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Université Victor Segalen Bordeaux 2 FACTEURS Université Victor Segalen Bordeaux 2 UFR Sciences de la Vie Année 2009 Thèse n°1688 THÈSE pour le DOCTORAT DE L’UNIVERSITÉ DE BORDEAUX Mention : Sciences, Technologie, Santé Option : Neurosciences Présentée et soutenue publiquement le 21 Décembre 2009 Par Nadège ROBERT (épouse BERSON) Née le 28 Novembre 1981 à Périgueux (24) FACTEURS NEUROBIOLOGIQUES ASSOCIÉS À L’ADDICTION A LA COCAÏNE : ETUDE AU MOYEN D’UN MODELE D’ADDICTION CHEZ LE RAT Membres du jury Président : M. Bruno Aouizerate, PU-PH, Université de Bordeaux, Bordeaux, France Rapporteur : M. Rafael Maldonado, Professeur, Université Pompeu Fabra, Barcelone, Espagne Rapporteur : M. François Tronche, DR CNRS, CNRS FRE2401, Collège de France, Paris, France Invité : M. Pier Vincenzo Piazza, DR INSERM, CRI U862, Bordeaux, France Directrice de thèse : Mme Véronique Deroche-Gamonet, CR INSERM, U862, Bordeaux À mes Amours Pascal et Pierric… REMERCIEMENTS Le meilleur ami de "merci" est "beaucoup". Michel Bouthot. Ce travail de thèse s’est déroulé dans le laboratoire INSERM U862 sous la direction du Docteur Véronique Deroche-Gamonet que je souhaite tout particulièrement et très sincèrement remercier pour son implication dans l’ensemble de ces travaux et son dévouement à m’enseigner la rigueur scientifique et la passion pour le travail bien fait. Cette thèse n’aurait pas été ce qu’elle est sans vous : un grand merci ! Je voudrais également remercier le Docteur Pier-Vincenzo Piazza de m’avoir accompagnée en tant que Directeur de l’unité INSERM U862 « Physiopathologie de l’addiction » tout au long de cette thèse. Merci au Professeur Michel Le Moal pour ses encouragements, sa gentillesse et les longues discussions scientifiques que nous avons eu certains WE « comportementaux ». Cela m’a beaucoup aidé. Je suis profondément reconnaissante aux docteurs Rafaël Maldonado et François Tronche de m’avoir fait l’honneur de porter leur jugement expert sur ce travail. Je tiens également à exprimer ma reconnaissance au Professeur Bruno Aouizerate d’avoir accepté de présider mon jury de thèse. Que tous les membres de l’unité INSERM U862 soient assurés de ma gratitude et de ma reconnaissance pour leur soutien et la chaleur humaine qu’ils m’ont apportée. Je souhaite remercier du fond du cœur le docteur Guillaume Drutel de m’avoir encadré en biologie moléculaire ainsi que Thierry Leste-Lasserre qui a accompli un travail considérable dans ce domaine. Merci à vous deux pour votre professionnalisme, votre patience et votre gentillesse. J’ai passé d’agréables moments en votre compagnie. Je souhaite remercier chaleureusement le Docteur Nora Abrous pour l’apprentissage des techniques d’immunohistochimie et pour tous ses précieux conseils et encouragements. Il m’est impossible d’oublier mes compères d’unité sans qui les jours de « comportement » auraient été bien tristes et beaucoup plus difficiles : Merci Eric de m’avoir appris les filons de l’autoadministration et pour ta patience, Merci Jean-Fançois de m’avoir si souvent écouté et pour ta bonne humeur et pour finir un grand Merci à toi Jean-Marc de m’avoir fait tant rire…et ainsi donné l’envie de revenir dans ce laboratoire les jours d’après, même quand ça n’allait pas très bien. Merci à vous trois, je vous dois beaucoup ! Un grand merci au C.B.I.B. (centre de bioinformatique de Bordeaux) pour le développement d’outils informatiques fondamentaux dans l’étude des micropuces à ADN et plus particulièrement à Alexandre BROCHARD, dit « Super Bio-Informaticien », pour son travail d’analyse et pour avoir su traduire avec brio le langage des biologistes en langage que les ordinateurs comprennent… Je souhaite également remercier les Docteurs Sophie Layé et Jan-Pieter Konsman pour l’accueil dans leur laboratoire, leur prêt de microscope, leur aide dans l’exploitation des images d’immunohistochimie et surtout leur gentillesse, une vrai bouffée d’air frais ! - I - RESUMÉ De nombreux individus consomment une, ou plusieurs, substances psychoactives au cours de leur vie. Alors que la majorité des consommateurs maintient une utilisation épisodique et contrôlée, certains perdent le contrôle sur l’usage de la substance ; symptôme majeur d’une addiction. Comprendre les mécanismes psychobiologiques, qui sous-tendent cette vulnérabilité à passer d’un usage contrôlé à un usage compulsif, constituerait une étape décisive dans la compréhension de la pathologie et l’identification de cibles thérapeutiques pertinentes. En effet, malgré un intense effort de recherche au cours des 40 dernières années, les thérapies disponibles se révèlent d’une efficacité limitée. Il faut probablement en chercher la cause dans la complexité de la pathologie, mais aussi dans l’inadéquation des préparations expérimentales à la définition clinique de l'addiction. Dans ce contexte, une étape décisive a été franchie il y a 5 ans lorsque des chercheurs de notre équipe ont développé le premier modèle pluri-symptomatique d’addiction à la cocaïne chez le rat. Grâce à ce modèle, il est possible d’identifier des animaux qui développent un comportement similaire à l’addiction, alors que