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Approches Pharmacologique Et Génétique in Vivo Chez La Souris Thanh Hai Nguyen

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Approches Pharmacologique Et Génétique in Vivo Chez La Souris Thanh Hai Nguyen Cibles sérotoninergiques et non sérotoninergiques des ISRS : approches pharmacologique et génétique in vivo chez la souris Thanh Hai Nguyen To cite this version: Thanh Hai Nguyen. Cibles sérotoninergiques et non sérotoninergiques des ISRS : approches pharma- cologique et génétique in vivo chez la souris. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2011. Français. NNT : 2011PA114833. tel-00663312 HAL Id: tel-00663312 https://tel.archives-ouvertes.fr/tel-00663312 Submitted on 26 Jan 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ PARIS-SUD 11 ECOLE DOCTORALE : INNOVATION THÉRAPEUTIQUE : DU FONDAMENTAL A L’APPLIQUÉ PÔLE : PHARMACOLOGIE ET TOXICOLOGIE DISCIPLINE : Neuropharmacologie ANNÉE 2010 - 2011 SÉRIE DOCTORAT N° THÈSE DE DOCTORAT Soutenue le 30 novembre 2011 Par Thanh Hai NGUYEN Cibles sérotoninergiques et non sérotoninergiques des ISRS : Approches Pharmacologique et Génétique in vivo chez la souris Directeur de thèse : Pr Alain GARDIER Co-directeur de thèse : Dr Bruno GUIARD Rapporteurs : Pr Michel BOULOUARD (Université de Caen) Dr Nasser HADDJERI (Unversité de Lyon) Membres du jury : Pr Catherine MARCHAND LEROUX (Université de Paris 5) Dr Alain GOBERT (Laboratoires Servier) Dr Bruno GUIARD (Université Paris-sud 11) Pr Alain GARDIER (Université Paris-sud 11) DEDICACE A MA MERE A MA FEMME A MA FILLE 2 REMERCIEMENTS Parce que sans vous, rien n’est possible ! Ce travail de thèse a été réalisé au sein du laboratoire de Neuropharmacologie-EA3544 de la faculté de pharmacie de Chatenay Malabry à l’Université de Paris Sud XI sous la co- direction du Professeur Alain GARDIER et du Docteur Bruno GUIARD. Je tiens à exprimer ma très vive reconnaissance au Professeur Alain GARDIER pour m’avoir accueilli au sein de son laboratoire, me permettant ainsi d’effectuer ce travail de recherche dans les meilleures conditions. Je le remercie également d’avoir accepté la direction de ces travaux durant lesquels il m’a offert sa confiance, son soutien et ses conseils, tout en restant l’exemple absolu du travailleur infatigable, avec un sens aigu pour le détail, ce qui m’a toujours motivé pendant ce projet. J’adresse ma profonde gratitude au Docteur Bruno GUIARD qui m’a encouragé dans cette voie scientifique et qui m’a ainsi encadré pendant ma formation de haut niveau depuis mes premiers pas dans la recherche. Merci de m’avoir transmis de nouveaux principes scientifiques fondés sur une base de créativité, de rigueur et de motivation. J’ai beaucoup apprécié son esprit ouvert aux nouvelles initiatives, ce qui traduit ainsi sa vision sur la formation d’un chercheur et sa capacité à devenir autonome. J’espère pouvoir poursuivre ce qu’il m’a enseigné dans le cadre de ma recherche au Vietnam, à l’Université de Pharmacie de Hanoï. Merci pour toute sa confiance, ainsi que pour ses conseils sur le plan professionnel et personnel. Je remercie Monsieur le Docteur Michel BOULOUARD, Professeur des universités (Université de Caen Basse-Normandie) ; Monsieur le Docteur Nasser HADDJERI, Chargé de recherche à l’INSERM U512 (Université Claude Bernard Lyon 1, France) qui ont accepté d’évaluer et de juger ce manuscript en qualité de rapporteurs et experts des travaux neuropsychopharmacologiques réalisés chez le Rongeur. Je remercie également, Monsieur le Docteur Alain GOBERT, Responsable de l’Institut de Recherches Servier et Madame le Professeur Catherine MARCHAND- LEROUX, Responsable de l’EA 4475 (Université Paris 5 Descartes) qui me font l’honneur de juger mon travail de doctorant en tant que spécialistes de neuropharmacologie expérimentale. 