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)

We describe the immunocytochemical distribution of adenosine A1 receptors in the rat hippocampus. Adenosine A1 receptor-like immunoreactivity was seen on the cell soma and dendrites of pyramidal cells and the cell soma and proximal part of dendrites of granule cells, but not on glial cells. Developmentally, adenosine A1 receptor-like immunoreactivity was diffuse on postnatal day 7 and increased in intensity in individual cells by day 21. In the CA2/CA3a region, the adult pattern of A1 receptor distribution was established by day 28. In the adult rat hippocampus, rostrocaudal inspection revealed that immunoreactivity in CA2/CA3a was greatest. Confocal microscopy revealed differences in the staining patterns for the adenosine A receptor and synaptophysin, a marker of presynaptic terminals. This result suggests that the adenosine A1 receptor might have postsynaptic physiological functions. Double-labeling of adenosine A1 receptors and anterogradely-labeled fibers from the supramammillary nucleus showed that the fibers from the supramammillary nucleus terminate directly on the cell soma of the A1 receptor-immunopositive neurons in CA2/CA3a and the dentate gyrus. These results indicate that the adenosine A 1 receptor in CA2/CA3a and the dentate gyrus are in a position to regulate hippocampal theta activity and that resultant strong synaptic depression in CA2/CA3a could play a role in regulating the intrinsic signal flow between CA3 and CA1.
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PMID:High level of adenosine A1 receptor-like immunoreactivity in the CA2/CA3a region of the adult rat hippocampus. 1047 60

1. Adenosine is a depressant in the central nervous system with pre- and postsynaptic effects. In the present study, intracellular recording techniques were applied to investigate the modulatory effects of adenosine on projection neurons in the lateral rat amygdala (LA), maintained as slices in vitro. 2. Adenosine reversibly reduced the amplitude of a fast inhibitory postsynaptic potential (IPSP) that was evoked by electrical stimulation of the external capsule and pharmacologically isolated by applying an N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor antagonist, DL-(-)-2-amino-5-methyl-4-isoxazolepropionic acid and 6, 7-Dinitroquinoxaline-2,3-dione, respectively, and the gamma-aminobutyric acidB (GABAB) receptor antagonist CGP 35348. The postsynaptic potential that remained was abolished by locally applying bicuculline. 3. Adenosine reduced the amplitude of the fast IPSP on average by 40.3%. It had no significant effect on responses to exogenously applied GABA, on membrane potential or on input resistance, suggesting that the site of action was at presynaptic inhibitory interneurons in the LA. 4. The response to adenosine was mimicked by the selective adenosine A1 receptor agonist N6-cyclohexyladenosine and blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. 5. Neuronal responsiveness in the amygdala is largely controlled by inhibitory processes. Adenosine can presynaptically downregulate inhibitory postsynaptic responses and could exert dampening effects likely by depression of both excitatory and inhibitory neurotransmitter release.
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PMID:Modulatory effects of adenosine on inhibitory postsynaptic potentials in the lateral amygdala of the rat. 1049 51

1. The effects of adenosine on synaptic transmission in magnocellular neurosecretory cells were investigated using whole-cell patch-clamp recordings in acute rat hypothalamic slices that included the supraoptic nucleus. 2. Adenosine reversibly reduced the amplitude of evoked inhibitory (IPSCs) and excitatory (EPSCs) postsynaptic currents in a dose-dependent manner (IC50 approximately 10 microM for both types of current). 3. Depression of IPSCs and EPSCs by adenosine was reversed by the application of the A1 adenosine receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT; 10 microM). 4. When pairs of stimuli were given at short intervals, adenosine inhibitory action was always less effective on the second of the two responses than on the first, resulting in an increased paired-pulse facilitation and suggesting a presynaptic site of action. This observation was confirmed by analysis of spontaneous miniature synaptic currents whose frequency, but not amplitude or kinetics, was reversibly reduced by 100 microM adenosine. 5. CPT had no effect on synaptic responses evoked at a low frequency of stimulation (0.05-0.5 Hz), indicating the absence of tonic activation of A1 receptors under these recording conditions. However, CPT inhibited a time-dependent depression of both IPSCs and EPSCs induced during a 1 Hz train of stimuli. 6. Taken together, these results suggest that adenosine can be released within the supraoptic nucleus at a concentration sufficient to inhibit the release of GABA and glutamate via the activation of presynaptic A1 receptors. By its inhibitory feedback action on the major afferent inputs to oxytocin and vasopressin neurones, adenosine could optimally adjust electrical and secretory activities of hypothalamic magnocellular neurones.
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PMID:Adenosine-induced presynaptic inhibition of IPSCs and EPSCs in rat hypothalamic supraoptic nucleus neurones. 1054 29

