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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The magnocellular neurons of the supraoptic nucleus have been intensively studied because of their unique bursting and phasic activity patterns. While these can be explained in part by intrinsic membrane conductances, it is now also apparent that afferent inputs are important in sculpting and initiating the activity patterns. Modulation of these inputs, therefore, provides a powerful way to regulate magnocellular neuronal activity. The paper by Oliet & Poulain in this issue of The Journal of Physiology provides evidence that adenosine may be such a modulator in that it acts presynaptically in the supraoptic nucleus (SON) to inhibit both excitatory and inhibitory synaptic currents onto magnocellular neurons. Furthermore, the authors were able to demonstrate an action of endogenous adenosine in the slice by blocking, with an A1-type antagonist, a progressive synaptic depression brought about by continuous afferent stimulation at 1 Hz over 2 min or more. This paper therefore adds to a compelling body of evidence that adenosine has transmitter action in the central nervous system (Dunwiddie, 1985). Several aspects of this study deserve comment and raise questions amenable to experimentation. Adenosine was equipotent in inhibiting IPSCs and EPSCs, thereby raising questions as to the consequences of adenosine action on the output of the nucleus. While it could be argued that intense excitatory inputs would be attenuated, the same would be true for inhibition, making the net effect rather minor. One possible effect could be to stabilize activity levels of the postsynaptic cell at levels conducive for the generation of intrinsic voltage-dependent activity patterns. Another possibility is that adenosine is simply acting to reduce overall metabolic activity; since the metabolic consequences of activity in the presynaptic terminal would be similar in excitatory and inhibitory terminals, it may be irrelevant as to the nature of the transmitter. It is also interesting that the maximum inhibition attained in response to adenosine is only 60 % for either excitatory or inhibitory inputs. This is in contrast to such presynaptic modulators as baclofen, acting at GABAB receptors, where there is 100 % attenuation of afferent evoked potentials (Pittman et al. 1998). Whether this is due to a distribution of adenosine receptors on only a limited number of afferent terminals, or whether it reflects a mechanism of action that is only partially effective in reducing the transmitter release is not known. For example, if adenosine receptors were coupled to only a subset of the calcium channels engaged in transmitter release, one might predict that only part of the transmitter release would be inhibited. However, data from the Oliet & Poulain paper indicate that miniature EPSCs and miniature IPSCs are inhibited by adenosine; as most evidence indicates that TTX-resistant spontaneous currents in magnocellular neurons are calcium insensitive, this suggests that adenosine acts downstream of the calcium influx, perhaps by interfering with the transmitter release machinery (reviewed in Wu & Saggau, 1997). It would also be interesting to determine whether the presynaptic A1 receptors identified here display a sensitivity to pertussis toxin pretreatment. While such receptors are known to be G-protein coupled, presynaptic receptors are often insensitive to inhibition by pertussis toxin. The identification of an action of endogenous adenosine required repetitive stimulation, perhaps because reuptake mechanisms at lower frequencies efficiently removed adenosine. The source of this endogenous adenosine is still unknown. While it could be released by a nucleoside transporter from either glial cells or neurons, another possibility is that it may be produced by metabolic breakdown of ATP (Cunha et al. 1998). ATP is known to be released in the SON from noradrenergic afferents (Buller et al. 1996) and there is also some evidence that it may be released from the magnocellu
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PMID:The action is at the terminal. 1054 46

