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)

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

The effects on locomotor activity (LA) of selective agonists for adenosine receptor subtypes were examined in mice following bilateral injections into the nucleus accumbens (ACB). The ACB is not only richly innervated by dopaminergic (DA) terminals but also exhibits the highest densities of adenosine A2a receptors in the brain. CGS 21680 (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosi ne), a potent and highly selective adenosine A2a receptor agonist, elicited pronounced, dose-related reductions in LA (ID50 dosage = 0.0031 nmol/mouse). NECA (5'-N-ethylcarboxamidoadenosine), a mixed adenosine receptor agonist which exhibits high selectivity and potency at striatal A2a receptors, similarly elicited dose-related reductions in LA (ID50 dosage = 0.0023 nmol/mouse). In contrast, intra-ACB injections of CPA (N6-cyclopentyladenosine), a highly selective agonist for adenosine A1 receptors, did not exert any significant effects on LA, even at 2.0 nmol/mouse, a dosage at which both CGS 21680 and NECA depressed LA by almost 90% compared to vehicle controls. Further, the pronounced locomotor depression elicited by intra-ACB injections of both CGS 21680 and NECA, at approximately the ID65 dosage, was significantly antagonized by IP pretreatment with DMPX, (3,7-dimethyl-1-propargylxanthine), an adenosine receptor antagonist with selectivity for A2 receptors in the striatum, at a dosage (0.15 micromol/mouse) [corrected] which alone had no significant effect on LA. These observations provide support for the notion that adenosine may selectively modulate DA-mediated mesolimbic behavioral circuits via agonist actions at a population of A2a receptors densely concentrated in the ventral striatum.
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PMID:Adenosine A2a receptors in the nucleus accumbens mediate locomotor depression. 849 Jul 38

The molecular layer of the dentate gyrus exhibits extensive circuit and receptor reorganization after entorhinal lesions and in Alzheimer's disease, including decreased adenosine (A1) receptor binding in the terminal zone of damaged perforant path fibers. We examined the adenosine-sensitivity of evoked synaptic activity recorded from the rat dentate gyrus molecular layer in hippocampal slices prepared after electrolytic lesions were placed in approximately the middle third of the entorhinal cortex. Extracellular field potentials (EFPs) recorded in slices prepared from animals two days post-lesion were small, upward-going, and exhibited paired-pulse potentiation, but by two weeks post-lesion EFPs had recovered to large, downward-going responses that exhibited paired-pulsed depression. EFPs recorded from two week post-lesion slices were about 2-fold more sensitive (P < or = 0.05) to exposure to adenosine when compared to EFPs recorded from slices from unlesioned animals. Adenosine-induced reduction of paired-pulse depression was similar between unlesioned and post-lesion slices. AChE histochemistry performed after recording revealed dense staining in the dentate gyrus molecular layer of post-lesion slices as compared to slices from unlesioned animals, confirming that sprouting of cholinergic fibers occurred as expected from previous entorhinal lesion studies. Autoradiography performed on adjacent slices showed a decrease in binding to A1-adenosine receptors in the dentate gyrus molecular layer in post-lesion slices as compared to slices from unlesioned animals, indicating that there was a loss of presynaptically located A1-adenosine receptors on damaged perforant pathway terminals. These results indicate that, in addition to the recovery of the major excitatory signal to the hippocampus after entorhinal cell loss, this signal is more sensitive to modulation by adenosine, suggesting an increase in A1-adenosine receptor efficacy in the reinnervated region.
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PMID:Increased sensitivity to adenosine in the rat dentate gyrus molecular layer two weeks after partial entorhinal lesions. 850 4

Most reported actions of kainate are mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors. Here we report that, unlike AMPA which stimulates, kainate elicits a dose-dependent decrease in L-glutamate release from rat hippocampal synaptosomes and also depresses glutamatergic synaptic transmission. Brief exposure to kainate inhibited Ca(2+)-dependent [3H]L-glutamate release by up to 80%. Inhibition was reversed by kainate antagonists but not by the AMPA-selective non-competitive antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466). A corresponding reversible kainate-evoked depression of NMDA (N-methyl-D-aspartate) receptor-mediated excitatory postsynaptic currents (e.p.s.cs) was observed when AMPA receptors were blocked by GYKI 52466. The synaptic depression was preceded by a brief period of enhanced release and a small inward current was also observed. The effects of kainate were unaffected by metabotropic glutamate (mGlu), GABAA, GABAB, glycine and adenosine receptor antagonists. These results indicate that glutamate release can be modulated directly by kainate autoreceptors.
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PMID:Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. 853 45

