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Versuchungsresistenz - Entwicklung eines fMRT-Paradigmas zur Erfassung von Selbstkontrolle und Impulsivität - neuronale Aktivierungsmuster, Persönlichkeit und genetische Faktoren -Wimmer, Lioba 29 February 2016 (has links) (PDF)
Täglich treffen Menschen zahlreiche Entscheidungen. Häufig stellt sich dabei die Frage, ob man einer direkt verfügbaren Versuchung nachgibt oder versucht, ein in der Zukunft liegendes Ziel zu erreichen. Impulsivität und Selbstkontrolle können dabei als konfligierende Persönlichkeitseigenschaften im Entscheidungsprozess gesehen werden.
In der Entscheidungsforschung wird postuliert, dass zwei getrennte Systeme existieren, die bei jeder Wahl berücksichtigt werden: ein eher impulsives und ein reflektives System. Je nach Stärke der Anteile der beiden Systeme werde eine Entscheidung getroffen. Neben behavioralen Theorien haben die Befunde der kognitiven Neurowissenschaften dazu beigetragen, den beschriebenen Systemen relevante Hirnregionen zuzuschreiben: limbische Regionen, vor allem das ventrale Striatum, werden dabei vor allem mit dem impulsiven System in Verbindung gebracht, während kortikale Strukturen, im Besonderen dorsolateraler präfrontaler (DLPFC) und anteriorer cingulärer Kortex (ACC), mit Selbstkontrolle assoziiert werden. Das Belohnungssystem ist eng mit dopaminergen Signalübertragungswegen verbunden, die unter anderem durch Gene für Dopamin- Rezeptor, -Transporter und -Abbau beeinflusst werden.
Studien zur Erforschung der behavioralen Grundlagen und neuronalen Zusammenhänge menschlicher Entscheidungen haben bislang vor allem Forced-Choice-Paradigmen verwendet, bei denen sich die Probanden zwischen einer sofort verfügbaren, kleineren Belohnung und einer späteren, größeren Belohnung entscheiden müssen. Bei dieser Operationalisierung erfolgt bei jeder Entscheidung eine eindeutige Zuordnung zum impulsiven oder selbstkontrollierten System, alltägliche Entscheidungen hingegen sind meist deutlich weniger eindeutig und transparent.
Aus diesem Grund wurde im Rahmen der vorliegenden Arbeit ein fMRT-Paradigma entwickelt, das menschliche Entscheidungen abbildet, ohne auf diese dichotome Einteilung zurückzugreifen. So sollten mithilfe des Versuchsresistenz-Paradigmas (VR-Paradigma) sowohl Belohnungsareale aktiviert, als auch schwierige Entscheidungen abgebildet werden. Dabei wurden den Probanden in neun Blöcken jeweils zwanzig kleine Geldbeträge (zwischen einem und 99 Cent) angeboten, von denen pro Block nur fünf gutgeschrieben werden konnten.
Es wurden zwei aufeinander aufbauende Studien an unterschiedlichen Stichproben durchgeführt: Im Rahmen der ersten Studie wurden 53 männliche Studenten untersucht. Neben dem VR-Paradigma wurden psychologische Fragebögen erhoben, bei 30 Probanden erfolgte außerdem eine genetische Analyse hinsichtlich dreier Dopamin-assoziierter Polymorphismen (COMT Val158Met, DAT1 und DRD2/ANKK1 Taq 1A).
In einer zweiten Studie wurden die Daten 16 männlicher alkoholabhängiger Patienten sieben bis 14 Tage nach Beginn eines Entzugs und 16 männlicher Kontrollprobanden analysiert. Diese wurden ebenfalls dem VR-Paradigma unterzogen und begleitend mithilfe psychologischer Fragebögen untersucht.
Bei der Auswertung wurden die Entscheidungen im Sinne eines 2x2-Designs nach Antwort (Ja oder Nein) und Höhe (Hoch (≥ individuellem Median der gutgeschriebenen Beträge) oder Niedrig (< individuellem Median) eingeteilt. Dabei sollten Belohnungsreaktionen vor allem bei höheren Beträgen auftreten, während schwierige Entscheidungen und Versuchungsresistenz über die Ablehnung hoher Beträge und die Annahme niedriger Beträge abgebildet werden.
