329 research outputs found
effects of serotonergic lesions on the striatal high affinity dopamine uptake in rats
Titelblatt, Inhaltsverzeichnis, Lebenslauf
1\. Einleitung
2.1 Literatur Teil 1
2.2 Literatur Teil 2
2.3 Literatur Teil 3
3\. Zielstellung der Arbeit
4\. Material und Methoden
5\. Versuchsauswerung und Statistik
6\. Ergebnisse
7\. Diskussion
8\. Zusammenfassung
9\. Summary
LiteraturverzeichnisInteraktive Regulationsmuster verschiedener Transmissionssysteme sind
grundlegende Mechanismen physiologischer Hirnfunktion. Nicht die Betrachtung
von Transmissionssystemen in ihrer SingularitÀt, sondern der
Untersuchungsansatz, die Funktionsweise des ZNS als interagierendes System zu
verstehen, verspricht eine Weiterentwicklung in der Erkenntnis physiologischer
sowie pathophysiologischer ZusammenhĂ€nge. Bisherige Daten ĂŒber wechselseitige
Beziehungen zwischen dopaminergem und serotonergem Transmissionssystem
verweisen auf eine KomplexitÀt, die mit ihrem klinischem Hintergrund ein
Potential der gegenseitigen Kompensation zentraler Funktionsdefizite erwarten
lÀsst. Mit dem Ziel, diese Interaktion auf Ebene der dopaminergen
Transmissionsregulation im STR genauer zu charakterisieren, ist in
vorliegender Arbeit mit Hilfe in vivo voltammetrischer Methodik die Funktion
des striatalen DAT in Folge einer 5-HT-LĂ€sion untersucht worden.
Aufgabenstellung war, den DAT-vermittelten hochaffinen striatalen DA-Uptake
nach LĂ€sion der kranialen Raphekerne (DRN bzw. MRN) zu ermitteln und einen
möglichen lÀsionsbedingten Effekt in seiner zeitlichen AusprÀgung sowie
AltersabhÀngigkeit darzustellen. Die Untersuchungen wurden an Ratten vom Stamm
Sprague Dawley vorgenommen. Tiere zweier Altersklassen (7 Wochen bzw. 10
Monate) erhielten durch Applikation des Neurotoxins 5,7-DHT in jeweils einen
der kranialen Raphekerne, DRN oder MRN, eine direkte LĂ€sion der
Ursprungsgebiete der zentralen serotonergen Projektion. Nach einem Zeitraum
von einer, drei oder neun Wochen folgte unter Anwendung des voltammetrischen
Verfahrens der CA und nach elektrisch stimulierter Transmitterfreisetzung
(Stimulation des MFB) die Bestimmung der striatalen DA-Clearancerate. Es
wurden Messreihen jeweils vor und nach Blockade der DAT durch den DAT-
Inhibitor GBR 12909 vorgenommen. Im Anschluss an die voltammetrische
Untersuchung wurden die Gehirne perfusionsfixiert und der LĂ€sionserfolg 5-HT-
immunhistochemisch ĂŒberprĂŒft. Die Auswertung des amperometrischen Messsignals
mit Berechnung der Geschwindigkeitskonstanten k [1/s] des hochaffinen
striatalen DA-Uptakes erfolgte auf Grundlage eines kinetischen Modells. Die
Ergebnisse vorliegender Studie verdeutlichen eine AbhÀngigkeit des striatalen
DAT von der serotonergen Funktion. Sowohl bei den jungen, als auch den adulten
Tieren zeigte sich im Vergleich zu ScheinlÀsionen und unbehandelten Kontrollen
eine Verlangsamung des striatalen hochaffinen DA-Uptakes eine Woche nach 5-HT-
LĂ€sion. Bei den Jungtieren, nicht aber bei den Adulten, war dieser Effekt auch
drei Wochen nach LĂ€sionswirkung feststellbar, nach neun Wochen konnte diese
DAT-FunktionsÀnderung bei beiden Altersklassen nicht mehr beobachtet werden.
