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

The behavioral profile of a range of adenosine receptor ligands was examined in rats using a locomotor activity model. Adenosine receptor agonists, including the selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) and the A2A agonist, 2-[(2-aminoethylamino)carbonylethyl-phenylethylamino]- 5'-ethylcarboxa midoadenosine (APEC), reduced spontaneous motor activity in a dose-dependent manner. CPA-induced locomotor depression was attenuated by adenosine A1 receptor selective antagonists, such as 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-2-piperidine ethanol (FK453), and (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-piperidin-2-yl acetic acid (FK352), but not by the A2A receptor antagonist, (E)-1,3-dipropyl-8-(3, 4-dimethoxystyryl)-7-methylxanthine (KF17837). By contrast, APEC-induced hypolocomotion was attenuated by KF17837 but not by DPCPX, confirming that adenosine A1 and A2A receptor activation mediates locomotor output independently. It was found that two peripheral adenosine receptor antagonists, 8-(p-sulphophenyl)-1, 3-dipropylxanthine (DPSPX) and 8-(p-sulphophenyl)-1, 3-dimethylxanthine (8-PST), did not alter CPA-induced hypolocomotion. This confirmed that pharmacological reversal of the adenosine A1 receptor-mediated response involved a central site of drug action. The relationship between occupancy of central adenosine A1 receptors and behavioral effect was therefore assessed. Regression analysis on log transformed data confirmed associations between antagonist affinity for brain [3H]DPCPX binding sites and, in order of increasing significance, the equivalent behavioral dose (EBD) for reversal of CPA-induced hypolocomotion (r2 = 0.32), the serum concentration of drug (r2 = 0.65), and most significantly with the brain concentration of drug detected 20 min after administration of the (EBD) (r2 = 0.95). These data suggest that competition between agonists and antagonists, for occupancy of central adenosine A1 receptors, is intrinsic to the pharmacological reversal of CPA-induced hypolocomotion. The validity of the model as a simple predictive screen for the blood/brain barrier permeability of adenosine A1 receptor antagonists was thereby confirmed.
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PMID:Pharmacological characterization of a simple behavioral response mediated selectively by central adenosine A1 receptors, using in vivo and in vitro techniques. 961 4

Using sharp-electrode intracellular recordings, we studied the dopaminergic facilitation of synaptic plasticity in layer I-II afferents--layer V neuron glutamatergic synapses in rat prefrontal cortex in vitro. Tetanic stimulation (100 pulses at 50 Hz, four times at 0.1 Hz) to layer I-II afferents induced N-methyl-D-aspartate receptor-independent long-term depression (>40 min) of the glutamatergic synapses when the stimulation was coupled with a bath-application of dopamine. Tetanic stimulation alone did not induce lasting synaptic changes. Dopamine application alone transiently depressed synaptic responses, which fully recovered within 30 min. Pharmacological analyses with antagonists suggested that dopamine action on either D1-like or D2-like receptors can facilitate the induction of long-term depression. However, results with agonists were not fully consistent with the antagonist results: while a D2 agonist mimicked the facilitatory dopamine effect, D1 agonists failed to mimic the effect. We also analysed the synaptic responses during tetanus and found that dopamine prolongs membrane depolarization during high-frequency inputs. Postsynaptic membrane depolarization is indeed critical for long-term depression induction in the presence of dopamine, since postsynaptic hyperpolarization during tetanus blocked the dopaminergic facilitation of long-term depression induction. Postsynaptic injection of the Ca2+ chelator bis-(o-aminophenoxy)-N,N,N',N'-tetra-acetic acid (100 mM in the electrode) also blocked long-term depression induction. Our results show that dopamine lowers the threshold for long-term depression induction in rat prefrontal glutamatergic transmission. A possible underlying mechanism of this dopaminergic facilitation is the enhancement of postsynaptic depolarization during tetanus by dopamine, which may increase the amount of Ca2+ entry from voltage-gated channels to the level sufficient for plasticity induction.
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PMID:Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex. 963 64