Die Auswertung der ersten Studie erbrachte einen signifikanten Unterschied der Reaktionszeiten im VR-Paradigma bezogen auf die Höhe der angebotenen Beträge und die Interaktion von Antwort und Höhe, wobei die Ablehnung eines hohen Betrags die längsten Reaktionszeiten hervorrief. Bei hohen im Vergleich zu niedrigen Beträgen konnten Aktivierungen im bilateralen ventralen Striatum, rechten DLPFC, ACC, in der bilateralen Insula und im inferioren parietalen Lobus (IPL) nachgewiesen werden. Bei der Ausübung von Versuchungsresistenz (Interaktion der Haupteffekte) wurde dagegen der linke DLPFC aktiviert. Im Rahmen einer Konnektivitätsanalyse (psychophysiologische Interaktionen) konnte eine Korrelation der Aktivierung des linken DLPFC mit dem ventralen Striatum nur bei hohen abgelehnten Beträgen, nicht aber bei niedrigen zurückgewiesenen Beträgen gefunden werden. Bezüglich der Verbindung zwischen neuronaler Aktivierung und Persönlichkeit konnten Zusammenhänge der Belohnungsreaktion mit hohen Werten auf Impulsivitätsskalen und für Risikoverhalten sowie niedrigen Werten für Selbstkontrolle nachgewiesen werden. Für die Aktivierung in Kontrollarealen bei Versuchungsresistenz konnte ein entgegengesetzter Effekt beobachtet werden. Die Auswertung der genetischen Daten ergab eine signifikante stärkere Aktivierung des ventralen Striatums bei 10R- Homozygoten. Bei 10R-Homozygoten liegt eine erhöhte Zahl von Dopamin-Transportern an der Synapse vor, was am ehesten zu einer verringerten Verfügbarkeit von Dopamin im synaptischen Spalt führt.
Die Auswertung von Studie 2 erbrachte signifikante Unterschiede der Reaktionszeiten nur bezüglich der Höhe der angebotenen Belohnung, die Gruppenzugehörigkeit (Patient- Kontrolle) und die Interaktion der Haupteffekte hatten keinen Einfluss. Die Patienten behielten signifikant häufiger eine Kaufoption bis zum Ende eines Blocks übrig. Bei der neuronalen Aktivierung konnte eine stärkere Aktivierung des linken DLPFC und linken IPL bei Patienten nachgewiesen werden. Außerdem fanden sich signifikant höhere Werte auf impulsivitätsassoziierten Persönlichkeitsskalen für Patienten im Vergleich zu Kontrollen.
Im Rahmen der vorliegenden Arbeit konnten mit dem neu entwickelten VR-Paradigma neuronale Aktivierungen in Belohnungs- (v.a. ventrales Striatum) und Kontrollarealen (v.a. linker DLPFC und ACC) nachgewiesen werden. Außerdem scheint eine Konnektivität zwischen DLPFC und ventralem Striatum abhängig von der Notwendigkeit zur Ausübung kognitiver Kontrolle zu bestehen. Das Ausmaß neuronaler Aktivierung war mit Persönlichkeitsmaßen von Impulsivität und Selbstkontrolle korreliert, hier haben also interindividuelle Unterschiede in neuronaler Aktivierung Auswirkungen auf die Persönlichkeit. Der gefundene Einfluss des DAT1-Gens steht im Gegensatz zu bisherigen Befunden, dies kann mit der unterschiedlichen Operationalisierung zusammenhängen. Unterschiede zwischen alkoholabhängigen Patienten und Kontrollen hinsichtlich einer stärkeren Aktivierung in Kontrollarealen bei Patienten lassen vermuten, dass Patienten einen höheren kognitiven Aufwand zur Kontrollausübung aufwenden müssen.
Mithilfe des neuartigen Versuchungsresistenz-fMRT-Paradigmas zur Versuchungsresistenz werden bekannte Hirnregionen im Entscheidungsprozess angesprochen und es bietet darüber hinaus neue Einblicke in Interaktionseffekte. Weiterführende Studien können über eine Anwendung des Paradigmas an einer größeren klinischen Stichprobe in Verbindung mit genetischer Analytik neue Einblicke in Suchtmechanismen und deren Aufrechterhaltung ermöglichen.
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La perception du contraste de 1er et de 2e ordre chez des personnes atteintes de la maladie de Parkinson sous médication dopaminergiqueChevrier, Éliane January 2007 (has links)
Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.
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Caractérisation de la vulnérabilité sélective des neurones dopaminergiques dans le contexte de la maladie de ParkinsonGiguère, Nicolas 10 1900 (has links)
No description available.
