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 adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is very effective in reducing wind-up in intact but not in spinalized adult rats with carrageenan-induced inflammation, suggesting an adenosine-mediated supraspinal modulation. Since wind-up is a spinal cord mediated phenomenon but highly influenced by descending modulatory systems, especially in situations of sensitization, we assessed the possible involvement of adenosine in the modulation of wind-up. We studied the effect of the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) in the presence and in the absence of the adenosine A(1) receptor agonist CPA. The experiments were carried out in spinalized male Wistar rats under alpha-chloralose anaesthesia. Withdrawal reflexes, studied as single motor units, were activated by noxious mechanical and high-intensity repetitive electrical stimulation (wind-up). While CPA and CPT were not able to induce any change on wind-up when injected alone, the combination of the two drugs, in any order, lead to an important enhancement of wind-up. This enhancement not always paralleled an increase of responses to noxious mechanical stimulation, indicating that the effect is mainly located in the spinal cord. In addition, the enhancement of wind-up was not further increased by the administration of the opioid receptor antagonist naloxone. We conclude that the depression of the wind-up phenomenon observed in spinalized animals is, at least in part, dependent of adenosine systems and can be relieved by the combined administration of CPA and CPT.
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PMID:Enhancement of wind-up by the combined administration of adenosine A1 receptor ligands on spinalized rats with carrageenan-induced inflammation. 1589 24

Memory loss in humans begins early in adult life and progresses thereafter. It is not known whether these losses reflect the failure of cellular processes that encode memory or disturbances in events that retrieve it. Here, we report that impairments in hippocampal long-term potentiation (LTP), a form of synaptic plasticity associated with memory, are present by middle age in rats but only in select portions of pyramidal cell dendritic trees. Specifically, LTP induced with theta-burst stimulation in basal dendrites of hippocampal field CA1 decayed rapidly in slices prepared from 7- to 10-month-old rats but not in slices from young adults. There were no evident age-related differences in LTP in the apical dendrites. Both the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and a positive AMPA receptor modulator (ampakine) offset age-related LTP deficits. Adenosine produced greater depression of synaptic responses in middle-aged versus young adult slices and in basal versus apical dendrites. These results were not associated with variations in A1 receptor densities and may instead reflect regional and age-related differences in adenosine clearance. Pertinent to this, brief applications of A1 receptor antagonists immediately after theta stimulation fully restored LTP in middle-aged rats. We hypothesize that the build-up of extracellular adenosine during theta activity persists into the postinduction period in the basal dendrites of middle-aged slices and thereby activates the A1 receptor-dependent LTP reversal effect. Regardless of the underlying mechanism, the present results provide a candidate explanation for memory losses during normal aging and indicate that, with regard to plasticity, different segments of pyramidal neurons age at different rates.
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PMID:Long-term potentiation is impaired in middle-aged rats: regional specificity and reversal by adenosine receptor antagonists. 1597 84

The adenosine A1 receptor (A1R) inhibits beta-adrenergic-induced contractile effects (antiadrenergic action), and the adenosine A2A receptor (A2AR) both opposes the A1R action and enhances contractility in the heart. This study investigated the A1R and A2AR function in beta-adrenergic-stimulated, isolated wild-type and A2AR knockout murine hearts. Constant flow and pressure perfused preparations were employed, and the maximal rate of left ventricular pressure (LVP) development (+dp/dt(max)) was used as an index of cardiac function. A1R activation with 2-chloro-N6-cyclopentyladenosine (CCPA) resulted in a 27% reduction in contractile response to the beta-adrenergic agonist isoproterenol (ISO). Stimulation of A2AR with 2-P(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxyamidoadenosine (CGS-21680) attenuated this antiadrenergic effect, resulting in a partial (constant flow preparation) or complete (constant pressure preparation) restoration of the ISO contractile response. These effects of A2AR were absent in knockout hearts. Up to 63% of the A2AR influence was estimated to be mediated through its inhibition of the A1R antiadrenergic effect, with the remainder being the direct contractile effect. Further experiments examined the effects of A2AR activation and associated vasodilation with low-flow ischemia in the absence of beta-adrenergic stimulation. A2AR activation reduced by 5% the depression of contractile function caused by the flow reduction and also increased contractile performance over a wide range of perfusion flows. This effect was prevented by the A2AR antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385). It is concluded that in the murine heart, A1R and A2AR modulate the response to beta-adrenergic stimulation with A2AR, attenuating the effects of A1R and also increasing contractility directly. In addition, A2AR supports myocardial contractility in a setting of low-flow ischemia.
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PMID:Contractile effects of adenosine A1 and A2A receptors in isolated murine hearts. 1614 49

Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl) glycine (DCGIV; 5 microM), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 microM), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 microM) was combined with a cell-permeant PKA inhibitor H-89 (10 microM), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 microM), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 microM), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6-cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 microM), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity.
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PMID:Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses. 1632 19

Adenosine A1 receptor agonists are effective antinociceptive agents in neuropathic and inflammatory pain, though they appear to be weak analgesics in acute nociception. Important discrepancies are observed on the effectiveness and potency of adenosine analogues when comparing different studies, probably due to the use of different ligands, models of antinociception, routes of administration and types of sensitization. We studied the systemic antinociceptive effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) in spinal cord neuronal responses from adult male rats in acute nociception and in sensitization due to arthritis and neuropathy. The experiments showed that CPA was effective in the three experimental conditions, with a similar potency in reducing responses to noxious mechanical stimulation (ID50s: 20 +/- 1.2 microg/kg in acute nociception, 18 +/- 1.1 microg/kg in arthritis, 17.4 +/- 2 microg/kg in neuropathy). The phenomenon of wind-up was also dose-dependently reduced by CPA in the three experimental situations although the main action was seen in arthritis. Depression of blood pressure by CPA was not dose-dependent. We conclude that systemic CPA is a potent and effective analgesic in sensitization due to arthritis and neuropathy but also in acute nociception. The effect is independent of the cardiovascular activity and is centrally mediated since wind-up was inhibited.
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PMID:The antinociceptive effects of the systemic adenosine A1 receptor agonist CPA in the absence and in the presence of spinal cord sensitization. 1640 70

Caffeine, used in many pain medications as an adjuvant analgesic, is an adenosine A1 and A2A receptor antagonist. Here we examined the effects of acute or chronic caffeine administration in rats after partial sciatic nerve injury. The hindpaw response to mechanical or cold stimulation was assessed following photochemically induced sciatic nerve injury which leads to hypersensitivity to these stimuli. Caffeine was administered i.p. acutely or in the drinking water chronically. The mechanical and cold hypersensitivity of sciatic nerve-injured rats was dose-dependently alleviated by acute systemic administration of caffeine (10-80 mg/kg). The effect of caffeine was, however, associated with side effects including locomotor stimulation or depression. Chronic oral administration (average daily doses 27.5 mg/kg/day or 61.5 mg/kg/day for 2 weeks) of caffeine starting at the time of nerve injury did not significantly affect the development of pain-like behaviors. Thus, acute, but not long term, caffeine intake reduced neuropathic pain state in nerve-injured rats, but only at very high doses. The potential hyperalgesic effect of chronic A1 adenosine receptor blockade may have been compensated for by an antinociceptive effect of caffeine through antagonism of A2A receptors and tolerance development.
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PMID:Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury. 1664 14

Adenosine is one of the most important neuromodulators in the CNS, both under physiological and pathological conditions. In the isolated spinal cord of the neonatal rat in vitro, acute hypercapnic acidosis (20% CO2, pH 6.7) reversibly depressed electrically evoked spinal reflex potentials. This depression was partially reversed by 8-cyclopentlyl-1,3-dimethylxanthine (CPT), a selective A1 adenosine receptor antagonist. Isohydric hypercapnia (20% CO2, pH 7.3), but not isocapnic acidosis (5% CO2, pH 6.7), depressed the reflex potentials, which were also reversed by CPT. An ecto-5'-nucleotidase inhibitor did not affect the hypercapnic acidosis-evoked depression. An inhibitor of adenosine kinase, but not deaminase, mimicked the inhibitory effect of hypercapnic acidosis on the spinal reflex potentials. Accumulation of extracellular adenosine and inhibition of adenosine kinase activity were caused by hypercapnic acidosis and isohydric hypercapnia, but not isohydric acidosis. These results indicate that the activation of adenosine A1 receptors is involved in the hypercapnia-evoked depression of reflex potentials in the isolated spinal cord of the neonatal rat. The inhibition of adenosine kinase activity is suggested to cause the accumulation of extracellular adenosine during hypercapnia.
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PMID:Involvement of adenosine in depression of synaptic transmission during hypercapnia in isolated spinal cord of neonatal rats. 1677 47

