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New insights into the circuitry underlying levodopa-induced dyskinesia in rodent models of Parkinson's disease
No full textAbnormal involuntary movements (AIMs) or dyskinesias are probably the most debilitating side-effect elicited by levodopa pharmacotherapy of Parkinson’s disease. Development of levodopa-induced dyskinesias (LID) reflects a processes of sensitization to levodopa taking place primarily in striatum, and leading to the abnormal response to dopaminomimetics. Despite the growing knowledge about the intracellular pathways involved in the development of LID, little is known about the impact of antidyskinetic treatments on the basal ganglia circuitry. In the present thesis, we used microdialysis to investigate the neurochemical and behavioural changes exerted by different antidyskinetic treatments or approaches in basal ganglia. We first found that levodopa evoked AIMs, and simultaneously elevated GABA levels in the substantia nigra reticulata but not globus pallidus of dyskinetic mice and rats, suggesting the involvement of the striato-nigral “direct” GABAergic pathway in both species (Bido et al., J Neurochem 118, 1043-1055, 2011). Amantadine (the only antidyskinetic drug marketed for treating LID) attenuated AIMs expression and prevented the nigral GABA rise (Bido et al., J Neurochem 118:1043-55, 2011), suggesting nigral GABA as a neurochemical correlate of LID. To further investigate which pathway is involved in LID and in the antidyskinetic effect of amantadine, we took advantage from recent studies showing the specificity of Ras-guanine nucleotide-releasing factor 1 and 2 to selectively couple NR2B and NR2A NMDA receptor subunits, respectively. We showed that blockade of striatal expression of Ras-GRF1 using a lentiviral vector carrying a short hairpin RNA (LV Ras-GRF1) caused an attenuation of LID development and expression, which was accompanied by the lack of the increase in nigral GABA. However, in LV Ras-GRF1 mice the antidyskinetic effect of amantadine and its neurochemical correlates were lost, suggesting LV Ras-GRF1 might interfere with the antidyskinetic effect of amantadine by acting on the same target (possibly the NR2B receptor). Conversely, injection of a viral construct expressing a small hairpin directed against RasGRF2 caused only a not significant reduction of LID, and did not prevent the increase of nigral GABA following L-DOPA. In these mice, also the antidyskinetic effect of amantadine remained unaltered (Bido et al., in preparation).
To confirm the involvement of the direct pathway in LID, and dissect out the role of striatal and nigral dopamine D1 and D2 receptors we performed regional perfusion (striatum and substantia nigra pars reticulata) of selective D1 and D2 antagonists simultaneously with systemic L-DOPA
administration. Intrastriatal blockade of D1 receptor attenuated LID and prevented the accompanying rise of nigral GABA levels whereas blockade of D2 receptor was ineffective (Mela et al., Neurobiol Dis 45, 574-583, 2012). When perfused in the substantia nigra, both the D1 and D2 antagonists attenuated LID expression, although only the D1 antagonist prevented the GABA rise.
Overall, the data provide neurochemical evidence that LID is accompanied by activation of D1-receptor expressing striato-nigral GABAergic neurons, and that the antidyskinetic effect of amantadine partly relies on the modulation of this pathway, possibly through NR2B-subunit expressing NMDA receptors. Nonetheless, by using different antidyskinetic approaches we were able to cause only ~50% reduction of LID in face of a complete inhibition of the GABA rise in substantia nigra. This points to the existence of other important neurochemical modulators of LID, possibly also in brain structures outside the basal ganglia
Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels
No full textAmantadine is the only drug marketed for treating levodopa-induced dyskinesia. However, its impact on basal ganglia circuitry in the dyskinetic brain, particularly on the activity of striatofugal pathways, has not been evaluated. We therefore used dual probe microdialysis to investigate the effect of amantadine on behavioral and neurochemical changes in the globus pallidus and substantia nigra reticulata of 6-hydroxydopamine hemi-lesioned dyskinetic mice and rats. Levodopa evoked abnormal involuntary movements (AIMs) in dyskinetic mice, and simultaneously elevated GABA release in substantia nigra reticulata (∼3-fold) but not globus pallidus. Glutamate levels were unaffected in both areas. Amantadine (40 mg/kg, i.p.), ineffective alone, attenuated (∼50%) AIMs expression and prevented the GABA rise. Moreover, it unraveled a facilitatory effect of levodopa on pallidal glutamate levels. Levodopa also evoked AIMs expression and a GABA surge (∼2-fold) selectively in the substantia nigra of dyskinetic rats. However, different from mice, glutamate levels rose simultaneously. Amantadine, ineffective alone, attenuated (∼50%) AIMs expression preventing amino acid increase and leaving unaffected pallidal glutamate. Overall, the data provide neurochemical evidence that levodopa-induced dyskinesia is accompanied by activation of the striato-nigral pathway in both mice and rats, and that the anti-dyskinetic effect of amantadine partly relies on the modulation of this pathway. © 2011 International Society for Neurochemistry
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson’s disease: a behavioral and neurochemical study in reserpinized mice
No full textThe contribution of nociceptin/orphanin FQ (N/OFQ) to reserpine-induced parkinsonism was evaluated in mice. A battery of motor tests revealed that reserpine caused dose-dependent and long-lasting motor impairment. Endogenous N/OFQ sustained this response since N/OFQ peptide (NOP) receptor knockout (NOP-/-) mice were less susceptible to the hypokinetic action of reserpine than wild-type (NOP+/+) animals. Microdialysis revealed that reserpine elevated glutamate and reduced GABA levels in substantia nigra reticulata, and that resistance to reserpine in NOP-/- mice was accompanied by a milder increase in glutamate and lack of inhibition of GABA levels. To substantiate this genetic evidence, the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) simultaneously reduced akinesia and nigral glutamate levels in reserpinized NOP+/+ mice, being ineffective in NOP-/- mice. Moreover, repeated J-113397 administration in reserpinized mice resulted in faster recovery of baseline motor performance which was, however, accompanied by a loss of acute antiakinetic response. The short-term beneficial effect of J-113397 was paralleled by normalization of nigral glutamate levels, whereas loss of acute response was paralleled by loss of the ability of J-113397 to inhibit glutamate levels. We conclude that endogenous N/OFQ contributes to reserpine-induced parkinsonism, and that sustained NOP receptor blockade produces short-term motor improvement accompanied by normalization of nigral glutamate release
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe 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
In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels
No full textEvidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or 02 receptor blockade on abnormal involuntary movements (AIMS) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMS coincided with a prolonged surge of GABA and glutamate levels in the substantia nigra reticulata. Intrastriatal SCH23390 attenuated the levodopa-induced AIM scores (similar to 50%) and prevented the accompanying neurochemical response whereas raclopride was ineffective. When perfused in the substantia nigra, both antagonists attenuated AIM expression (similar to 21-40%). However, only intranigral SCH23390 attenuated levodopa-induced nigral GABA efflux, whereas raclopride reduced basal GABA levels without affecting the response to levodopa. In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum. (C) 2011 Elsevier Inc. All rights reserved
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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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