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Étude électrophysiologique des effets du tabac, de sa fumée et de la nicotine sur des neurones dopaminergiques de l’aire tegmentale ventrale in vivo chez le rat, la souris sauvage et la souris β2 KO / An electrophysiological study of the effects of tobacco, its smoke, and nicotine, on ventral tegmental area dopaminergic neurons in vivo in the rat, the wild type mice and the ß2 KO miceArib, Ouafa 15 September 2009 (has links)
La nicotine est considérée comme étant la « molécule » addictogène de la cigarette et du tabac. Mais différentes études cliniques, utilisant notamment des substituts nicotiniques, débouchent pratiquement toutes sur une même conclusion : efficacité ne dépassant que de peu celle d’un placebo, et très limitée dans le temps, contrastant avec le pouvoir hautement addictif du tabac, qu'il soit chiqué, prisé ou fumé. Dans ce travail de thèse, nous avons essayé de mettre en évidence le rôle que pourraient avoir certains des autres composés présents dans le tabac ou produits par pyrolyse. Nous avons d’abord utilisé des extraits aqueux de fumée et de tabac pour approcher un aspect global de ce que les fumeurs absorbent chaque fois qu’ils fument une cigarette, nous rapprochant ainsi des conditions physiologiques du fumeur. Puis nous avons choisi un certain nombre de substances. La cotinine, métabolite de la nicotine. L’harmane, une ß-carboline, synthétisée au cours de la combustion et dans l’organisme des fumeurs. La norharmane, une ß-carboline, présente en partie dans le tabac et synthétisée dans la fumée par pyrolyse. La technique utilisée tout au long de ce travail est l’enregistrement électrophysiologique. Cette technique s’applique très bien à l’étude in vivo de différents systèmes neuronaux y compris le système dopaminergique. Nous l’avons utilisée chez le rat, la souris WT et la souris Knockout ß2 (ß2KO). Nous nous sommes intéressés à deux aspects de l’activité cellulaire des neurones dopaminergiques de l’aire tegmentale ventrale : la fréquence de décharge (le firing) et les bouffées (bursts). En parallèle, nous avons conduit des expériences de liaison (binding) sur des cultures de cellules exprimant le récepteur nicotinique α4ß2. Nos résultats les plus significatifs ont montré que : Les bursts sont le plus souvent absents après les injections d’extraits de tabac et de fumée. Cela pourrait, entre autres, impliquer qu’il existe dans le tabac et la fumée des composés autres que la nicotine qui bloquent les effets de la nicotine sur les bursts. Les effets des extraits de tabac et de fumée sur le firing et les bursts ne sont plus présents chez les souris ß2 KO, ce qui implique que l’ensemble des composés du tabac agit essentiellement sur les récepteurs nicotiniques porteurs de la chaine ß2, même si des hypothèses alternatives existent. L’harmane a des effets activateurs très puissants sur le firing des neurones dopaminergiques, et ces effets sont bloqués à 80% par la mécamylamine, ce qui démontre qu’un des principaux composés du tabac et de la fumée autre que la nicotine agit par un mécanisme essentiellement nicotinique. Les expériences de binding confirment que les effets du tabac et de la fumée impliquent les récepteurs nicotiniques d’une façon majeure, mais d’une façon qui diffère légèrement de celle de la nicotine.Les résultats que nous avons obtenus montrent que les effets pharmacologiques du tabac ne se résument pas à ceux de la seule nicotine. Ils peuvent constituer un point de départ pour d’autres travaux, notamment pour étudier de plus près les effets des ß-carbolines. Il est nécessaire d’identifier les types de récepteurs sur lesquels elles se fixent, en utilisant des agonistes et antagonistes de récepteurs aux neurotransmetteurs contrôlant l’activité des neurones dopaminergiques. Des expériences sur des souris transgéniques chez lesquelles différents types de sous-unités de récepteurs nicotiniques ont été supprimés doivent également être envisagées, pour déterminer les mécanismes d’action des composants autres que la nicotine contenus dans le tabac et sa fumée sur les neurones dopaminergiques / Nicotine is generally considered as the sole tobacco addictive compound. However, nicotine replacement therapy studies almost all end with the same conclusion: the effectiveness of nicotine replacement is very limited on the short-term, and hardly exceeds that of placebo on the long-term. In addition, studies dealing with the effects of denicotinized cigarettes have provided evidence that these cigarettes have an addictive potential. In the present work, we tried to determine the behavioral role of some tobacco or smoke compounds other than nicotine at the neuronal level. We first compared the effects of nicotine with those of whole tobacco and smoke extracts, given that these preparations closer mimic the smoking situation than nicotine alone. We then examined the effects of a number of selected tobacco or smoke compounds. Cotinine, a major nicotine metabolite. Harmane and norharmane, two ß-carbolines synthesized in smoke as well as in the body of smokers. The technique used consists in the in vivo recording of the firing rate and bursts of dopamine neurons in the ventral tegmental area after intravenous injections of compounds in rats and mice. This electrophysiological technique is known to be a useful way to investigate the properties of selected compounds. In the case of mice, we used wild type and ß2 KO mice. We also made a series of in vitro experiments investigating the binding properties of the compounds on cells expressing high densities of α4ß2 nicotinic receptors. The main results of our studies are the following: Bursts are absent most of the times after the injection of the extracts. These results suggest that tobacco and smoke extracts contain compounds that inhibit the burst-promoting effects of nicotine. Increased firing is no longer present in ß2 KO mice treated with tobacco or smoke extracts, indicating