1. Comparative studies were performed on eighteen rats 54 days old made chronically hypoxic from birth in an hypoxic chamber at 12% O2 (CHB), and in eight weight-matched control rats (NB, 42 days old); both CHB and NB rats were anaesthetized with Saffan. 2. In NB rats, breathing 12 or 8% O2 for 5 min induced a pattern of response comparable to that described in older rats (10-11 weeks old): an initial increase and secondary fall in minute volume (VE), a fall in arterial pressure (ABP), an increase in muscle vascular conductance, while cerebral blood flow (CBF) increased at the 1st minute in six animals and fell by the 5th minute in all animals. The adenosine receptor antagonist 8-phenyl-theophylline (8-PT, 10 mg kg-1) reduced the secondary fall in VE, the fall in ABP and muscle vasodilatation, indicating they were partly mediated by adenosine. 3. In CHB rats breathing 12% O2, VE was higher (277 +/- 12 vs. 204 +/- 18 ml min-1), arterial partial pressures of O2 (45 +/- 2 vs. 88 +/- 3 mmHg), CO2 (32 +/- 1 vs. 44 +/- 1 mmHg) and ABP (105 +/- 5 vs. 131 +/- 5 mmHg) were lower, while muscle vascular conductance was higher (0.08 +/- 0.01 vs. 0.03 +/- 0.01 ml min-1 mmHg-1) than in NB rats breathing air; these differences were reduced, but not abolished, when CHB rats acutely breathed air for 5 min. 4. In CHB rats, the smaller change from 12 to 8% O2 for 5 min evoked a similar pattern of response to that evoked by 8% O2 in NB rats, except that heart rate (HR) and CBF decreased progressively. However, 8-PT increased baseline VE and reduced ABP in 12% O2 and reduced the secondary decrease in VE and HR evoked by 8% O2, but had no effect on the fall in ABP, or change in muscle vascular conductance. 5. We propose that in CHB rats (i) there is accentuation of the components of the response to acute hypoxia (the fall in ABP, HR and CBF) that form a positive feedback loop which promotes central ventilatory depression and (ii) that adenosine exerts a tonic inhibitory influence on VE and vasodilator influence in muscle and mediates the secondary fall in VE, but not the muscle vasodilation induced by acute hypoxia.
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PMID:A study on rats of the effects of chronic hypoxia from birth on respiratory and cardiovascular responses evoked by acute hypoxia. 855 80

High-frequency stimulation (HFS) of afferent fibers produced short-term depression (STD) and long-term depression (LTD) of corticostriatal synaptic transmission. Application of the non-selective adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) or the selective A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) blocked the induction of STD but not LTD. Application of adenosine or the selective A1 receptor agonist R(-)N6-(2-phenylisopropyl)adenosine (R-PIA) induced synaptic depression, while the A2a receptor agonist CGS 21680 did not consistently alter synaptic transmission. Depression induced by adenosine or R-PIA was not accompanied by changes in postsynaptic input resistance and appeared to involve a presynaptic depressant effect previously characterized at this synapse. These observations indicate that HFS leads to the production of endogenous adenosine that acts on presynaptic A1 receptors to initiate STD at corticostriatal synapses. Initiation and maintenance of LTD appear to be independent of A1 receptor activation.
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PMID:Activation of adenosine A1 receptors initiates short-term synaptic depression in rat striatum. 858 33

1. Purine analogues have been examined for anxiolytic- and anxiogenic-like activity in mice, by use of the elevated plus-maze. 2. The selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) had marked anxiolytic-like activity at 10 and 50 microg kg(-1), with no effect on locomotor performance at these doses. 3. The A1 selective adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (CPX) had no significant effect on anxiety-related measures or locomotor behaviour, but blocked the anxiolytic-like activity of CPA. The hydrophilic xanthine, 8-(p-sulphophenyl) theophylline did not prevent anxiolysis by CPA. 4. Caffeine had anxiogenic-like activity at 30 mg kg(-1) which was prevented by CPA at 50 micro kg(-1). 5. The A2 receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2(2-methylphenyl)-ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg(-1). The A2 receptor antagonist, 1,3-dimethyl-l-propargylxanthine (DMPX) had no effect on anxiety-related measures or locomotion and did not modify the anxiolytic-like activity of CPA. 6. Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic-like activity of the latter. 7. The results suggest that the selective activation of central A1 adenosine receptors induces anxiolytic-like behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of A1 receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus-maze in mice are not activated tonically by endogenous adenosine.
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PMID:Anxiolytic activity of adenosine receptor activation in mice. 864 Mar 55