Adenosine is known to modulate synaptic plasticity in the hippocampus of young animals through activation of adenosine A1 receptors. The objective of the present study is to investigate whether the modulatory role of adenosine on phenomena of synaptic plasticity is maintained or modified in the hippocampus of aged animals. We compared the effects of the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), on paired-pulse facilitation (PPF), long-term depression (LTD), long-term potentiation (LTP) and depotentiation elicited in hippocampal slices taken from young adult (5-6 weeks) and old (2 years old) male Wistar rats. DPCPX attenuated PPF both in young (1.64 +/- 0.05 vs. 1.76 +/- 0.05%, n = 6) and in old rats (1.33 +/- 0.05 vs. 1.55 +/- 0.1%, n = 6). LTD was only observed in the presence of DPCPX in both young (21.3 +/- 0.6%, n = 4) and old rats (14.4 +/- 0.9%, n = 6). LTP induced by high-frequency stimulation (HFS) was not significantly different in young and old animals, in the presence or in the absence of DPCPX. A larger depotentiation was observed in the presence of DPCPX in young rats (27.6 +/- 4.4% vs. 16.8 +/- 4.7%, n = 7) as well as in old rats (41.3 +/- 5.1% vs. 16.1 +/- 2.7%, n = 6). LTP induced by theta-burst stimulation was observed only in the presence of DPCPX (53.9 +/- 4.9%, n = 5) in young rats, but could be obtained either in the control solution (81.8 +/- 17.9%, n = 7) or in the presence of DPCPX (98.5 +/- 24.2%, n = 7) in old rats. The modulatory role of endogenous adenosine on synaptic plasticity is generally maintained in aged animals. Drugs interfering with adenosine A1 receptor effects could then be used in old animals to modify synaptic plasticity with relevant behavioural consequences.
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PMID:Adenosine modulates synaptic plasticity in hippocampal slices from aged rats. 1064 48

G-protein inhibition of voltage-gated calcium channels can be transiently relieved by repetitive physiological stimuli. Here, we provide evidence that such relief of inhibition contributes to short-term synaptic plasticity in microisland-cultured hippocampal neurons. With G-protein inhibition induced by the GABA(B) receptor agonist baclofen or the adenosine A1 receptor agonist 2-chloroadenosine, short-term synaptic facilitation emerged during action potential trains. The facilitation decayed with a time constant of approximately 100 msec. However, addition of the calcium channel inhibitor Cd(2+) at 2-3 microM had no such effect and did not alter baseline synaptic depression. As expected of facilitation from relief of channel inhibition, analysis of miniature EPSCs implicated presynaptic modulation, and elevating presynaptic Ca(2+) entry blunted the facilitation. Most telling was the near occlusion of synaptic facilitation after selective blockade of P/Q- but not N-type calcium channels. This was as predicted from experiments using recombinant calcium channels expressed in human embryonic kidney (HEK) 293 cells; we found significantly stronger relief of G-protein inhibition in recombinant P/Q- versus N-type channels during action potential trains. G-protein inhibition in HEK 293 cells was induced via recombinant M2 muscarinic acetylcholine receptors activated by carbachol, an acetylcholine analog. Thus, relief of G-protein inhibition appears to produce a novel form of short-term synaptic facilitation in cultured neurons. Similar short-term synaptic plasticity may be present at a wide variety of synapses, as it could occur during autoreceptor inhibition by glutamate or GABA, heterosynaptic inhibition by GABA, tonic adenosine inhibition, and in many other instances.
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PMID:Relief of G-protein inhibition of calcium channels and short-term synaptic facilitation in cultured hippocampal neurons. 1064 93