that tobacco and smoke components, as a whole, primarily acts on nicotinic receptors that carry the ß2 chain, although alternative hypotheses may exist. Harmane very strongly activates the firing of dopaminergic neurons. Up to 80% of this effect is blocked by mecamylamine, demonstrating that that a major component of tobacco and smoke other than nicotine acts primarily through a nicotinic mechanism. The binding experiments confirm that the effects of tobacco and smoke involve nicotinic receptors in a major way, but in a way that slightly differs from that of nicotine. Our results may constitute a new starting point for further work, especially for a closer look at the effects of ß-carbolines. Attempts to identify the types of receptors involved in these effects are needed, using agonists and antagonists of neurotransmitter receptors that control the activity of dopamine neurons. Experiments on transgenic mice with deletion of different types of subunits of nicotinic receptors should also be made, to determine the different mechanisms of action of tobacco and smoke compounds other than nicotine on dopaminergic neurons
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Envolvimento de mecanismos dopaminérgicos na expressão do medo condicionado contextual em ratos / Involvement of dopaminergic mechanisms in the expression of contextual conditioned fear in ratsCaetano, Kátia Alessandra de Souza 09 April 2012 (has links)
É reconhecido que as experiências que geram reações de medo são praticamente indeléveis do encéfalo dos organismos e que condicionamentos aversivos suscitam inúmeras respostas defensivas, como o congelamento, sendo esta resposta um indicador de medo em roedores. Vários trabalhos têm apontado para a relação entre alterações na transmissão dopaminérgica e os estados aversivos. Entretanto, observam-se resultados conflitantes com a utilização de drogas dopaminérgicas em diferentes modelos animais de ansiedade. Assim, investigações devem ainda ser realizadas objetivando avaliar a funcionalidade da modulação dopaminérgica nos estados emocionais aversivos. O objetivo do presente estudo foi avaliar o envolvimento de mecanismos dopaminérgicos na expressão do medo condicionado ao contexto. Inicialmente foram avaliados os efeitos de agonistas (SKF 38393 e quimpirole) e antagonistas (SCH 23390 e sulpirida) de receptores D1 e D2 administrados sistemicamente sobre a expressão do medo condicionado contextual, sendo mensurado o tempo de congelamento dos animais. A atividade motora foi avaliada com o teste do campo aberto. Os resultados indicam que os receptores da família D2, e não D1, estão envolvidos na expressão do medo condicionado contextual, uma vez que a administração de quimpirole e sulpirida, mas não de SCH 23390 e SKF 38393, levou a uma diminuição do congelamento condicionado ao contexto. Não houve alterações na atividade motora dos animais. Com base nestes resultados foi levantada a hipótese de que a capacidade da sulpirida e do quimpirole em diminuir o medo condicionado poderia ocorrer devido a uma ação em receptores pós-sinápticos de estruturas do sistema mesocorticolímbico e em autoreceptores da área tegmental ventral (ATV), respectivamente, levando ao efeito comum de diminuição da atividade dopaminérgica. A fim de testar esta hipótese, foram realizadas microinjeções de quimpirole na ATV. Os resultados obtidos mostram uma diminuição da expressão do congelamento condicionado e que os efeitos obtidos com a administração sistêmica desse agonista de receptores D2 provavelmente devem-se a sua ação na ATV. Portanto, a ATV parece atuar na modulação das respostas de medo condicionado e a ativação desta estrutura deve ser importante para a recuperação da aprendizagem aversiva ocorrida no dia do condicionamento. / It is well established that experiences that generate fear reactions are practically unforgettable and that aversive conditioning raises several defensive responses such as freezing, which is an index of fear in rodents. Several studies have pointed to the existence of a relationship between changes in dopaminergic neurotransmission and aversive states. However, there are conflicting results in the literature with the use of dopaminergic drugs in different animal models of anxiety. Thus, further investigations should be conducted to evaluate the importance of dopaminergic modulation of aversive states. The aim of the present study was to evaluate the involvement of dopaminergic neurotransmission in the expression of contextual conditioned fear in rats. Initially, we evaluated the effects of intraperitoneal injections of D1 and D2 receptors agonists (SKF 38393 and quinpirole) and antagonists (SCH 23390 and sulpiride) in the expression of contextual conditioned fear by measuring the time of freezing response of the animals. The motor activity was evaluated in the open field test. The results indicate that the D2 receptors, but not D1 receptors, are involved in the expression of contextual conditioned fear, since administration of quinpirole and sulpiride, but not SCH 23390 and SKF 38393, decreased conditioned freezing to the context. There were no changes in motor activity of animals. Based on these results it was hypothesized that quinpirole and sulpiride probably acted on presynaptic and postsynaptic D2 receptors, respectively, leading to a decrease of dopaminergic neurotransmission in both cases. To test this hypothesis, microinjections of quinpirole were performed into the ventral tegmental area (VTA). The results show a decrease in the expression of conditioned freezing, indicating that the effects obtained with the intraperitoneal administration of the dopamine D2 receptor agonist is probably due to its action in the VTA. Therefore, dopaminergic mechanisms in the VTA seem to be important in the modulation of conditioned fear responses and activation of this structure appears to take place during the fear memory following the context aversive conditioning.