Astrocytes play a critical role in brain homeostasis controlling the local environment in normal as well as in pathological conditions, such as during hypoxic/ischemic insult. Since astrocytes have recently been identified as a source for a wide variety of gliotransmitters that modulate synaptic activity, we investigated whether the hypoxia-induced excitatory synaptic depression might be mediated by adenosine release from astrocytes. We used electrophysiological and Ca2+ imaging techniques in hippocampal slices and transgenic mice, in which ATP released from astrocytes is specifically impaired, as well as chemiluminescent and fluorescence photometric Ca2+ techniques in purified cultured astrocytes. In hippocampal slices, hypoxia induced a transient depression of excitatory synaptic transmission mediated by activation of presynaptic A1 adenosine receptors. The glia-specific metabolic inhibitor fluorocitrate (FC) was as effective as the A1 adenosine receptor antagonist CPT in preventing the hypoxia-induced excitatory synaptic transmission reduction. Furthermore, FC abolished the extracellular adenosine concentration increase during hypoxia in astrocyte cultures. Several lines of evidence suggest that the increase of extracellular adenosine levels during hypoxia does not result from extracellular ATP or cAMP catabolism, and that astrocytes directly release adenosine in response to hypoxia. Adenosine release is negatively modulated by external or internal Ca2+ concentrations. Moreover, adenosine transport inhibitors did not modify the hypoxia-induced effects, suggesting that adenosine was not released by facilitated transport. We conclude that during hypoxia, astrocytes contribute to regulate the excitatory synaptic transmission through the release of adenosine, which acting on A1 adenosine receptors reduces presynaptic transmitter release. Therefore, adenosine release from astrocytes serves as a protective mechanism by down regulating the synaptic activity level during demanding conditions such as transient hypoxia.
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PMID:Adenosine released by astrocytes contributes to hypoxia-induced modulation of synaptic transmission. 1700 32

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1 receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1 receptor activation [with N6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1 receptors. Phospho-p38 MAPK activation by A1 receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1 receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 microM), the A1 receptor agonist CPA (40 nM), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1 receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nM) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 microM) blocked the inhibitory actions of A1 receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4'-pyridyl)-1H-imidazole] (25 microM) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2'-amino-3'-methoxyflavone] (50 microM) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABA(B)-mediated synaptic depression. These data suggest A1 receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3-CA1 synaptic transmission.
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PMID:p38 mitogen-activated protein kinase contributes to adenosine A1 receptor-mediated synaptic depression in area CA1 of the rat hippocampus. 1713 4

Adenosine A1 receptors are ubiquitous mediators of presynaptic inhibition of neurotransmission in the central nervous system, yet the signalling pathway linking A1 receptor activation and decreased neurotransmitter release remains poorly resolved. We tested the contribution of c-Jun N-terminal kinase (JNK) to adenosine A1 receptor-mediated depression of field excitatory postsynaptic potentials (fEPSPs) in area CA1 of the rat hippocampus. We found that inhibition of JNK with SP600125 or JNK inhibitor V, but not an inactive analogue, attenuated the depression of fEPSPs induced by adenosine, hypoxia, and the A1 receptor agonist N(6)-cyclopentyladenosine (CPA). In contrast, the JNK inhibitor SP600125 did not inhibit GABA(B)-mediated synaptic depression. In support of our electrophysiological findings, Western blot analysis showed that A1 receptor stimulation resulted in a transient increase in JNK phosphorylation in the membrane fraction of hippocampal lysates. The total amount of JNK in the membrane fraction was unchanged by CPA treatment. The increase in phosphorylated JNK induced by A1 receptor stimulation was blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), indicating that A1 receptors specifically activate JNK in the hippocampus. Together with functional data indicating that JNK inhibition decreased CPA-induced paired pulse facilitation, these results suggest that JNK activation is necessary for adenosine A1 receptor-mediated synaptic depression occurring at a presynaptic locus The adenosine A1 receptor-JNK signalling pathway may represent a novel mechanism underlying inhibition of neurotransmitter release in the CNS.
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PMID:C-Jun N-terminal kinase regulates adenosine A1 receptor-mediated synaptic depression in the rat hippocampus. 1796 69


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