1. An understanding of the physiological and pathological roles of metabotropic glutamate receptors (mGluRs) is currently hampered by the lack of selective antagonists. Standard extracellular recording techniques were used to investigate the activity of recently reported mGluR antagonists on agonist-induced depressions of synaptic transmission in the lateral perforant path of hippocampal slices obtained from 12-16 day-old rats. 2. The group III specific mGluR agonist, (S)-2-amino-4-phosphonobutanoate (L-AP4) depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean (+/-s.e. mean) depression obtained with 100 microM L-AP4 (the maximum concentration tested) was 74 +/- 3% and the IC50 value was 3 +/- 1 microM (n = 5). 3. The selective group II mGluR agonists, (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate ((1S,3s)-ACPD) and (2S, 1'R, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) also depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean depression obtained with 200 microM (1S,3S)-ACPD was 83 +/- 8% and the IC50 value was 12 +/- 3 microM (n = 5). The mean depression obtained with 1 microM DCG-IV was 73 +/- 7% and the IC50 value was 88 +/- 15 nM (n = 4). 4. Synaptic depressions induced by the actions of 20 microM (1S,3S)-ACPD and 10 microM L-AP4 were antagonized by the mGluR antagonists (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4), (2S,1'S,2'S)-2-methyl-2(2'-carboxycyclopropyl)glycine (MCCG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) (all tested at 500 microM). 5. (+)-MCPG was a weak antagonist of both L-AP4 and (1S,3S)-ACPD-induced depressions. MCCG was selective towards (1S,3S)-ACPD, but analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L-AP4-induced effects. 6. The most effective antagonist tested against 10 microM L-AP4 was MPPG (mean reversal 90 +/- 3%; n = 4). In contrast, the most effective antagonist tested against 20 microM (1S,3S)-ACPD induced depressions was MTPG (mean reversal 64 +/- 4%; n = 4). Both antagonists produced parallel shifts in agonist dose-response curves. Schild analysis yielded estimated KD values of 11.7 microM and 27.5 microM, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2-chloroadenosine (500 nM; n = 3). 7. We conclude that both group II and group III mGluRs can mediate synaptic depressions induced by mGluR agonists in the lateral perforant path. The mGlur antagonists MTPG, MPPG and MAP4 should be useful in determining the roles of group II and III mGluRs in the central nervous system.
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PMID:Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices. 873 Jul 39

Adenosine is a potent neuromodulator in the CNS, but the mechanisms that regulate adenosine concentrations in the extracellular space remain unclear. The present study demonstrates that increasing the intracellular concentration of adenosine in a single hippocampal CA1 pyramidal neuron selectively inhibits the excitatory postsynaptic potentials in that cell. Loading neurons with high concentrations of adenosine via the whole-cell patch-clamp technique did not affect the GABAA-mediated inhibitory postsynaptic potentials, the membrane resistance, or the holding current, whereas it significantly increased the adenosine receptor-mediated depression of excitatory postsynaptic currents. The effects of adenosine could not be mimicked by an agonist at the intracellular adenosine P-site, but the effects could be antagonized by a charged adenosine receptor antagonist and by adenosine deaminase, demonstrating that the effect was mediated via adenosine acting at extracellular adenosine receptors. The effect of adenosine loading was not blocked by BaCl2 and therefore was not caused by an adenosine-activated postsynaptic potassium conductance. Adenosine loading increased the paired-pulse facilitation ratio, demonstrating that the effect was mediated by presynaptic adenosine receptors. Finally, simultaneous extracellular field recordings demonstrated that the increase in extracellular adenosine was confined to excitatory synaptic inputs to the loaded cell. These data demonstrate that elevating the intracellular concentration of adenosine in a single CA1 pyramidal neuron induces the release of adenosine into the extracellular space in such a way that it selectively inhibits the excitatory inputs to that cell, and the data support the general conclusion that adenosine is a retrograde messenger used by pyramidal neurons to regulate their excitatory input.
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PMID:Modulation of excitatory synaptic transmission by adenosine released from single hippocampal pyramidal neurons. 879 16

We examined the effects of Ca(2+)-free medium containing 20 mM Mg2+, a non-selective adenosine receptor antagonist, theophylline, and adenosine transport inhibitors, dipyridamole and nitrobenzylthioinosine, on high K(+)-evoked spreading depression, glutamate, and taurine release from the rat hippocampus using brain microdialysis. High K+ alone perfusion evoked spreading depression and increased glutamate release followed by taurine efflux. Perfusion of Ca(2+)-free medium with high K+ never evoked spreading depression and decreased the high K(+)-evoked taurine release. Perfusion of theophylline (1 mM) increased the occurrence of high K(+)-evoked spreading depression and glutamate release, but did not modify taurine release. In contrast, simultaneous perfusion of dipyridamole (100 microM) and nitrobenzylthioinosine (50 microM) reduced the occurrence of spreading depression and the high K(+)-evoked glutamate release, but enhanced significantly the taurine efflux. These findings suggest that endogenous taurine with adenosine may have neuroprotective actions against high K(+)-evoked glutamate release and spreading depression in the rat hippocampus, in addition to its osmoregulatory action.
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PMID:Adenosine transport inhibitors enhance high K(+)-evoked taurine release from rat hippocampus. 881 38


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