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Reconnaissance et mimétisme des émotions exprimées sur le visage : vers une compréhension des mécanismes à travers le modèle parkinsonien / Facial emotion recognition and facial mimicry : new insights in Parkinson's diseaseArgaud, Soizic 07 November 2016 (has links)
La maladie de Parkinson est une affection neurodégénérative principalement associée à la dégénérescence progressive des neurones dopaminergiques du mésencéphale provoquant un dysfonctionnement des noyaux gris centraux. En parallèle de symptômes moteurs bien connus, cette affection entraîne également l’émergence de déficits émotionnels impactant en outre l’expression et la reconnaissance des émotions. Ici, se pose la question d’un déficit de reconnaissance des émotions faciales chez les patients parkinsoniens lié au moins en partie aux troubles moteurs. En effet, selon les théories de simulation des émotions, copier les émotions de l’autre nous permettrait de mieux les reconnaître. Ce serait le rôle du mimétisme facial. Automatique et inconscient, ce phénomène est caractérisé par des réactions musculaires congruentes à l’émotion exprimée par autrui. Dans ce contexte, une perturbation des capacités motrices pourrait conduire à une altération des capacités de reconnaissance des émotions. Or, l’un des symptômes moteurs les plus fréquents dans la maladie de Parkinson, l’amimie faciale, consiste en une perte de la mobilité des muscles du visage. Ainsi, nous avons examiné l’efficience du mimétisme facial dans la maladie de Parkinson, son influence sur la qualité du processus de reconnaissance des émotions, ainsi que l’effet du traitement dopaminergique antiparkinsonien sur ces processus. Pour cela, nous avons développé un paradigme permettant l’évaluation simultanée des capacités de reconnaissance et de mimétisme (corrugator supercilii, zygomaticus major et orbicularis oculi) d’émotions exprimées sur des visages dynamiques (joie, colère, neutre). Cette expérience a été proposée à un groupe de patients parkinsoniens comparé à un groupe de sujets sains témoins. Nos résultats supportent l’hypothèse selon laquelle le déficit de reconnaissance des émotions chez le patient parkinsonien pourrait résulter d’un système « bruité » au sein duquel le mimétisme facial participerait. Cependant, l’altération du mimétisme facial dans la maladie de Parkinson et son influence sur la reconnaissance des émotions dépendraient des muscles impliqués dans l’expression à reconnaître. En effet, ce serait davantage le relâchement du corrugateur plutôt que les contractions du zygomatique ou de l’orbiculaire de l’œil qui nous aiderait à bien reconnaître les expressions de joie. D’un autre côté, rien ne nous permet ici de confirmer l’influence du mimétisme facial sur la reconnaissance des expressions de colère. Enfin, nous avons proposé cette expérience à des patients en condition de traitement habituel et après une interruption temporaire de traitement. Les résultats préliminaires de cette étude apportent des éléments en faveur d’un effet bénéfique du traitement dopaminergique tant sur la reconnaissance des émotions que sur les capacités de mimétisme. L’hypothèse d’un effet bénéfique dit « périphérique » sur la reconnaissance des émotions par restauration du mimétisme facial reste à tester à ce jour. Nous discutons l’ensemble de ces résultats selon les conceptions récentes sur le rôle des noyaux gris centraux et sous l’angle de l’hypothèse de feedback facial. / Parkinson’s disease is a neurodegenerative condition primarily resulting from a dysfunction of the basal ganglia following a progressive loss of midbrain dopamine neurons. Alongside the well-known motor symptoms, PD patients also suffer from emotional disorders including difficulties to recognize and to produce facial emotions. Here, there is a question whether the emotion recognition impairments in Parkinson’s disease could be in part related to motor symptoms. Indeed, according to embodied simulation theory, understanding other people’s emotions would be fostered by facial mimicry. Automatic and non-conscious, facial mimicry is characterized by congruent valence-related facial responses to the emotion expressed by others. In this context, disturbed motor processing could lead to impairments in emotion recognition. Yet, one of the most distinctive clinical features in Parkinson’s disease is facial amimia, a reduction in facial expressiveness. Thus, we studied the ability to mimic facial expression in Parkinson’s disease, its effective influence on emotion recognition as well as the effect of dopamine replacement therapy both on emotion recognition and facial mimicry. For these purposes, we investigated electromyographic responses (corrugator supercilii, zygomaticus major and orbicularis oculi) to facial emotion among patients suffering from Parkinson’s disease and healthy participants in a facial emotion recognition paradigm (joy, anger, neutral). Our results showed that the facial emotion processing in Parkinson’s disease could be swung from a normal to a pathological, noisy, functioning because of a weaker signal-to-noise ratio. Besides, facial mimicry could have a beneficial effect on the recognition of emotion. Nevertheless, the negative impact of Parkinson’s disease on facial mimicry and its influence on emotion recognition would depend on the muscles involved in the production of the emotional expression to decode. Indeed, the corrugator relaxation would be a stronger predictor of the recognition of joy expressions than the zygomatic or orbicularis contractions. On the other hand, we cannot conclude here that the corrugator reactions foster the recognition of anger. Furthermore, we proposed this experiment to a group of patients under dopamine replacement therapy but also during a temporary withdrawal from treatment. The preliminary results are in favour of a beneficial effect of dopaminergic medication on both emotion recognition and facial mimicry. The potential positive “peripheral” impact of dopamine replacement therapy on emotion recognition through restoration of facial mimicry has still to be tested. We discussed these findings in the light of recent considerations about the role of basal ganglia-based circuits and embodied simulation theory ending with the results’ clinical significances.
