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Rôles Des Récepteurs Nucléaires Nur77 Et Nor-1 Et Des Rôles des récepteurs nucléaires Nur77 et Nor-1 et des neuropeptides enképhaline et dynorphine dans les comportements médiés par la dopamine et induits par les psychostimulants Thèse Céline Hodler Programme de doctorat en Neurobiologie Philosophiae doctor (Ph.D.) Faculté de médecine Québec, Canada © Céline Hodler, 2012 RÉSUMÉ Cette thèse démontre que les récepteurs nucléaires Nur77 et Nor-1 ainsi que les neuropeptides dynorphine (DYN) et enképhaline (ENK) sont des facteurs déterminants de la régulation du système dopaminergique. Notre premier manuscrit démontre d’une part que Nur77 et Nor-1 sont très clairement impliqués dans la régulation de l’homéostasie du système dopaminergique et qu’ils y jouent des rôles distincts, voire opposés, dans les conditions basales et dans les réponses comportementales et biochimiques aux psychostimulants. La délétion génétique de Nur77 augmente la proportion des récepteurs D2 en haute affinité (D2high), supprime les stéréotypies et perturbe la persistance de la préférence de place induites par l’administration répétée de psychostimulants. À l’inverse, la délétion de Nor-1 diminue la proportion des récepteurs D2high, atténue les comportements moteurs en réponse à l’amphétamine et supprime la sensibilisation comportementale. La délétion de Nor-1 module également l’expression de la DYN et de l’ENK favorisant ainsi une diminution de la réponse comportementale alors que celle de Nur77 induit l’effet inverse. Ainsi, Nor-1 et Nur77 jouent des rôles opposés, la délétion de Nor-1 tempère les comportements moteurs, celle de Nur77 les exacerbe. Notre second manuscrit démontre d’autre part que la DYN et l’ENK sont toutes deux nécessaires et ont des rôles opposés dans la manifestation des comportements de base médiés par la dopamine. Par contre, dans les conditions d’une exposition répétée aux psychostimulants, la DYN et l’ENK agissent de concert en potentialisant l’exacerbation de l’activité locomotrice et sont donc toutes deux indispensables à la sensibilisation comportementale. Nos travaux révèlent également l’existence d’interactions entre les neurotransmissions enképhalinergique et dynorphinergique et donc entre les deux voies de sortie indirecte et directe des ganglions de la base. Aussi, les neuropeptides DYN et ENK sont modulés différentiellement par la délétion de Nur77 et de Nor-1 et inversement leur délétion régule de manière différente l’expression de ces facteurs de transcription. Ceci suggère l’existence d’une relation de régulation réciproque entre les récepteurs nucléaires et ces neuropeptides. Nur77 et Nor-1 sont donc des régulateurs clés de la transmission dopaminergique et des réponses comportementales aux psychostimulants et ce, principalement via la modulation des récepteurs dopaminergiques et des neuropeptides striataux. I ABSTRACT This present study demonstrates that the nuclear receptors Nur77 and Nor-1 and the neuropeptides dynorphin (DYN) and enkephalin (ENK) are crucial in dopaminergic system regulation. On one hand, our first manuscript shows that Nur77 and Nor-1 are deeply involved in the homeostatic regulation of the dopaminergic system and play distinct, mostly opposite roles, in basal dopaminergic neurotransmission and in psychostimulants-induced behavioral and biochemical effects. In particular, Nur77 deletion exacerbates the behavioral effects of both acute and chronic amphetamine (AMPH) administrations while Nor-1 deletion has the opposite effect. In fact, Nur77 deletion favors the upregulation of the proportion of D2 receptors in high affinity state (D2high) and suppress AMPH-induced stereotyped behavior. On the contrary, Nor-1 deletion downregulates the D2high receptors proportion, attenuates locomotor activity in response to chronic AMPH administration and consequently suppresses the development of behavioral sensitization. Nor-1 deletion modulates DYN and ENK expression in a way that promotes decreased behavioral responses to psychostimulants and that is opposite to the effects of Nur77 deletion on these very same neuropeptides. Also, Nur77 deletion suppresses the persistance of cocaine- induced place preference wherese Nor-1 deletion has no effect. Thus, Nor-1 and Nur77 mostly play opposite roles, Nor-1 deletion dampens ambulatory activity whereas Nur77 deletion exacerbates it. On the other hand, our second manuscript shows that DYN and ENK are both necessary and play opposite roles in dopamine-mediated basal behaviors. However, during chronic psychostimulants exposure, DYN and ENK both contribute to the exacerbation of locomotor activity and they are consequently both essential for the expression of behavioral sensitization. Besides, our results highlight a cross-talk between ENK and DYN neurotransmissions and thus between the indirect