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      EFECTO DE LA ADMINISTRACIÓN INTRACEREBRAL DE MK-801 Y (-) NICOTINA EN LAS CONCENTRACIONES EXTRACELULARES DE GLU Y GABA EN EL NÚCLEO PEDUNCULOPONTINO DE RATAS Translated title: Effect of the Mk801 and (-) Nicotine Intracerebral Administration on Glu and Gaba Extracellular Concentration in the Pedunculopontine Nucleus from Rats

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          Abstract

          Aunque la manipulación farmacológica de los sistemas glutamatérgico y colinérgico se ha tratado en modelos experimentales de enfermedad de Parkinson (EP), pocos autores han realizado estudios de esta temática a nivel del núcleo pedunculopontino (NPP). El presente trabajo aborda los cambios en las concentraciones extracelulares (CE) de glutamato (Glu) y ácido δ-amino butírico (GABA) en el NPP de ratas hemiparkinsonizadas por inyección de 6-hidroxidopamina (6-OHDA) y sometidas a infusión local de MK-801 (10 µmol/L) o (-) nicotina (10 mM). La infusión se realizó mediante microdiálisis cerebral y la determinación de CE de neurotransmisores se realizó a través de cromatografía líquida de alta resolución acoplada a detección de fluorescencia. La infusión de MK-801 en el NPP produjo disminución significativa de CE de Glu (p< 0,01) y de GABA (p < 0,01) en ratas hemiparkinsonizadas y controles. La infusión de (-) nicotina mostró un incremento significativo de CE de Glu (p < 0,001) y GABA (p< 0,001) en el NPP de ratas hemiparkinsonizadas y controles. El bloqueo local de receptores NMDA por MK-801 facilita la interacción de Glu con sus receptores metabotrópicos que participan en mecanismos de inhibición presináptica y bloquean la liberación de neurotransmisores. Mientras que la infusión de nicotina en el NPP suma los efectos de activación de los receptores nicotínicos a los cambios conocidos en la neurotransmisión glutamatérgica y gabaérgica en el NPP en parkinsonismo. La infusión de fármacos glutamatérgicos y colinérgicos en el NPP, impone un reajuste a la neurotransmisión a este nivel que se añade a los cambios neuroquímicos asociados a denervación dopaminérgica.

          Translated abstract

          Although the pharmacological manipulation of the glutamatergic and cholinergic systems have been studied in animal models of Parkinson´s disease (PD), only some authors have done work on this topic at the pedunculopontine nucleus (PPN). The present work studied the changes in glutamate (Glu) and δ-aminobutyric acid (GABA) extracellular concentrations (EC) in the PPN from hemiparkinsonian rats by 6hydroxydopamine injection. The rats were locally perfused by MK-801 (10 µmol/L) or (-) nicotine (10 mM) solutions by cerebral microdyalisis. The biochemical studies were carried out through high performance liquid chromatography coupled to fluorescence detection. MK-801 infusion induced a significant decrease of Glu (p< 0.01) and GABA (p< 0.01) EC in PPN. On the other hand (-) nicotine infusion induced a significant increase of Glu (p< 0.001) and GABA (p< 0.001) EC in PPN from hemiparkinsonian rats. The local blockade of NMDA receptors by MK-801 infusion facilitates the interaction between Glu and their metabotropic receptors that take part in presynaptic inhibition mechanisms and interfere with neurotransmitters release. Meanwhile, the nicotine infusion sums the effects of nicotinic receptor activation with the glutamatergic and gabaergic neurotransmission changes produced in the PPN in the parkinsonian condition. The cholinergic and glutamergic drug infusion in PPN impose a new adjustment to the neurotransmition at this level that is added to the neurochemical changes associated to dopaminergic denervation.

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          Most cited references52

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          Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

          Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.
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            Dopamine receptor signaling.

            The D1-like (D1, D5) and D2-like (D2, D3, D4) classes of dopamine receptors each has shared signaling properties that contribute to the definition of the receptor class, although some differences among subtypes within a class have been identified. D1-like receptor signaling is mediated chiefly by the heterotrimeric G proteins Galphas and Galphaolf, which cause sequential activation of adenylate cyclase, cylic AMP-dependent protein kinase, and the protein phosphatase-1 inhibitor DARPP-32. The increased phosphorylation that results from the combined effects of activating cyclic AMP-dependent protein kinase and inhibiting protein phosphatase 1 regulates the activity of many receptors, enzymes, ion channels, and transcription factors. D1 or a novel D1-like receptor also signals via phospholipase C-dependent and cyclic AMP-independent mobilization of intracellular calcium. D2-like receptor signaling is mediated by the heterotrimeric G proteins Galphai and Galphao. These pertussis toxin-sensitive G proteins regulate some effectors, such as adenylate cyclase, via their Galpha subunits, but regulate many more effectors such as ion channels, phospholipases, protein kinases, and receptor tyrosine kinases as a result of the receptor-induced liberation of Gbetagamma subunits. In addition to interactions between dopamine receptors and G proteins, other protein:protein interactions such as receptor oligomerization or receptor interactions with scaffolding and signal-switching proteins are critical for regulation of dopamine receptor signaling.
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              Desensitization of nicotinic ACh receptors: shaping cholinergic signaling.

              Nicotinic ACh receptors (nAChRs) can undergo desensitization, a reversible reduction in response during sustained agonist application. Although the mechanism of desensitization remains incompletely understood, recent investigations have elucidated new properties underlying desensitization, indicating that it might be important to control synaptic efficacy, responses to cholinergic agents, and certain nAChR-related disease states. Thus, studying how different nAChR subunits contribute to desensitization might help to explain variations in responsiveness to drugs, and might thus improve their therapeutic applications. Agonist-specific desensitization, desensitization arising from resting receptors, natural mutations dramatically altering desensitization, and the possibility that recovery from desensitization is an important process for modulating receptor function, together provide a new framework for considering desensitization as a target to shape cholinergic signaling.
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                Author and article information

                Journal
                abc
                Acta Biológica Colombiana
                Acta biol.Colomb.
                Universidad Nacional de Colombia, Facultad de Ciencias, Departamento de Biología (Bogotá, Cundinamarca, Colombia )
                0120-548X
                April 2011
                : 16
                : 1
                : 61-76
                Affiliations
                [01] Ciudad Habana orgnameCentro Internacional de Restauración Neurológica (CIREN) Cuba
                [03] Habana orgnameGrupo de Investigación Modelos Experimentales para las Ciencias ZooHumanas orgdiv1Universidad del Tolima Cuba lisette.blanco@ 123456infomed.sld.cu
                [02] Ciudad Habana orgnameCentro Comunitario de Salud Mental Cuba
                Article
                S0120-548X2011000100004 S0120-548X(11)01600104
                66aaaf21-60b5-4d61-b25b-a1e429624b19

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

                History
                : 15 October 2010
                : 10 September 2010
                : 03 February 2011
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 53, Pages: 16
                Product

                SciELO Colombia

                Self URI: Texto completo solamente en formato PDF (ES)
                Categories
                Artículos

                MK-801,Nicotine,Pedunculopontine nucleus,Glutamate,GABA,nicotina,núcleo pedunculopontino,glutamato

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