1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2-chloroadenosine (2-ClAdo) and beta-adrenoceptor activation with isoproterenol were studied in wild-type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor. 2. Treatment of wild-type hearts with 2-ClAdo induced bradycardia (pEC50 6.4+/-0.2) and vasodilatation (pEC50 7.9+/-0.1; minimal resistance 2.2+/-0.2 mmHg/mL per min per g). The A1 receptor-mediated bradycardia was 20-fold more sensitive in transgenic hearts (pEC50 7.7+/-0.2), whereas coronary vasoactivity of 2-ClAdo was unaltered (pEC50 7.6+/-0.1). 3. beta-Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5+/-0.2; maximal rate 594+/-23 b.p.m.) and produced vasodilation (pEC50 8.7+/-0.1; minimal resistance 1.7 +/-0.2 mmHg/ml, per min per g) in wild-type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653+/-27 b.p.m.) without altering potency (pEC50 8.5+/-0.1). Antagonism of A1 receptors with 10nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695+/-26b.p.m.) without altering potency (pEC50 8.3+/-0.1). 4. Isoproterenol-mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during beta-adrenoceptor stimulation by 35% (to 381 +/-28 b.p.m.) without altering potency (pEC50 8.4+/-0.2). At 10nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484+/-36 b.p.m.) without altering potency (pECs50 8.3+/-0.2). 5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the beta-adrenoceptor-mediated chronotropic response in mouse heart. The A1 receptor-mediated depression of beta-adrenoceptor responsiveness is non-competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non-competitively inhibits effector mechanisms activated by beta-adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
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PMID:Chronotropic and vasodilatory responses to adenosine and isoproterenol in mouse heart: effects of adenosine A1 receptor overexpression. 1074 45

We investigated whether volume-regulated anion channels (VRACs) contributed to the accumulation of extracellular adenosine during hypoxia in area CA1. The rapid hypoxic depression of the fEPSP was greatly attenuated by the selective adenosine A1 receptor antagonist DPCPX (50 nM), but not affected by the VRAC blockers tamoxifen (10-30 microM) or DNDS (1 mM). Our data argue against the efflux of adenosine per se or its precursor ATP through VRACs as making a significant contribution to extracellular adenosine during the early stages of hypoxia.
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PMID:Volume-regulated anion channels do not contribute extracellular adenosine during the hypoxic depression of excitatory synaptic transmission in area CA1 of rat hippocampus. 1097 48

Superfusion of rat hippocampal slices with ATP induces a form of facilitation that has been poorly characterised. The present study has confirmed that at low concentrations of ATP (10 microM or less), an initial depression of evoked potential size is followed by a rebound facilitation which is not reproduced by alphabeta-methyleneATP, betagamma-methyleneATP, or the dinucleotide P1,P6-diadenosine hexaphosphate. The post-ATP facilitation could be prevented by the adenosine A1 receptor antagonists 8-phenyltheophylline or 1,3-dipropyl-8-cyclopentyltheophylline (50 nM), or superfusion of adenosine deaminase. The adenosine A2A receptor antagonist 8-(chlorostyryl)-caffeine did not affect the inhibition but prevented the post-ATP facilitation. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid prevented the establishment of post-ATP facilitation. The post-ATP facilitation was also blocked by suramin at a concentration (50 microM) that does not block glutamate receptors. Suramin prevented the induction but not the maintenance phase of the post-ATP facilitation. The repeated induction of post-ATP facilitation by bursts of electrical stimulation designed to saturate the normal mechanisms of long-term potentiation prevented the induction of post-ATP facilitation. However, repeated applications of ATP to achieve saturation of its receptor did not prevent the subsequent induction of electrically evoked long-term potentiation. It is concluded that ATP can induce a form of synaptic facilitation which resembles only partially that induced by electrical stimulation and which may require the simultaneous activation of P1 and P2 receptors.
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PMID:Characterisation of ATP-induced facilitation of transmission in rat hippocampus. 1110 29

