1,721,118 research outputs found
L-DOPA promotes striatal dopamine release through D1 receptors and reversal of dopamine transporter
No full textPrevious studies have pointed out that L-DOPA can interact with D1 or D2 receptors independent of its conversion to endogenous dopamine. The present study was set to investigate whether L-DOPA modulates dopamine release from striatal nerve terminals, using a preparation of synaptosomes preloaded with [3H]DA. Levodopa (1 μM) doubled the K+-induced [3H]DA release whereas the D2/D3 receptor agonist pramipexole (100 nM) inhibited it. The L-DOPA-evoked facilitation was mimicked by the D1 receptor agonist SKF38393 (30–300 nM) and prevented by the D1/D5 antagonist SCH23390 (100 nM) but not the DA transporter inhibitor GBR12783 (300 nM) or the aromatic L-amino acid decarboxylase inhibitor benserazide (1 μM). Higher L-DOPA concentrations (10 and 100 μM) elevated spontaneous [3H]DA efflux. This effect was counteracted by GBR12783 but not SCH23390. Binding of [3H]SCH23390 in synaptosomes (in test tubes) revealed a dense population of D1 receptors (2105 fmol/mg protein). Both SCH23390 and SKF38393 fully inhibited [3H]SCH23390 binding (Ki 0.42 nM and 29 nM, respectively). L-DOPA displaced [3H]SCH23390 binding maximally by 44% at 1 mM. This effect was halved by addition of GBR12935 and benserazide. We conclude that L-DOPA facilitates exocytotic [3H]DA release through SCH23390-sensitive D1 receptors, independent of its conversion to DA. It also promotes non-exocytotic [3H]DA release, possibly via conversion to DA and reversal of DA transporter. These data confirm that L-DOPA can directly interact with dopamine D1 receptors and might extend our knowledge of the neurobiological mechanisms underlying L-DOPA clinical effects
Comparison of the binding affinity of CGP-12177A at recombinant rat alpha(1D)-adrenoceptors expressed in BHK-21 cell membranes and alpha(1)-adrenoceptors present in rat cerebral cortex membranes
No full textRecent in vitro studies, performed in rat aorta, mesenteric and intrapulmonary arteries, and human pulmonary artery, demonstrated that the beta-adrenoceptor ligand CGP-12177A (4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one) is also provided with antagonist or partial agonist properties at alpha(1)-adrenoceptors. These observations were supported by estimates of CGP-12177A binding affinity at alpha(1)-adrenoceptors, which have been always performed in rat cerebral cortex membranes, as a surrogate of vascular tissue. Since alpha(1D)-adrenoceptors are predominant in both rat aorta and mesenteric artery, in the present study, we measured, for the first time, the binding affinity of CGP-12177A at recombinant rat alpha(1D)-adrenoceptors expressed in BHK-21 cell membranes. CGP-12177A binding affinity was also determined in rat cerebral cortex membranes, where various alpha(1)-adrenoceptor subtypes are present. By means of [(3)H]prazosin binding competition experiments, we found that CGP-12177A bound to alpha(1D)-adrenoceptor-expressing BHK-21 cell membranes, with a binding affinity (pK(i)=5.39+/-0.27) almost identical to that measured in cerebral membranes (pK(i)=5.44+/-0.07), indicating that it is a non-subtype selective alpha(1)-adrenoceptor ligand. Moreover, CGP-12177A binding affinity was very close to its functional affinity evaluated in rat aorta in terms of antagonist potency against phenylephrine-induced contraction (pK(B)=5.65+/-0.07). In conclusion, our results demonstrate that, in order to evaluate CGP-12177A binding affinity at aorta and mesenteric artery alpha(1)-adrenoceptors, estimates in rat cerebral membranes are as reliable as those in recombinant rat alpha(1D)-adrenoceptors, since both values are very close to CGP-12177A functional affinities in isolated vessels
Targeting adenosine receptors: A potential pharmacological avenue for acute and chronic pain
No full textAdenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A1, A2A, A2B, and A3 adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon A1AR activation located at peripheral, spinal, and supraspinal sites. The role of A2AAR and A2BAR is more controversial since their activation has both pro-and anti-nociceptive effects. A3AR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain
Carteolol, a non-conventional partial agonist of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through antagonism at alpha(1)-adrenoceptors
No full textThis in vitro study was designed to investigate whether carteolol, a non-conventional partial agonists of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through activation of the low-affinity state of beta(1)-adrenoceptors or antagonist effect at alpha(1)-adrenoceptors. Carteolol-induced complete concentration-dependent relaxation of phenylephrine-contracted aorta (pD(2)=3.65+/-0.04), this effect not being modified by endothelium removal and not antagonised by NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (100 microM) or cyclo-oxygenase inhibitor indomethacin (10 microM). The effect of carteolol was unaffected by the non-selective beta-adrenoceptor antagonist propranolol (1 microM), or the beta(2)-adrenoceptor selective antagonist (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551, 1 microM). Increasing concentrations of carteolol produced a parallel rightward shift of the concentration-response curves for phenylephrine-induced contraction, exhibiting a pK(B) of 4.28+/-0.07. Carteolol affinity for alpha(1)-adrenoceptors was evaluated by means of competition experiments carried out in BHK-21 cell membranes expressing rat recombinant alpha(1D)-adrenoceptor, the alpha(1)-adrenoceptor subtype mainly present in rat aorta. Carteolol competed monophasically with [(3)H]prazosin, exhibiting a pK(i) value (3.39+/-0.31) similar to its pD(2) and not very far from its pK(B). In conclusion, this study indicates that carteolol relaxes phenylephrine-contracted aorta through its alpha(1)-adrenoceptor antagonist properties, excluding the possibility that the relaxant effect is due to the activation of beta-adrenoceptors, particularly of the low-affinity state of beta(1)-adrenoceptors, by the drug
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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