Die Daten vor und nach Gabe von GBR 12909 verweisen zusÀtzlich auf weitere
regulative Mechanismen, die mit serotonerger LĂ€sion bzw. einer herabgesetzten
DAT-Funktion auftreten. Es hat sich mit den Ergebnissen dieser Studie
bestÀtigt, dass das serotonerge und dopaminerge System in enger Wechselwirkung
bzw. einem AbhÀngigkeitsverhÀltnis zueinander stehen. Die herausragende Rolle
des dopaminergen Systems fĂŒr striatale- und insgesamt BG-Funktionen hebt die
Bedeutung von Erkenntnissen hervor, die mit dem VerstÀndnis regulativer
SteuergröĂen einhergehen. Die AbhĂ€ngigkeit des gezeigten Effektes vom
Tieralter unterstĂŒtzt Studien zu Alterungsprozessen des ZNS, welche verĂ€nderte
anatomische, biochemische und elektrophysiologische Bedingungen beschreiben.
Es liegt daher nahe, dass auftretenden Funktionsstörungen altersabhÀngig
unterschiedliche Regulationsmuster entgegenwirken. Obwohl die Daten dieser
Studie eine umfassende Interpretation des gezeigten Effektes nicht
ermöglichen, kann mit Hintergrund der bisherigen Erkenntnisse zu Interaktionen
beider aminerger Transmittersysteme vermutet werden, dass es sich bei den
VerÀnderungen der DAT-Funktion um eine kompensatorische Leistung des ZNS
handeln könnte, das serotonerge Defizit auszugleichen.The fundamental physiological functions of the brain can be described by
interactive regulation models of various transmission systems. A better
understanding of physiological and pathophysiological connections can be
achieved, if, rather than describing transmissions systems singly, the
functions of the central nervous system are seen as an interactive network.
Previous research on cross-relations between the dopamine and serotonin
transmission systems suggest a complexity, with reciprocal compensation of
functional deficits. The objective of this study was to investigate the
interaction of both transmission systems by characterising regulative
mechanisms of dopaminergic transmission in the striatum. In vivo voltammetry
was used to examine the function of the striatal dopamine transporter (DAT)
after 5,7-dihydroxytryptamine-lesion of the cranial raphe nuclei of Sprague
Dawley rats. The aim was to describe the DAT-mediated high affinity dopamine
uptake after lesions to the dorsal or median raphe nucleus and also to detect
any lesion-related time-dependent or age-dependent effects. Seven and ten
weeks old animals were lesioned with the neurotoxin 5,7-DHT injected in one of
the cranial raphe nuclei to ensure direct lesion of the original areas of
serotonergic projection. The electrically evoked striatal dopamine clearance
was measured one, three or nine weeks after lesion using continuous
amperometry. Measurements were conducted before and after the DAT was blocked
by the DAT-inhibitor GBR 12909. Following the voltammetric investigations
brains were preserved by perfusion, and successful lesions were confirmed by
5-HT immunohistochemistry. A kinetic model was used to calculate the
rateconstante k [1/s] of high affinity dopamine uptake from the measured
amperometric signals. The results of this study demonstrate the dependence of
the striatal DAT on the serotonin function. A slow down of the striatal high
affinity dopamine uptake one week after 5-HT lesion was observed in both,
young and old animals, when compared to sham-lesioned rats and untreated
controls. Young animals, but not adults, showed the same effect three weeks
post-lesion, while no functional DAT-changes were detected after nine weeks.
Measurements taken before and after administration of GBR 12909 also suggest
additional regulatory mechanisms, which appear with serotonergic lesions and
reduced DAT-function. The results of this study show, that the serotonergic
and dopaminergic systems have a close interaction and interdependence. The
importance of the dopamine system for the striatal and general basal ganglia
functions emphasises necessity of understanding regulative control mechanisms.