The pharmacological properties of (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) were evaluated on GABA(B) receptors in rat neocortical slices. The GABA(B) receptor agonist, baclofen, produced a concentration-dependent depression of the frequency of spontaneous discharges in slices maintained in Mg2+-free Krebs medium with an EC50 of 6 microM, reversibly antagonised by Sch 50911 (5, 10 and 25 microM) with an apparent pA2 of 6.0 +/- 0.1. The (-) enantiomer Sch 50910 (500 microM) and the racemic des-methyl analogue Sch 48588 (500 microM) were inactive. In slices preloaded with [3H]GABA, Sch 50911 antagonised GABA(B) autoreceptors, increasing the electrically-stimulated 3H overflow in a concentration-dependent manner, with an IC50 of 3 microM. The maximal effect (148 +/- 10.5%) was found at 10 microM, but at 50 microM the response was reduced to 67 +/- 19%. In contrast, evoked release was unaffected by Sch 50910 (100 microM) whilst Sch 48588 at 100 microM increased the overflow by 51.3 +/- 11.6%. In summary, Sch 50911 is a relatively potent antagonist of considerable potential in studies of GABA(B) receptor function.
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PMID:The morpholino-acetic acid analogue Sch 50911 is a selective GABA(B) receptor antagonist in rat neocortical slices. 986 27

The authors studied the effect of two modified steroids containing different proportions (%) of alkylating agents alone or in combination on sister chromatid exchange (SCE) rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The two chemicals in mixtures enhance SCE induction and antitumor activity in a synergistic manner. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenyl acetic acid was found to be more effective than the homo-aza-steroidal ester of o-bis(2-chloroethyl)aminobenzoic acid in causing cytogenetic damage and antineoplastic activity. A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The order of the antitumor effectiveness of the five different treatments tested coincided with the order of the cytogenetic effects they induced.
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PMID:Enhanced cytogenetic and antineoplastic effects by the combined action of two esteric steroidal derivatives of nitrogen mustards. 987 11

Epidemiological studies have shown that cigarette smoking is associated with peptic ulceration. This study aims to investigate the mechanisms by which cigarette smoking delays ulcer healing in rats. Gastric ulcers were induced by applying acetic acid to the luminal surfaces in rats. Twenty-four hours later, rats were exposed to different concentrations of cigarette smoke (0, 2, or 4%) for a 1-h period once daily for 3 or 6 days. Cigarette smoke exposure delayed ulcer healing and decreased gastric blood flow and angiogenesis at the ulcer margin. These changes were accompanied by a significant reduction of constitutive nitric oxide synthase (cNOS) activity but not PGE2 production and vascular endothelial growth factor levels. Administration of L-arginine (10 mg/kg iv) completely reversed the adverse actions on ulcer healing, gastric blood flow, and angiogenesis in the mucosa at the ulcer margin but partially restored angiogenesis in granulation tissues. In conclusion, cigarette smoke exposure delays ulcer healing through depression of gastric blood flow and angiogenesis at the ulcer margin. Reduction of cNOS expression and activity is suggested to be involved in these ulcerogenic processes.
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PMID:Cigarette smoking delays ulcer healing: role of constitutive nitric oxide synthase in rat stomach. 988 1

In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen depressed the rate of spontaneous discharges in a concentration-dependent manner (EC50 = 4.5 microM). This depression was reversibly antagonised by 5-(S,R)-hydroxymethyl-5-methylmorpholinyl-2-(R,S)-acetic acid (Sch 54679) and 2-(R,S)-5-[spirocyclopentyl]-morpholinyl-acetic acid (Sch 51324) (respective pA2 values of 5.8+/-0.15 and 5.4+/-0.2). In electrically-stimulated slices preloaded with [3H]gamma-aminobutyric acid (GABA), Sch 54679 (EC50 = 3 microM) was 2.3 times more potent than Sch 51324 (EC50 = 7 microM) in increasing [3H]GABA release through antagonism of GABA(B) autoreceptors. These structurally novel analogues may be pharmacologically useful for elucidating GABA(B) receptor functions.
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PMID:Antagonism of GABA(B) receptors by morpholino-2-acetic acid derivatives Sch 54679 and Sch 51324 in rat brain. 1020 78

