental hypoxia in the hippocampus of the rat. Endogenous adenosine, rapidly released at the initiation of a hypoxic episode, produced synaptic depression, which could protect sensitive neurons. In the present experiments, an inhibitor of the reuptake of adenosine, soluflazine (R64719) was employed to increase the levels of endogenous adenosine under normoxic and hypoxic conditions in slices of the hippocampus of the rat. Soluflazine produced a slow-onset, concentration-dependent depression of population excitatory postsynaptic potentials, which was reversed by the specific A1 adenosine receptor antagonist, 8-cyclopentyltheophylline. During severe N2-induced hypoxia, soluflazine significantly delayed hypoxic depolarization. These results suggest that inhibition of the reuptake of adenosine may have therapeutic potential in the amelioration of hypoxic/ischemic neuronal damage, particularly in the hippocampus.
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PMID:The effects of the adenosine reuptake inhibitor soluflazine on synaptic potentials and population hypoxic depolarizations in area CA1 of rat hippocampus in vitro. 838 14

The characteristics of adenosine and inosine outflow evoked by 5 min of ischemia-like conditions in vitro (superfusion with glucose-free Krebs solution gassed with 95% N2/5% CO2) were investigated on rat hippocampal slices. The viability of the slices after "ischemia" was evaluated by extracellular recording of the evoked synaptic responses in the CA1 region. The evoked dendritic field potentials were abolished after 5 min of superfusion under "ischemia" but a complete recovery occurred after 5 min of reperfusion with normal oxygenated Krebs solution. No recovery took place after 10 min of "ischemia." The addition of the adenosine A1 receptor antagonist 8-phenyltheophylline to the superfusate antagonized the depression of the evoked field potentials caused by 5 min of "ischemia." Five minutes of "ischemia" brought about a six- and fivefold increase in adenosine and inosine outflow, respectively, within 10 min. Tetrodotoxin reduced the outflow of adenosine and inosine by 42 and 33%, respectively, whereas the removal of Ca2+ caused a further increase. The NMDA receptor antagonist D(-)-2-amino-7-phosphonoheptanoic acid and the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione brought about small, not statistically significant decreases of adenosine and inosine outflow. The glutamate uptake inhibitor dihydrokainate did not affect the outflow of adenosine and inosine. Inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP and GMP did not affect basal adenosine outflow but potentiated "ischemia"-evoked adenosine outflow. It is concluded that ischemia-like conditions in vitro evoke a Ca(2+)-independent adenosine and inosine outflow, through a mechanism that partly depends on propagated nervous activity but does not involve excitatory amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Investigations into the adenosine outflow from hippocampal slices evoked by ischemia-like conditions. 851 75

High levels of norepinephrine in the heart are cardiotoxic resulting in contractile dysfunction and arrhythmic activity via beta-adrenoceptor mediated mechanisms. A low flow heart model perfused with physiological saline containing glucose and bubbled with an O2 gas mixture was used to determine whether adenosine, a nucleoside with antiadrenergic properties, could reduce the functional manifestations of catecholamine cardiotoxicity. Isolated rat hearts were treated with dipropylcyclopentylxanthine (DPCPX; 0.1 microM; A1 receptor antagonist) to block endogenous adenosine. In DPCPX-treated hearts stimulated with isoproterenol (ISO; 1 microM) during 45 min of low flow (0.5 ml/min) perfusion, the recovery of contractile function (ConF) at 15 min after the restoration of normal flow was 64% of control (before low flow) values as compared to 110% recovery of ConF in the absence of ISO. The incidence of arrhythmias observed upon restoration of control flow was increased by ISO when the action of endogenous adenosine was blocked with DPCPX. In the absence of DPCPX both the functional depression and arrhythmias induced by ISO were prevented in the presence of phenylisopropyladenosine (PIA; 1 microM; A1 receptor agonist). At 15 min after normal flow was restored. ConF in ISO-treated hearts with PIA was 53% greater than in the absence of PIA and presence of DPCPX. This enhancement of ConF by PIA was significantly reduced by DPCPX. By 30 min after flow restoration, these significant differences were absent. DPCPX reversed the PIA-induced reduction in arrhythmias observed upon restoration of normal flow. PIA and DPCPX alone in the absence of ISO, and ISO in the absence of PIA and DPCPX, did not result in altered ConF upon restoration of normal flow. These findings indicate that intense beta-adrenergic stimulation of the heart during low-flow perfusion in the absence of adenosine A1 receptor activity induces contractile depression and arrhythmicity subsequent to restoration of control perfusion. It is concluded that endogenous adenosine protects the heart against catecholamine toxicity via stimulation of adenosine A1 receptors.
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PMID:Endogenous adenosine reduces depression of cardiac function induced by beta-adrenergic stimulation during low flow perfusion. 857 51

