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)

Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this action appears to be the depression of calcium entry, thus decreasing presynaptic neurotransmitter release. Adenosine uptake inhibitors and adenosine deaminase inhibitors potentiate the depressant actions of adenosine. Caffeine and theophylline, methylxanthines, antagonize these actions. Adenosine is therefore likely to be released and to exert an ongoing modulation of the neuron excitability in the intact brain. Adenosine uptake by nerve terminals appears to be important in regulating the extracellular concentration of adenosine and thus of adenosine's action. A number of groups of centrally active sedative, anxiolytic and anticonvulsant drugs inhibit adenosine uptake by brain synaptosomal preparations. It is proposed that these agents exert their sedative effects by inhibiting adenosine uptake and thus potentiating depressant actions by locally released adenosine on neuronal activity.
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PMID:Adenosine mediates sedative action of various centrally active drugs. 613 Apr 65

The postsynaptic potential (PSP) was recorded from thin slices of the olfactory cortex of the guinea pig. Application of adenosine and adenine nucleotides such as 5'-ATP, 5'-ADP and 5'-AMP in the incubation medium, depressed the amplitude of the PSP without altering the presynaptic fiber potential. The other purine and pyrimidine derivatives had no inhibitory effect. The inhibitory action of adenosine and adenine nucleotides on the PSP were manifest at concentrations of 5 microM-1 mM. Adenosine, 5'-ATP, 5'-ADP and 5'-AMP were equipotent in evoking depression of PSPs. Inhibition occurred within 10-20 sec after administration of the agents and the depressant effect disappeared rapidly after the removal of the compounds from the medium. Theophylline reversed and prevented the inhibition produced by adenosine and adenine nucleotides. To test the structure-activity relationships of these compounds, adenosine analogs and adenine nucleotide derivatives were applied to the medium. The 6-aminopurine riboside (adenosine radical) was found to be essential for inhibitory action on the PSP. Among adenosine analogs, the presence of at least one hydrogen atom in the amino group at the 6-position of the purine, and the OH group at the 2'-position of the ribose was essential for inhibitory activity.
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PMID:Inhibitory action of adenosine and adenosine analogs on neurotransmission in the olfactory cortex slice of guinea pig - structure-activity relationships. 624 64

The effects of a series of purine nucleosides, including the novel marine natural product 1-methylisoguanosine, have been examined on muscle relaxation in conscious animals and on spinal reflexes and neuromuscular transmission in mice anaesthetized with sodium pentobarbitone. 1-Methylisoguanosine (5--15 mumol kg--1) and 2-chloroadenosine (1--5 mumol kg--1), both of which cause muscle relaxation in conscious animals, depressed both mono- and polysynaptic spinal reflexes but did not affect neuromuscular transmission. At much higher doses (300 mumol kg--1) both compounds did depress neuromuscular transmission. Adenosine and 1-methyladenosine did not produce muscle relaxation in conscious animals and only slightly depressed polysynaptic reflexes at the highest doses tested (300 mumol kg--1). Theophylline 50 mumol kg--1 enhanced polysynaptic reflexes and antagonized the depression of these reflexes by 1-methylisoguanosine. Neither adenosine nor 1-methylisoguanosine affected the development of tension by isolated diaphragm muscles in vitro. It is concluded that the muscle relaxant purine nucleosides 2-chloroadenosine and 1-methylisoguanosine produce their effects primarily by depressing activity in the central nervous system. Transmission at the neuromuscular junction is not affected at doses in the range of those producing muscle relaxation.
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PMID:The site of action of muscle relaxant purine nucleosides. 626 99