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La perception du contraste de 1er et de 2e ordre chez des personnes atteintes de la maladie de Parkinson sous médication dopaminergiqueChevrier, Éliane January 2007 (has links)
Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal
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The monoamine oxidase inhibition properties of caffeine analogues containing saturated C–8 substituents / Paul GroblerGrobler, Paul Johan January 2010 (has links)
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized
pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling
movement disorders. PD can be treated by inhibiting monoamine oxidase (MAO), specifically
MAO–B, since this is a major enzyme involved in the catabolism of dopamine in the substantia
nigra of the brain. Inhibition of MAO–B may conserve the dopamine supply in the brain and may
therefore provide symptomatic relief for PD patients.
Selegiline is an irreversible MAO–B inhibitor and is currently used for the treatment of PD.
Irreversible inhibitors inactivate enzymes by forming stable covalent complexes. The process is
not readily reversed either by removing the remainder of the free inhibitor or by increasing the
substrate concentration. Even dilution or dialysis does not dissociate the enzyme inhibitor
complex and restore enzyme activity. From a safety point of view it may therefore be more
desirable to develop reversible inhibitors of MAO–B. In this study, caffeine was used as lead
compound to design, synthesize and evaluate new reversible inhibitors of MAO–B. This study is
based on the finding that C–8 substituted caffeine analogues are potent MAO inhibitors.
For example, (E)–8–(3–chlorostyryl)caffeine (CSC) is an exceptionally potent competitive inhibitor
of MAO–B with an enzyme–inhibitor dissociation constant (Ki value) of 128 nM. In this study
caffeine was similarly conjugated at C–8 to various side–chains. The effect that these chosen
side–chains had on the MAO–B inhibition activity of C–8 substituted caffeine analogues will then
be evaluated. The caffeine analogues were also evaluated as human MAO–A inhibitors. For the
purpose of this study, saturated C–8 side chains were selected with the goal of discovering new
C–8 side chains that enhance the MAO–A and ?B inhibition potency of caffeine. As mentioned
above, the styryl side chain is one example of a side chain that enhances the MAO–B inhibition
potency of caffeine. Should a side chain with promising MAO inhibition activity be identified in this study, the inhibition potency will be further optimized in a future study by the addition of a
variety of substituents to the C–8 side chain ring. For example, halogen substitution of (E)–8–
styrylcaffeine enhances the MAO–B inhibition potency by up to 10 fold. The saturated side
chains selected for the present study included the phenylethyl (1), phenylpropyl (2), phenylbutyl
(3) and phenylpentyl (4) functional groups. Also included are the cyclohexylethyl (8), 3–oxo–3–
phenylpropyl (5), 4–oxo–4–phenylbutyl (6) moieties. A test compound containing an unsaturated
linker between C–8 of caffeine and the side chain ring, the phenylpropenyl analogue 7, was also
included. This study is therefore an exploratory study to discover new C–8 moieties that are
favorable for MAO– inhibition. All the target compounds were synthesized by reacting 1,3–dimethyl–5,6–diaminouracil with an
appropriate carboxylic acid in the presence of a carbodiimide dehydrating agent. Following ring
closure and methylation at C–7, the target inhibitors were obtained. Inhibition potencies were
determined using recombinant human MAO–A and MAO–B as enzyme sources. The inhibitor
potencies were expressed as IC50 values. The most potent MAO–B inhibitor was 8–(5–
phenylpentyl)caffeine (4) with an IC50 value of 0.656 ?M. In contrast, all the other test inhibitors
were moderately potent MAO–B inhibitors. In fact the next best MAO–B inhibitor, 8–(4–
phenylbutyl)caffeine (3) was approximately 5 fold less potent than 4 with an IC50 value of 3.25
?M. Since the 5–phenylpentyl moiety is the longest side chain evaluated in this study, this
finding demonstrates that longer C–8 side chains are more favorable for MAO–B inhibition. Interestingly, compound 5 containing a cyclohexylethyl side chain (IC50 = 6.59 ?M) was
approximately 4 fold more potent than the analogue containing the phenylethyl linker (1) (IC50 =
26.0 ?M). This suggests that a cyclohexyl ring in the C–8 side chain of caffeine may be more
optimal for MAO–B inhibition and should be considered in future studies. The caffeine analogues
containing the oxophenylalkyl side chains (5 and 6) were weak MAO–B inhibitors with IC50
values of 187 ?M and 46.9 ?M, respectively. This suggests that the presence of a carbonyl
group in the C–8 side chain is not favorable for the MAO–B inhibition potency of caffeine. The
unsaturated phenylpropenyl analogue 7 was also found to be a relatively weak MAO–B inhibitor
with an IC50 value of 33.1 ?M.