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

This study aimed to test whether nerve-evoked and adenosine-induced synaptic depression are due to reduction in Ca2+ entry in nerve terminals of the frog neuromuscular junction. Nerve terminals were loaded with the fluorescent Ca2+ indicator fluo 3 (fluo 3-AM) or loaded with dextran-coupled Ca2+ green-1 transported from the cut end of the nerve. Adenosine (10-50 microM) did not change the resting level of Ca2+ in the presynaptic terminal, whereas it induced large Ca2+ responses in perisynaptic Schwann cells, indicating that adenosine was active and might have induced changes in the level of Ca2+ in the nerve terminal. Ca2+ responses in nerve terminals could be induced by nerve stimulation (0.5 or 100 Hz for 100 ms) over several hours. In the presence of adenosine (10 microM), the size and duration of the nerve-evoked Ca2+ responses were unchanged. When extracellular Ca2+ concentration was lowered to produce the same reduction in transmitter release as the application of adenosine, Ca2+ responses induced by nerve stimulations were reduced by 40%. This indicates that changes in Ca2+ responsible for the decrease in release should have been detected if the mechanism of adenosine depression involved partial block of Ca2+ influx. Ca2+ responses evoked by prolonged high frequency trains of stimuli (50 Hz for 10 or 30 s), which caused profound depression of transmitter release, were sustained during the whole duration of the stimulation, and adenosine had no effect on these responses. These data indicate that neither adenosine induced synaptic depression nor stimulation-induced synaptic depression are caused by reductions in Ca2+ entry into the presynaptic terminal in the frog neuromuscular junction.
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PMID:Effects of adenosine on Ca2+ entry in the nerve terminal of the frog neuromuscular junction. 1056 48

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

When ATP or the related stable analogue, betagamma-imidoATP, were applied to rat hippocampal slices showing population spikes larger than 5 mV peak-to-peak amplitude, a depression of spike size was obtained, which showed a marked fade during the 10-min period of superfusion. The inhibitory responses were prevented by adenosine deaminase or 8-phenyltheophylline. Adenosine responses showed no fade. alphabeta-MethyleneADP enhanced the fade, while suramin at 50 micrometer prevented the early component of the responses. The results suggest that in slices with large population spikes, inhibitory responses to nucleotides are partly due to their conversion to adenosine, and partly due to the activation of P2 receptors which trigger the release of endogenous adenosine.
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PMID:Complex hippocampal responses to ATP: fade due to nucleotidase inhibition and P2-receptor-mediated adenosine release. 1072 36

Imipramine, a tricyclic antidepressant, is one of the main drugs used for the treatment of depression. We investigated the effects of the repeated administration of imipramine (10 mg/kg po for 14 days, twice daily) on adenosine receptor-mediated actions using extracellular and intracellular recording techniques in the rat hippocampal slices. Adenosine and 2-chloroadenosine dose-dependently decreased the amplitude of population spikes and the slope of the field excitatory postsynaptic potentials (fEPSPs) evoked in the CA1 cell layer and apical dendrites of the CA1 cells, respectively, by stimulation of the Schaffer collateral/commissural pathway. As revealed by intracellular recording, a membrane hyperpolarization and a strong attenuation of excitatory synaptic transmission contribute to the decrease in the population spikes and fEPSPs induced by adenosine and 2-chloroadenosine. The repeated administration of imipramine enhanced the effect of adenosine (3 microM) and 2-chloroadenosine (0.15 microM) on fEPSPs while the inhibition of population spikes was not changed. When higher concentration of 2-chloroadenosine (0.25 microM) was tested, repeated imipramine administration enhanced its inhibitory effect on population spikes but not on fEPSPs. The present report provides evidence that the inhibitory effect of adenosine receptor activation in the hippocampus is enhanced by repeated treatment with imipramine.
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PMID:Imipramine-induced increase in the inhibitory effect of adenosine receptor activation in the hippocampus. 1081 43

The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions in both adult and developing hippocampus, together with a pronounced increase in the release of excitatory amino acids and the neuromodulator adenosine. We studied the effects of adenosine receptor agonists and antagonists as well as adenosine transport inhibitors on hippocampal [(3)H]taurine release in normoxia and ischemia, using a superfusion system. Under standard conditions the adenosine A(1) receptor agonists N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine potentiated basal taurine release in developing mice and depressed the release in adults in a receptor-mediated manner. Adenosine A(2) receptor compounds had only minor effects on the basal release and the K(+)-stimulated release was not affected by these drugs. The adenosine uptake inhibitor dipyridamole enhanced basal taurine release in the developing hippocampus and reduced it in the adult. In ischemia the adenosine compounds had no marked effects on taurine release in immature animals, whereas A(1) receptor activation was still able to evoke taurine release in adults by a receptor-mediated mechanism. The results show that the basal release of taurine is modulated by A(1) receptors in both mature and immature hippocampus, whereas in ischemia these receptors potentiate taurine release only in adults. The elevated taurine levels together with the depression of excitatory amino acid release by adenosine receptor activation could be beneficial under ischemic conditions, protecting neural cells against excitotoxicity and hyperexcitation.
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PMID:Modulation of the ischemia-induced taurine release by adenosine receptors in the developing and adult mouse hippocampus. 1082 25