1. Within the hypothalamus, adenosine has been reported to influence temperature regulation, sleep homeostasis, and endocrine secretions. The effects of adenosine on hypothalamic neurons have not been studied at the cellular level. Adenosine (5 nM-30 microM) showed no influence on intracellular Ca2+ or electrical activity in the presence of glutamate receptor antagonists D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione; consequently, we examined the role of adenosine in modulating the activity of glutamate in cultured hypothalamic neurons (n > 1,700) with fura-2 Ca2+ digital imaging and whole cell patch-clamp electrophysiology in the absence of glutamate receptor block. 2. When glutamate receptors were not blocked, adenosine (1-30 microM) and the selective adenosine A1 receptor agonist N6-cyclopentyl adenosine (CPA; 5 nM-1 microM) caused a large reduction in intracellular Ca2+ and electrical activity, suggesting that glutamate neurotransmission was critical for an effect of adenosine to be detected. Neuronal Ca2+ levels were reversibly depressed by CPA (50 nM), with a maximum depression of 90%, and these effects were blocked by coadministration of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 3. Ca2+ levels in immature neurons before the time of synaptogenesis were not affected by adenosine. Adenosine A1 receptor activation suppressed glutamate-mediated Ca2+ activity in neurons in vitro 8 to 73 days. 4. Adenosine (1 or 10 microM) caused a hyperpolarization of membrane potential and a reduction of large postsynaptic potentials arising from endogenously released glutamate. The administration of low concentrations of CPA (5 nM) decreased the frequency of glutamate-mediated, neuronally synchronized Ca2+ transients and the frequency of postsynaptic potentials. 5. To compare the relative effects of adenosine on hypothalamic neurons with cells from other brain regions, we assayed the effects of CPA on glutamate-mediated Ca2+ in hippocampal and cortical cultures. CPA (50 nM) reversibly depressed glutamate-mediated Ca2+ rises in hypothalamic neurons by 35%, compared with 54% in hippocampal neurons and 46% in cortical neurons. 6. If it does play a functional role, adenosine should be released by hypothalamic cells. In some neurons the adenosine A1 receptor antagonists cyclopentyltheophylline or DPCPX caused an increase in intracellular Ca2+, suggesting that adenosine was secreted by hypothalamic cells, tonically depressing glutamate-enhanced neuronal Ca2+. 7. To determine whether adenosine could exert a postsynaptic effect, we coapplied it with glutamate agonists in the presence of tetrodotoxin. Within subpopulations of hypothalamic neurons, adenosine and CPA either inhibited (18% of total neurons) or potentiated (6% of total neurons) responses to glutamate, N-methyl-D-aspartate, and kainate by > or = 20%. 8. In contrast to the modest effects found in neurons, responses of hypothalamic astrocytes to the application of glutamate or the metabotropic glutamate receptor agonist (+/-)-trans-1-amino-1,3-cyclopentanedicarboxylic acid were strongly potentiated by adenosine (mean +225%) and CPA. 9. Together, these findings suggest that adenosine exerts a major presynaptic effect and a minor postsynaptic effect in the modulation of glutamate neurotransmission in the hypothalamus, where it can play a significant role in blocking a large part of the glutamate-induced Ca2+ rise. In the absence of glutamate transmission, adenosine has relatively little effect on either neuronal intracellular Ca2+ or electrical activity.
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PMID:Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons. 859 3

The relative contribution of adenosine and gamma-aminobutyric acid (GABA) for the hypoxia-induced depression of field excitatory postsynaptic potentials in the CA1 area of rat hippocampal slices, was investigated. It is concluded that both adenosine and GABA, by activating A1 and GABAA receptors, could be responsible for the inhibition of synaptic transmission during hypoxia, but the action of endogenous GABA becomes evident only when the adenosine A1 receptor action is precluded.
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PMID:Adenosine by activating A1 receptors prevents GABAA-mediated actions during hypoxia in the rat hippocampus. 889 Dec 95

The mechanism by which adenosine accumulates in the hippocampal slice during energy deprivation was investigated by examining the adenosine A1 receptor mediated depression of synaptically evoked field potentials in the CA1 area. Blocking of the mitochondrial electron transport chain with 200 microM sodium cyanide or mitochondrial uncoupling with 50 microM 2,4-dinitrophenol both produced a rapid depression of synaptic transmission that was antagonised by 1 microM 8-cyclopentyl-1, 3-dimethylxanthine, an adenosine A1 receptor antagonist. Cellular ATPase inhibition or elevation of cytosolic phosphocreatine failed to alter the 2,4-dinitrophenol induced depression of synaptic transmission. Attempts to block mitochondrial ATP synthesis with 3 microM oligomycin or 75 microM atractyloside did not cause depression of synaptic transmission. 100 microM iodotubercidin, an adenosine kinase inhibitor, alone produced a depression of synaptic transmission that was completely reversed by 1 microM 8-cyclopentyl-1,3-dimethylxanthine; however, a simultaneous or independent episode of hypoxia surmounted the adenosine A1 receptor antagonism and produced approximately 50% depression of synaptic transmission. Depression of synaptic transmission by hypoxia, cyanide or 2,4-dinitrophenol is a result of rapid adenosine accumulation and activation of extracellular adenosine A1 receptors. Although this early depression of synaptic transmission is a consequence of inhibition of normal mitochondrial function, it is not a result of depletion of cytosolic ATP, since attempts to preserve ATP did not maintain synaptic transmission during mitochondrial poisoning, and inhibitors of oxidative phosphorylation did not produce synaptic depression.
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PMID:Mechanism of adenosine accumulation in the hippocampal slice during energy deprivation. 901 69

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