In contrast to the results obtained with MAO–B, the test caffeine analogues were all weak MAOA
inhibitors. With the exception of compound 5, all of the analogues evaluated were selective
inhibitors of MAO–B. The most potent MAO–B inhibitor, 8–(5–phenylpentyl)caffeine (4) was the
most selective inhibitor, 48 fold more potent towards MAO–B than MAO–A.
This study also shows that two selected analogues (5 and 3) bind reversibly to MAO–A and ?B,
respectively, and that the mode of MAO–A and –B inhibition is competitive for these
representative compounds. / Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2011.
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The monoamine oxidase inhibition properties of caffeine analogues containing saturated C–8 substituents / Paul GroblerGrobler, Paul Johan January 2010 (has links)
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized
pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling
movement disorders. PD can be treated by inhibiting monoamine oxidase (MAO), specifically
MAO–B, since this is a major enzyme involved in the catabolism of dopamine in the substantia
nigra of the brain. Inhibition of MAO–B may conserve the dopamine supply in the brain and may
therefore provide symptomatic relief for PD patients.
Selegiline is an irreversible MAO–B inhibitor and is currently used for the treatment of PD.
Irreversible inhibitors inactivate enzymes by forming stable covalent complexes. The process is
not readily reversed either by removing the remainder of the free inhibitor or by increasing the
substrate concentration. Even dilution or dialysis does not dissociate the enzyme inhibitor
complex and restore enzyme activity. From a safety point of view it may therefore be more
desirable to develop reversible inhibitors of MAO–B. In this study, caffeine was used as lead
compound to design, synthesize and evaluate new reversible inhibitors of MAO–B. This study is
based on the finding that C–8 substituted caffeine analogues are potent MAO inhibitors.
For example, (E)–8–(3–chlorostyryl)caffeine (CSC) is an exceptionally potent competitive inhibitor
of MAO–B with an enzyme–inhibitor dissociation constant (Ki value) of 128 nM. In this study
caffeine was similarly conjugated at C–8 to various side–chains. The effect that these chosen
side–chains had on the MAO–B inhibition activity of C–8 substituted caffeine analogues will then
be evaluated. The caffeine analogues were also evaluated as human MAO–A inhibitors. For the
purpose of this study, saturated C–8 side chains were selected with the goal of discovering new
C–8 side chains that enhance the MAO–A and ?B inhibition potency of caffeine. As mentioned
above, the styryl side chain is one example of a side chain that enhances the MAO–B inhibition
potency of caffeine. Should a side chain with promising MAO inhibition activity be identified in this study, the inhibition potency will be further optimized in a future study by the addition of a
variety of substituents to the C–8 side chain ring. For example, halogen substitution of (E)–8–
styrylcaffeine enhances the MAO–B inhibition potency by up to 10 fold. The saturated side
chains selected for the present study included the phenylethyl (1), phenylpropyl (2), phenylbutyl
(3) and phenylpentyl (4) functional groups. Also included are the cyclohexylethyl (8), 3–oxo–3–
phenylpropyl (5), 4–oxo–4–phenylbutyl (6) moieties. A test compound containing an unsaturated
linker between C–8 of caffeine and the side chain ring, the phenylpropenyl analogue 7, was also
included. This study is therefore an exploratory study to discover new C–8 moieties that are
favorable for MAO– inhibition. All the target compounds were synthesized by reacting 1,3–dimethyl–5,6–diaminouracil with an
appropriate carboxylic acid in the presence of a carbodiimide dehydrating agent. Following ring
closure and methylation at C–7, the target inhibitors were obtained. Inhibition potencies were
determined using recombinant human MAO–A and MAO–B as enzyme sources. The inhibitor
potencies were expressed as IC50 values. The most potent MAO–B inhibitor was 8–(5–
phenylpentyl)caffeine (4) with an IC50 value of 0.656 ?M. In contrast, all the other test inhibitors
were moderately potent MAO–B inhibitors. In fact the next best MAO–B inhibitor, 8–(4–
phenylbutyl)caffeine (3) was approximately 5 fold less potent than 4 with an IC50 value of 3.25
?M. Since the 5–phenylpentyl moiety is the longest side chain evaluated in this study, this
finding demonstrates that longer C–8 side chains are more favorable for MAO–B inhibition. Interestingly, compound 5 containing a cyclohexylethyl side chain (IC50 = 6.59 ?M) was
approximately 4 fold more potent than the analogue containing the phenylethyl linker (1) (IC50 =
26.0 ?M). This suggests that a cyclohexyl ring in the C–8 side chain of caffeine may be more
optimal for MAO–B inhibition and should be considered in future studies. The caffeine analogues
containing the oxophenylalkyl side chains (5 and 6) were weak MAO–B inhibitors with IC50
values of 187 ?M and 46.9 ?M, respectively. This suggests that the presence of a carbonyl
group in the C–8 side chain is not favorable for the MAO–B inhibition potency of caffeine. The
unsaturated phenylpropenyl analogue 7 was also found to be a relatively weak MAO–B inhibitor
with an IC50 value of 33.1 ?M.