d’autres maintiennent un usage contrôlé, et ce, malgré une consommation préalable de drogue équivalente. S'appuyant sur ce modèle d'addiction chez le rat, le but de nos travaux de thèse était d’identifier des différences neurobiologiques entre usagers addicts et non-addicts et d’aborder les mécanismes neurobiologiques qui sous-tendent la transition vers l’addiction. Pour ce second point, nous avons considéré les différences majeures identifiées et étudié leur évolution de l’usage précoce de cocaïne (avant l'addiction) à l'usage tardif (après développement de l’addiction) en fonction des sujets (addicts versus non-addicts). Nous avons utilisé une approche multidisciplinaire associant les principales méthodes des neurosciences comportementales, moléculaires et des systèmes. Nous avons comparé addicts et non-addicts au moyen d’une stratégie ciblée et d’une stratégie non ciblée. La stratégie non ciblée a consisté à évaluer l'expression des gènes à grande échelle, dans des structures cérébrales clés, au moyen d’une technique de gene profiling (environ 28 000 gènes testés simultanément). L'approche ciblée a consisté à analyser des facteurs connus pour être modifiés par l'usage ou l’administration chronique de cocaïne. Nous nous sommes concentrés sur une structure majeure, le noyau accumbens, et avons étudié : i. l'expression de gènes cibles au moyen de la qPCR, ii. plusieurs formes de plasticité synaptique à l'aide de l’électrophysiologie in vitro, iii. l'activité des neurones dopaminergiques de l’aire tegmentale ventrale (VTA) (projetant vers le noyau accumbens) au moyen de l’électrophysiologie in vivo, iv. la libération de dopamine dans le noyau accumbens au moyen de la microdialyse in vivo. Nous avons montré que les rats addicts et non-addicts s'adaptent très différemment à la cocaïne. Les usagers non-addicts paraissent en mesure de contrecarrer les changements neurobiologiques précoces provoqués par la cocaïne, tandis que les addicts ne le sont pas. Ils présentent des réponses neurobiologiques similaires à celles d'animaux naïfs vis-à-vis de la cocaïne ou d'animaux ayant été exposés à la drogue sur une très courte période. En résumé, les données obtenues au cours de ce travail de thèse modifient drastiquement la perception commune de la psychopathologie de l’addiction. L'addiction résulterait moins de modifications produites par la drogue (comme on le pense depuis 40 ans) que de l'incapacité à lutter contre ces modifications. - II - ABSTRACT Numerous individuals consume one, or several, psychoactive substances during their lifetime. Although most consumers make only occasional and controlled use of a substance, some lose control of their use, which constitutes a major symptom of addiction. Understanding the psychobiological mechanisms which underlie this vulnerability to the transition from controlled drug use to addiction would constitute a decisive step forward in our understanding of the pathology and in our identification of the relevant therapeutic targets. Indeed despite intense research efforts during the last 40 years, the therapies available are of limited efficacy. This is probably related to the complexity of the pathology, as well as to the unsuitability of experimental preparations to the clinical definition of addiction. In such a context, there was a significant breakthrough 5 years ago when our research team developed the first pluri-symptomatic model of cocaine addiction in the rat. Thanks to this model it is possible to single out animals that develop an addiction-like behavior from others that, despite equivalent prior drug consumption, keep their use under control. The aim of our doctoral research, based on this rat addiction model, was to identify the neurobiological differences between addicted and non-addicted users, and then to start investigating neurobiological mechanisms that could underly transition to addiction. For this latter point we considered the major differences identified between addicts and non- addicts, and we studied their evolution from early (before addiction) to late cocaine use (after addiction development). We used a multidisciplinary approach associating behavioral, molecular and systems neuroscience. We compared addicts and non-addicts by means of a targeted strategy and a non-targeted strategy. The non-targeted strategy consisted in evaluating large-scale gene expression by means of a gene–profiling technique (approximately 28,000 genes tested simultaneously). The targeted approach consisted in analysing factors known to be modified by the use or chronic administration of cocaine. Concentrating on one main structure, the nucleus accumbens, we studied: (i) the expression of targeted genes by means of qPCR; (ii) several forms of synaptic plasticity using in vitro electrophysiology; (iii) the activity of the dopaminergic neurons of the ventral tegmental area (VTA) (projecting towards the nucleus accumbens) using in vivo electrophysiology; (iv) the liberation of dopamine in the nucleus accumbens by means of in vivo microdialysis. We showed that addict and non-addict rats adapt to cocaine in very different ways.
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