The hypothesis that adenosine A1 receptor (A1AdoR) selective antagonism limits cardiac depression and prolongs survival during acute global hypoxia was tested in a postinsult treatment model using KW-3902 ([8-(noradamantan-3-yl)-1,3-dipropylxanthine]), an A1AdoR selective antagonist. Rats were anesthetized, paralyzed, then ventilated with 8% O2 (hypoxia). In protocol I, 5 min after hypoxia, rats were treated with saline, drug vehicle, or KW-3902 (0.1 mg/kg i.v.). In protocol II, KW-3902 treatment occurred 2.5, 5, or 7.5 min after hypoxia. In protocol I, after hypoxia, left ventricular contractility, heart rate, and systemic mean arterial blood pressure decreased rapidly in saline-and vehicle-treated groups. In contrast, KW-3902 significantly attenuated the decline in these variables. Survival time (the time from the commencement of hypoxia until death) was more prolonged with KW-3902 (109.5 +/- 9.1 min) than with saline (37.6 +/- 5.0 min) or vehicle (35.0 +/- 4.2 min) (p < 0.001). In protocol II, survival time increased from 29.2 +/- 5.5 min in the 7.5-min treatment group to 109.5 +/- 9.5 min (5-min group) and 245.9 +/- 26.1 min (2.5-min group; p < 0.001). KW-3902 prolongs survival in this model, presumably by antagonizing A1AdoR-mediated inhibition of cardiac function. Also, treatment efficacy is highly time dependent.
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PMID:Adenosine A1 receptor antagonist prolongs survival in the hypoxic rat. 1148 43

Several reports have shown that energy deprivation, as a result of hypoxia, hypoglycaemia or ischaemia, depresses excitatory synaptic transmission in virtually all brain areas. How this pathological condition affects inhibitory synaptic transmission is still unclear. In the present in vitro study, we coupled whole-cell patch clamp recordings from striatal neurones with focal stimulation of GABAergic nerve terminals in order to characterize the electrophysiological effects of combined oxygen and glucose deprivation (in vitro ischaemia) on inhibitory postsynaptic currents (IPSCs) in this brain area. We found that brief periods (2-5 min) of in vitro ischaemia invariably caused a marked depression of IPSC amplitude. This inhibitory effect was fully reversible on removal of the ischaemic challenge. It was coupled with an increased paired-pulse facilitation, suggesting the involvement of presynaptic mechanisms. Accordingly, the ischaemic inhibition of striatal GABAergic IPSCs was not caused by a shift in the reversal potential of GABA(A)-receptor mediated synaptic currents, and was independ- ent of postsynaptic ATP concentrations. Endogenous adenosine, acting on A1 receptors, appeared responsible for this presynaptic action as the ischaemic depression of IPSCs was prevented by CPT [8-(4-chlorophenylthio) adenosine] and DPCPX, two adenosine A1 receptor antagonists, and mimicked by the application of adenosine in the bathing solution. Conversely, ATP-sensitive potassium channels were not involved in the inhibition of IPSCs by ischaemia, as demonstrated by the fact that tolbutamide and glipizide, two blockers of these channels, were ineffective in preventing this electrophysiological effect. The early depression of GABA-mediated synaptic transmission might play a role in the development of irreversible neuronal injury in the course of brain ischaemia.
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PMID:Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia. 1152 87


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