In contrast to the results obtained with MAO–B, the test caffeine analogues were all weak MAOA
inhibitors. With the exception of compound 5, all of the analogues evaluated were selective
inhibitors of MAO–B. The most potent MAO–B inhibitor, 8–(5–phenylpentyl)caffeine (4) was the
most selective inhibitor, 48 fold more potent towards MAO–B than MAO–A.
This study also shows that two selected analogues (5 and 3) bind reversibly to MAO–A and ?B,
respectively, and that the mode of MAO–A and –B inhibition is competitive for these
representative compounds. / Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2011.
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Generation of human dopaminergic neurons from induced pluripotent stem cells to model Parkinson's diseaseSánchez Danés, Adriana, 1984- 21 May 2012 (has links)
Parkinson’s disease (PD) is an incurable, chronically progressive neurodegenerative disease leading to premature invalidity and death. The locomotor disability of PD patients is mainly rooted in the gradual and insidious degeneration of dopaminergic neurons (DA) projecting from the midbrain substantia nigra (SN) to the basal ganglia striatum, a pathological process highlighted microscopically by the formation of insoluble cytosolic protein aggregates, known as Lewy bodies and Lewy neurites. The pathogenic mechanisms leading to PD remain poorly understood, arguably owing to the lack of suitable animal and cellular experimental models of the disease. Therefore, there is an urgent need for developing reliable experimental models that recapitulate the key features of PD. The recent development of induced pluripotent stem cell (iPSC) technology has enabled the generation of patient-specific iPSC and their use to model human diseases, although it is currently unclear whether this approach could be useful to successfully model age-related conditions. Importantly, disease modeling using iPSC largely relies on the existence of efficient protocols for the differentiation of disease-relevant cell types. Here, we first developed an efficient protocol for the differentiation of iPSC to authentic midbrain-specific DA neurons with SN properties by forced expression of LMX1A using a lentivirus-mediated gene delivery system. Next, we generated an iPSC-based cellular model of PD that recapitulates key phenotypic features of PD, such as DA neuron loss and α-synuclein accumulation in DA neurons from PD patients. Overall, our results demonstrate that we have developed a valuable tool for elucidating the pathogenic mechanisms leading to PD, as well as an experimental platform for screening new drugs that may prevent or rescue neurodegeneration in PD. / La malaltia de Parkinson (MP) és una malaltia neurodegenerativa incurable que causa invalidesa i mort prematura. Els pacients de la malaltia de Parkinson presenten alteracions motores degudes a una degeneració gradual de les neurones dopaminèrgiques que projecten des de la substància nigra fins a l’estriat. A nivell microscòpic s’observa la presència d’agregats proteics insolubles en el citosol de les neurones coneguts com cossos o neurites de Lewy. Els mecanismes patològics responsables de la MP no es coneixen bé, possiblement a causa de la manca de models animals i cel•lulars adequats. Per tant, existeix una gran necessitat de desenvolupar models experimentals fiables que recapitulin les característiques bàsiques de la MP. El recent desenvolupament de les cèl•lules mare pluripotents induïdes (iPSC) ha permès la generació de iPSC específiques de pacient i el seu ús per modelar malalties humanes, ara bé, no és clar si aquesta estratègia es pot utilitzar per modelar exitosament malalties d’origen tardà, com ara la MP. És important destacar que el modelatge de malalties utilitzant iPSC, es basa, en gran mesura en l'existència de protocols eficients per a la diferenciació de les iPSC cap al tipus cel•lular rellevant per a la malaltia. Durant aquest període, per primera vegada, s’ha desenvolupat un protocol per a l’eficient diferenciació de les iPSC cap a neurones dopaminèrgiques amb les propietats característiques de neurones dopaminèrgiques nigrostriatals, mitjançant l’expressió forçada de LMX1A utilitzant vectors lentivirals. A continuació, s’ha generat un model cel•lular usant iPSC derivades de pacients de MP que recapitula les principals característiques fenotípiques de la malaltia, com ara la pèrdua de neurones dopaminèrgiques i l'acumulació de α-sinucleïna en les neurones dopaminèrgiques. En general, els nostres resultats demostren que hem desenvolupat una eina valuosa per a l’estudi dels mecanismes patològics que condueixen a la MP, així com una nova plataforma pel descobriment de nous fàrmacs encaminats a prevenir o evitar la neurodegeneració.
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