1 Drug actions on electrical and mechanical properties of smooth muscle cells and neuromuscular transmission in the canine cerebral arteries were investigated by use of microelectrode and isometric tension recording methods. 2 In the basilar and middle cerebral arteries, the resting membrane potentials were--49.4 mV and -51.7 mV, respectively, the length constants 0.57 mm and 0.45 mm, respectively and the time constants 142 ms and 118 ms, respectively. 3 Outward current pulses did not evoke the spike in either artery but did evoke the spike under conditions of pretreatment with 10 mM tetraethylammonium (TEA). 4 The maximum slope of depolarization produced by a ten fold increase in [K]o plotted on a log scale was 40.1 mV in the basilar artery and 42.2 mV in the middle cerebral artery. 2-Nicotinamidoethyl nitrate, the K-permeability accelerator, had no effect on the membrane potential. 5 K-free or ouabain [10(-5)M] treatment slightly depolarized the membrane. Re-addition of K [5.9 mM] hyperpolarized the membrane by several mV. Thus, the contribution of an active Na-K pump in the membrane potential seems to be small. 6 In both arteries, acetylcholine, adenosine, noradrenaline and isoprenaline in concentrations up to 10(-5)M did not modify the membrane potential and resistance, while 5-hydroxytryptamine (over 10(-8)M) and ATP (over 10(-5)M) depolarized the membrane, decreased the membrane resistance and produced a dose-dependent contraction. Adenosine suppressed the contraction evoked by excess [K]o (39.8 mM). 7 Perivascular nerve stimulation produced excitatory junction potentials (e.j.ps). Often e.j.ps were followed by a hyperpolarization. Repetitive stimulation produced facilitation after several stimuli and depression followed. In some cells, this depression appeared without facilitation. 8 The e.j.ps ceased with pretreatment with guanethidine (10(-6)M) or tetrodotoxin (3 X 10(-7)M), while phentolamine (10(-7)M) and yohimbine (10(-7)M) enhanced the amplitude of e.j.ps. ATP (10(-5)M) and noradrenaline (10(-6)M) suppressed and prazosin had little effect on the e.j.ps. Atropine (10(-6)M) also had no effect on the e.j.ps. 9 Specific features of the cerebral artery and systemic vascular beds were compared, and the features of adrenoceptors on the smooth muscle membrane were compared with findings in other vascular beds.
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PMID:Membrane properties and excitatory neuromuscular transmission in the smooth muscle of dog cerebral arteries. 629 82

The electrical activity of transverse slices of hippocampus was used as a bioassay in which extracts of fresh brain tissue were screened for biological activity. A factor that depressed synaptic transmission was identified as nicotinamide adenine dinucleotide (NAD). This depressant action of NAD could be observed at concentrations in the range 1-10 microM and the degree of depression was monotonically related to the concentration of NAD in the bathing medium. NAD did not affect the antidromic invasion of the granule cells nor did it alter the relationship between the electrically evoked excitatory postsynaptic field potential (e.p.s.p.) and the population discharge of the granule cells (population spike). These results suggest that NAD did not affect the electrical excitability of the neuronal membranes. NAD had little effect on the sensitivity of granule cells to iontophoretically applied L-glutamate, the putative excitatory transmitter for the perforant path-granule cell pathway. Pure synaptosomal membranes, free of mitochondria, had two binding sites for NAD: a high affinity site with a Kd of 1 microM and a low affinity site with a Kd of 17 microM. These sites were similar in affinity to those of mitochondria, although the density of the high affinity sites was 5 X greater in the synaptosomal membranes. Adenosine had a relatively weak affinity for the NAD binding sites. It was concluded that NAD probably depressed synaptic transmission in the dentate gyrus by binding to sites on the presynaptic nerve terminal and reducing the amount of transmitter released by a nerve impulse. The physiological significance of this view is discussed.
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PMID:Nicotinamide adenine dinucleotide depresses synaptic transmission in the hippocampus and has specific binding sites on the synaptic membranes. 631 13

The effect of adenosine on intraparenchymal cerebral blood flow was examined in conscious rabbits with the 133Xe clearance technique. Perivascular application of 10(-3) and 10(-4) M adenosine to hypothalamic blood vessels increased hypothalamic blood flow by approximately 50% (p less than 0.005). This vasodilatation was attenuated by the intrahypothalamic injection of the beta-adrenergic receptor antagonist propranolol, but was unaffected by alpha-adrenoreceptor blockade with phenoxybenzamine, or depression of neuronal activity with barbiturate. 2-Chloroadenosine, a stable analogue of adenosine, also increased hypothalamic blood flow by 50% (p less than 0.005), but this dilatation was unaffected by propranolol. These results suggest that adenosine increased hypothalamic blood flow at high concentrations by vascular receptor systems dependent on adenosine receptors and adrenergic receptors. Adenosine (10(-6) M) reduced hypothalamic blood flow by approximately 25% (p less than 0.005). This vasoconstriction was unaffected by adrenergic blockade with propranolol or phenoxybenzamine, or by inhibition of neuronal activity with barbiturate. The results suggest that adenosine decreases hypothalamic blood flow at low concentrations by stimulation of adenosine receptors associated with vascular smooth muscle.
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PMID:Adenosine causes dilatation and constriction of hypothalamic blood vessels. 663 Mar 23