and direct output pathways of the basal ganglia. Interestingly, we also show that the striatal DYN and ENK deletions could differentially modulate Nur77 et Nor-1 expression. This suggests that the nuclear receptors and the neuropeptides ENK and DYN share an intimate reciprocal regulation relationship. Collectively, our results strongly establish that Nur77 and Nor-1 are key regulators of the dopaminergic neurotransmission and of behavioral responses to psychostimulants and this, mostly via the modulation of dopaminergic receptors and striatal neuropeptides. II AVANT-PROPOS Je tiens à remercier, en premier lieu, mon directeur et mon co-directeur de recherche, les Drs Claude Rouillard et Daniel Lévesque. Ce fut un privilège d'avoir pu travailler avec ces chercheurs compétents, passionnés et généreux. Merci pour votre soutien, vos encouragements, votre confiance, votre précieuse expérience et votre disponibilité. Avant tout, Claude, merci de m’avoir accordé ta confiance et de m'avoir donné la chance de travailler à tes côtés à la maîtrise puis au doctorat. Merci aussi pour ton soutien financier qui m'a permis de m'investir pleinement dans mes études. Merci pour ton encadrement bienveillant. J'ai tiré un grand plaisir de nos discussions au laboratoire, et je tiens en particulier à t’exprimer ma gratitude pour tes conseils avisés, tes encouragements, ton réconfort et ta compréhension lors de mes moments de fragilité et d’incertitude. Tu as contribué à rendre plus lumineuses et prometteuses mes années au Québec grâce à ton écoute et à ton soutien dans mes projets professionnels. Un immense merci à Brigitte Paquet, premièrement pour m'avoir assistée et formée pendant toutes ces années. Deuxièmement, et de façon encore plus significative à mes yeux, merci pour toutes ces petites attentions qui ont su égailler mes journées. Merci à tous mes amis et collaborateurs, je pense à, Joanie Baillargeon, Aurore Voisin, Emmanuelle Bourhis, Cécile Vue, Jérôme Maheux, Michel st-Hilaire, François Gilbert, Marc Cloutier. Un merci tout spécial à Emmanuelle Berret et Antoine Hone-Blanchet, vos personnalités joyeuses et votre esprit plaisantin ont su me motiver dans les moments de découragement. Merci pour votre aide précieuse et votre amitié. Vous avez tous été d’une aide essentielle pour l’élaboration et l’aboutissement de mon projet de recherche. J'aimerais aussi remercier mes parents, Marie-Claire et Jürg, pour m’avoir soutenu financièrement pendant mes études. Merci surtout à mes frères, David et Manuel, pour leur présence réconfortante, leur complicité, leur humour imparable et leur amour inconditionnel qui m’ont été indispensables et salutaires dans les moments difficiles. III Bien que je sois première auteure des deux articles composant les chapitres 2 et 3 de cette thèse, j'ai bénéficié de la collaboration de plusieurs de mes collègues et, bien évidemment, des Drs Claude Rouillard et Daniel Lévesque. Le chapitre 2 de ma thèse, « Distinct roles for the nuclear receptors Nur77 and Nor- 1 in dopamine-mediated and psychostimulant-induced behaviors », est un article en voie de soumission dans un journal international de haut calibre. J'ai été directement impliqué dans toutes les étapes qui ont menées à la réalisation de cette étude. J'ai effectué tous les traitements et quantifications des comportements chez les souris. J'ai également réalisé les perfusions et prélèvements des cerveaux. J’ai aussi effectué toutes les hybridations in situ. J'ai également procédé à la quantification et l'analyse statistique des résultats. La rédaction de l'article a été réalisée par moi-même et révisée par le Dr. Claude Rouillard. Antoine Hone-blanchet, est présenté comme second auteur car il m’a fourni les données biochimiques concernant l’expression de la DYN suite à l’administration aigüe d’amphétamine chez les souris Nur77 (-/-). Joanie Baillargeon et Brirgitte Paquet, nos deux assistantes de recherche, ont aidé à la quantification de certains protocoles et m’ont assistée lors des chirurgies. Le Dr. Philip Seeman m’a fourni les données concernant le pourcentage d’expression des récepteurs D2 en haute affinité. Le Dr. Daniel Lévesque a, avec le Dr. Claude Rouillard, participé à l'élaboration des hypothèses de recherche, à la mise sur pied des protocoles expérimentaux, ainsi qu’à la correction de l'article. Le chapitre 3, «Implication of the endogenous striatal neuropeptides Enkephalin and Dynorphin in dopamine-mediated and psychostimulant-induced behaviors.», est un article en voie de soumission dans un journal international. Dans cette étude, Brigitte Paquet m’a assistée pour la réalisation des expériences comportementales, et notamment lors de l'administration des traitements. J’ai réalisé les techniques d'hybridation in situ, la quantification, l'analyse et l'interprétation
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