The demonstrated age-dependent effect is in agreement with studies on aging
processes of the CNS, which describe anatomical, biochemical and
electrophysiological changes. It appears therefore that functional
disturbances are compensated by various regulatory mechanisms, dependent on
age. The data of this study do not allow extensive interpretation. However,
based on the knowledge of the interaction of the serotonin and dopamine
transmission systems, one could suggest that the recorded changes of dopamine
transmission are produced as a compensatory effort of the CNS to balance out
the deficit of central serotonin
Vorgehensmodell zur Informationsgewinnung â Prozessschritte und Methodennutzung -
Bei der modellgestĂŒtzten Analyse von Logistiksystemen umfasst der Aufwand fĂŒr die Informations- und Datenbeschaffungsaufgaben eine nicht zu unterschĂ€tzende GröĂenordnung. Untersuchungen wie beispielsweise [RHe01] weisen fĂŒr Simulationsstudien in Produktion und Logistik darauf hin, dass innerhalb einer Simulationsstudie ĂŒber 30 % des Aufwandes allein auf die Datenbeschaffung entfallen. Andere Autoren (vgl. [KGr95]) geben sogar eine GröĂenordnung von bis zu 50% des gesamten Projektaufwandes als Aufwand fĂŒr die Datenbeschaffung und -aufbereitung an. Hinzu kommt, dass die Simulationsexperten heute kaum methodische UnterstĂŒtzung zur Sicherstellung der QualitĂ€t der zu verwendenden Daten sowie zur Bestimmung ihrer richtigen QuantitĂ€t und GranularitĂ€t erhalten. Entsprechende Checklisten, Regelwerke und Vorgehensmodelle zur gezielten Informationsbeschaffung stehen meist gar nicht oder nur fĂŒr spezifische Anwendungen zur VerfĂŒgung. Diese Situation wird bei der Modellierung von Logistiknetzen noch dadurch erschwert, dass sich die Datenbeschaffung nicht nur auf ein Unternehmen, sondern auf mehrere Unternehmen mit zwangslĂ€ufig heterogenen DatenbestĂ€nden beziehen muss. Ein erstes Vorgehensmodell zur Informationsgewinnung fĂŒr die Modellierung und Simulation (M&S) von Logistiknetzen haben Wenzel und Bernhard bereits in [WBe03] vorgestellt. In diesem Beitrag wurde auch thematisiert, ob die in der Literatur i. d. R. benannte Datenbeschaffung die eigentliche Aufgabe unter methodischen Gesichtspunkten inhaltlich hinreichend umfassend charakterisiert. Die Autoren verweisen in diesem Zusammenhang auf die heute ĂŒbliche Differenzierung zwischen Wissen, Information und Daten (vgl. [NTa97]) und fordern in Analogie zur Modellierung von Entscheidungsprozessen innerhalb des unternehmensinternen Informationsmanagements eine informationstheoretische Betrachtungsweise auch fĂŒr M&S von logistischen Systemen. Detaillierte AusfĂŒhrungen zur Differenzierung der Begriffe Wissen, Information und Daten sind dem Technical Report 05001 [BDW05] zu entnehmen. Informationsgewinnung beinhaltet im Gegensatz zum Datenmanagement eine verĂ€nderte Sichtweise. Im Fokus steht die notwendige, richtige und gĂŒltige Information bezĂŒglich einer Aufgabenstellung; das Datum selbst, d. h. die Codierung der Information spielt eine untergeordnete Rolle. Die Informationsgewinnung erweitert damit das Aufgabenspektrum des Datenmanagements um Aufgaben der Informationsbeschaffung und -bewertung. Nicht mehr die Frage: Welche Daten werden benötigt?? steht im Vordergrund, sondern es muss zunĂ€chst primĂ€r diskutiert werden, wie sich der Informationsbedarf fĂŒr die Aufgabenstellung unter BerĂŒcksichtigung der gewĂ€hlten Modellierungsmethode darstellt. Diese Herangehensweise erlaubt eine Separation zwischen dem Informationsbedarf und der jeweiligen Codierung der Information in Daten und lĂ€sst damit letztendlich eine verbesserte Datenbereitstellung zu
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