Tramadol is a widely-used analgesic for pre- and post-operative pain which has a different pharmacological profile to that of classical opioids, since it does not induce respiratory depression, constipation, sedation, tolerance or dependence. However, tramadol frequently produces nausea and vomiting as side-effects. In the present study, the interactions between tramadol and several adrenergic and serotonergic compounds with antinociceptive activity were studied by isobolographic analysis. Antinociceptive activity was evaluated using the acetic acid writhing test in mice. Dose-response curves for the antinociceptive effect of tramadol, prazosin, clonidine, xylamine, clomipramine and cyproheptadine were obtained, and ED(50)s were calculated for isobolographic analysis, which was performed by administration of fixed-ratios of tramadol with each of these drugs, given both systemically and intrathecally. The isobolograms of all combinations tested, either systemically or intrathecally showed superadditivity. The synergies observed with these combinations suggest a complex modulation of the descending noradrenergic and serotonergic systems that exert inhibitory influences on the transmission of nociceptive information, probably in addition to effects on receptors in the primary neurons of the spinal cord. The co-administration of analgesic drugs that produce superadditive effects constitutes a significant new avenue for the treatment of pain, since a similar level of antinociception can be obtained with considerable reductions in the dose of each analgesic. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.
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PMID:Interactions in the antinociceptive effect of tramadol in mice: an isobolographic analysis. 1070 Mar 29

In rat neocortical slices maintained in Mg2+-free Kreb's medium, the effects of Ca2+ concentration on repetitive spontaneous discharges and on GABA(B) receptor-mediated responses were investigated. Over a concentration range of 0.3-2.4 mM Ca2+, there was a reduction of discharge amplitude, with a 50 +/- 6.5% reduction in 0.3 mM Ca2+, whilst the burst frequency remained unaffected. Baclofen, the GABA(B) receptor agonist, produced a concentration-dependent depression of discharge frequency, reversibly antagonised by the antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911). The EC50 value for baclofen in 2.4 mM Ca2+ was 11 microM, while the EC50 values in 0.3, 0.6, 1.2, and 1.8 mM Ca2+ were 1.3, 2.5, 3.6, and 10 microM, respectively, resulting in 8.5, 4.4, 3.1, and 1.1-fold leftward shifts. This enhanced action of baclofen in low extracellular Ca2+ concentrations in the neocortex may be the result of a lower concentration gradient which reinforces the action of baclofen.
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PMID:Effects of Ca2+ concentration on GABA(B) receptor function in rat neocortical slices. 1091 41

The present study was performed to analyse the structure of non-digested and digested collagen type I molecules by atomic force microscopy (AFM). Collagen type I molecules from the bovine skin were diluted with 0.05 N acetic acid, spread on a mica plate, air-dried and observed by non-contact mode AFM in air. Collagen molecules digested with Clostridium histolyticum collagenase were also examined by AFM. Intact collagen type I molecules were observed as twisted threads ranging mainly between 280 and 310 nm in length. The surface of the molecules was uneven and both ends usually slightly bulged like a globule. Depressions on the molecules were found throughout the length, and were most prominent approximately 70 nm from one end of the molecules. The collagenase-treated collagen molecules were degraded into fragments with various lengths, which corresponded to the data from sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The end of these fragments often appeared like a tuft, suggesting that the triple-helix unraveled at these regions.
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PMID:Atomic force microscopy of intact and digested collagen molecules. 1110 30

Accumulating evidence indicates that capsaicin sensitive afferent fibers play a pivotal role not only in gastroprotection but also in ulcer healing. Denervation of capsaicin sensitive afferent fibers exerts an adverse action on these effects. However, whether such an action is mediated through a depression on epidermal growth factor (EGF) is undefined. In this study, the effects of denervation of sensory neurons with capsaicin (100 mg/kg, s.c.) on acetic acid-induced chronic gastric ulcers and their relationship with the EGF expression in salivary glands, serum and gastric mucosa were investigated. Capsaicin significantly increased ulcer size, decreased gastric mucosal cell proliferation at the ulcer margin, angiogenesis in the granulation tissue and also gastric mucus content. Ulcer induction by itself dramatically elevated EGF levels in salivary glands and serum on day 1 and 4, and also in the gastric mucosa on day 4. However, capsaicin completely abolished these effects. It is concluded that stimulation of EGF expression in salivary glands and serum may be one of the mechanisms by which capsaicin sensitive nerves contribute to the gastroprotective and ulcer healing actions in the stomach.
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PMID:Role of capsaicin sensory nerves and EGF in the healing of gastric ulcer in rats. 1121 Jul 23


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