The Warburg method was used to study the action of adenosine on several phases of rat cerebral cortex metabolism, using cortex slices or homogenates. In the presence of exogenous glucose in vitro, oxygen consumption and lactate production are not affected by adenosine in sections. In vivo, there is an increase of oxygen consumption and of lactate production but which are not significant. Adenosine may activate metabolic pathways, since the observed metabolic changes remain constant during the period of activity of adenosine (30 to 60 min) and disappear concomitantly with adenosine. The action of adenosine is much more evident in sections from the brains of injected animals, where the increase of lactate production becomes significant. This suggests that in this case adenosine favors a better utilization of glycogen via an activation of adenylate cyclase. The increased activity of G-6-PDH was observed in vitro but was not significant in vivo. These observations were confirmed with homogenates from the in vivo series by the significant decrease of inorganic phosphate levels, consistent with an increased formation of nucleotide phosphates. The increased cerebral glucose concentration is perhaps a result of increased blood glucose levels, in turn resulting from the known depression of insulin release by adenosine, or from a preferential utilization of glycogen, resulting from the activation of adenylate cyclase.
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PMID:Action of adenosine on energy metabolism and on glucose-6-phosphate dehydrogenase in rat brains. 672 44

The effects of coformycin, a highly potent and specific inhibitor of the intracellular enzyme adenosine deaminase and the influence of dipyridamole, an inhibitor of the cellular adenosine uptake mechanism, were studied on the adenosine-induced changes in the electrical and mechanical activity of isolated electrically driven left atria of guinea-pig hearts. Adenosine (0.1 mumol/l-1 mmol/l) by itself elicited a concentration-dependent decrease in the action potential duration and contractile force of atrial preparations. Coformycin, when applied in a concentration inducing a nearly complete inhibition of adenosine deaminase activity in intact atrial myocardium (7 mumol/l), enhanced the adenosine-induced reduction both in the duration of the intracellularly recorded action potential and in the contractile force of the atria, preferentially at higher concentrations of adenosine (10 mumol/l-1 mmol/l). The calculated half recovery time during wash-out (t1/2) was found to be about 6 times longer than that of controls (317.5 +/- 47 and 51.3 +/- 4.3 sec, respectively). In contrast with adenosine, the action of 2-chloroadenosine (an adenosine deaminase resistant purine derivative) on the atrial contractile force was not affected in the presence of coformycin. Dipyridamole (0.3 mumol/l) was capable of significantly potentiating the adenosine-induced depression of atrial mechanical activity, mainly at lower concentrations of adenosine (0.1-10 mumol/l). Preincubation of atrial preparations with a combination of coformycin and dipyridamole produced a strong enhancement in the adenosine-induced decrease of mechanical activity at all concentrations of adenosine. It is suggested that adenosine might exert its myocardial actions not only through the known extracellular, but also via possible intracellular purinoceptors.
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PMID:Potentiation of the myocardial actions of adenosine in the presence of coformycin, a specific inhibitor of adenosine deaminase. 710 13

It can be readily shown in vitro that various compounds inhibit platelet aggregation but it has been difficult to demonstrate in vivo. A method is suggested here to enable in vivo testing of these compounds; the method utilizes relatively low doses of sodium arachidonate, made possible by the ligation of the pterygopalatine artery. Adenosine, ATP and sulfinpyrazone, agents known to inhibit platelet aggregation in vitro, were effective in varying degrees in inhibiting in vivo platelet aggregating response as suggested by their ability to antagonize arachidonate-induced EEG depression.
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PMID:Modification by antiplatelet drugs of acute EEG changes induced in the rat by sodium arachidonate. 738 90

This study extends previous investigations into the effect of adenosine on bicuculline-resistant paired-pulse inhibition between field potentials evoked 300 ms apart in the CA1 area of the rat hippocampal slice. A direct assessment of the effect of adenosine on paired-pulse inhibition is complicated by the facts that adenosine directly depresses evoked potentials and bicuculline-resistant paired-pulse inhibition is greater between pairs of small potentials than between pairs of larger potentials. Adenosine increased bicuculline-resistant paired-pulse inhibition when stimulus strength was constant between adenosine and control but paired-pulse inhibition of responses in adenosine was markedly less than paired-pulse inhibition of control responses of the same size. Furthermore, adenosine decreased the size of conditioned potentials to a significantly lesser extent than unpaired potentials of the same initial size. Taken together the results indicate that adenosine can decrease bicuculline-resistant paired-pulse inhibition in the hippocampus. A possible mechanism for this effect is that adenosine is suppressing transmission at excitatory terminals onto interneurones which would suggest that these receptors are more sensitive to adenosine than those on the Schaffer collateral/CA1 pyramidal cell synapses. In this case adenosine should reduce paired-pulse inhibition at lower concentrations than are required for depression of single evoked potentials. A comparison of the concentration-response relationships for the effects of adenosine on paired-pulse inhibition and on single evoked potentials ruled out greater sensitivity of adenosine receptors at excitatory terminals onto interneurones as an explanation for adenosine's action on bicuculline-resistant paired-pulse inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of adenosine on bicuculline-resistant paired-pulse inhibition in the rat hippocampal slice. 755 Jun 16


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