Endogenous adenosine, acting upon A(1) receptors, attenuates long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in hippocampal slices. Adenosine might exert these effects by inhibiting the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Theta burst-induced LTP was larger in the presence of the selective adenosine A(1) receptor antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX, 50nM, 40.5+/-6.6% increase in fEPSP) than in the control solution (18.2+/-4.7% increase), and was completely prevented in the presence of DPCPX (50nM) plus the selective NMDA receptor antagonist, DL-2-amino-5-phosphonopentanoate (AP5, 50microM, -3.3+/-7.0% change). In contrast, LTD was induced by low-frequency stimulation in the presence of DPCPX (50nM), even in experiments performed in AP5 (50microM). Thus LTP, but not LTD, observed upon blockade of adenosine A(1) receptors is dependent upon NMDA receptor activation.
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PMID:Long-term potentiation observed upon blockade of adenosine A1 receptors in rat hippocampus is N-methyl-D-aspartate receptor-dependent. 1097 79

Adenosine A2A receptors are present on enkephalinergic medium sized striatal neurons in the rat and have an important function in the modulation of striatal output. In order to establish more accurately whether adenosine transmission is a generalized phenomenon in mammalian striatum we compared the A2A R expression in the mouse, rat, cat and human striatum. Secondly we compared the modulation of enkephalin gene expression and A2A receptor gene expression in rat striatal neurons after 6-OH-dopamine lesion of the substantia nigra. Hybridization histochemistry was performed with a 35S-labelled radioactive oligonucleotide probe. The results showed high expression of A2A adenosine receptor genes only in the medium-sized cells of the striatum in all examined species. In the rat striatum, expression of A2A receptors was not significantly altered after lesion of the dopaminergic pathways with 6-OH-dopamine even though enkephalin gene expression was up-regulated. The absence of a change in A2A receptor gene expression after 6-OH-dopamine treatment speaks against a dependency on dopaminergic innervation. The maintained inhibitory function of A2A R on motor activity in spite of dopamine depletion could be partly responsible for the depression of locomotor activity observed in basal ganglia disorders such as Parkinson's disease.
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PMID:Adenosine A2A receptor gene expression in the normal striatum and after 6-OH-dopamine lesion. 1104 Dec 67

Adenosine plays a major modulatory and neuroprotective role in the mammalian CNS. During cerebral metabolic stress, such as hypoxia or ischemia, the increase in extracellular adenosine inhibits excitatory synaptic transmission onto vulnerable neurons via presynaptic adenosine A(1) receptors, thereby reducing the activation of postsynaptic glutamate receptors. Using a combination of extracellular and whole-cell recordings in the CA1 region of hippocampal slices from 12- to 24-d-old rats, we have found that this protective depression of synaptic transmission weakens with repeated exposure to hypoxia, thereby allowing potentially damaging excitation to both persist for longer during oxygen deprivation and recover more rapidly on reoxygenation. This phenomenon is unlikely to involve A(1) receptor desensitization or impaired nucleoside transport. Instead, by using the selective A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine and a novel adenosine sensor, we demonstrate that adenosine production is reduced with repeated episodes of hypoxia. Furthermore, this adenosine depletion can be reversed at least partially either by the application of exogenous adenosine, but not by a stable A(1) agonist, N(6)-cyclopentyladenosine, or by endogenous means by prolonged (2 hr) recovery between hypoxic episodes. Given the vital neuroprotective role of adenosine, these findings suggest that depletion of adenosine may underlie the increased neuronal vulnerability to repetitive or secondary hypoxia/ischemia in cerebrovascular disease and head injury.
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PMID:A depletable pool of adenosine in area CA1 of the rat hippocampus. 1126 5


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