3 Je tiens à remercier Thu Thuy, ma femme merveilleuse, pour s’être occupée de notre amour, la petite princesse Thao Vy au cours de ces denières années. Ce travail, c’est la liberté que tu m’as offerte qui m’a permis de le concrétiser. Maintenant, je voudrais rentrer chez nous et j’essaierai de t’épauler aussi bien que tu l’as fait pour moi ! Mes remerciements les plus chaleureux sont dédiés à tous (tes) mes amis (es) qui, au cours de ces années, m’ont stimulé et aidé dans une ambiance très agréable. Un remerciement tout particulier aux collègues du Laboratoire de Neuropharmacologie-EA 3544: Docteur Denis David, Docteur Jean Philippe Guilloux, Docteur Thierry Deltheil, Docteur Quentin Rainer, Professeur François Coudoré, Gaël Quesseveur, Sophie Orvöen, Guillaume Hache, Yannick Le Dantec, Lin Xia, Christelle Répérent, Isabelle Seif et Louise Huchard. Merci à vous tous, car vous avez modelé mon esprit et mon caractère pendant ces quatre années en France. Merci enfin au personnel du Service Commun de l’Animalerie de la faculté qui, au cours de ces années, a tout mis en œuvre pour le bien-être des (malheureuses !) Souris. 4 PUBLICATIONS GUILLOUX JP, DAVID DJP, XIA L, NGUYEN TH, REINER Q, GUIARD BP, REPERANT C, DELTHEIL T, TOTH M, HEN R, GARDIER AM. Characterization of 5- HT1A/1B -/- mice: a new animal model sensitive to anxiolytic treatments. Neuropharmacology 2011, 61(3):478-88. ARTICLE 1. RICHARDSON-JONES JW, CRAIGE CP, NGUYEN TH, KUNG HF, GARDIER AM, DRANOVSKY A, DAVID DJ, GUIARD BP, BECK SG, HEN R, LEONARDO ED. Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. The journal of Neuroscience. 2011, 31(16): 6008-18. ARTICLE 2. QUESSEVEUR G*, NGUYEN TH*, DAVID I, XIA L, GARDIER AM, GUILLOUX JP, DAVID DJP, GUIARD BP. Importance of 5-HT1A auto- and 5-HT2A hetero-receptors interaction the in maintenance of a negative feedback on the serotonergic system. En préparation. ARTICLE 3. RAINER Q*, NGUYEN TH*, QUESSEVEUR G, GARDIER AM, DAVID DJ, GUIARD BP. Functional status of somatodendritic 5-HT1A autoreceptor after chronic treatment with fluoxetine in a mouse model of anxiety/depression. Molecular Pharmacology. ARTICLE 4. NGUYEN TH, GUIARD BP, BACQ A, DAVID DJ, DAVID I, QUESSEVEUR G, GAUTRON S, SANCHE C, GARDIER AM. Blockade of the high-affinity norepinephrine transporter (NET) by the selective serotonin reuptake inhibitor escitalopram: an in vivo microdialysis study in mice. BJP. ARTICLE 5. 5 COMMUNICATIONS AFFICHEES NGUYEN TH, GUIARD BP, REPERANT C, DAVID D.J.D, SANCHEZ C, GARDIER AM. Effects of chronic treatment with escitalopram on extracellular serotonin, norepinephrine and dopamine levels in the frontal cortex of freely moving Swiss mice: an in vivo microdialysis study. 39th Annual Meeting Soc. Neurosci 2009, Chicago. GUIARD BP, NGUYEN TH, XIA L, RAINER Q, DAVID DJ, GUILLOUX JP, GARDIER AM. Evidence of the involvement of 5-HT2 receptor on SSRI-induced inhibition of dorsal Raphe 5-HT neurons firing rate in double 5-HT1A/1B receptor knockout mice. 27th Annual Meeting of International College of Neuro-Psychopharmacology. 2010, Hong-Kong. NGUYEN TH, GUIARD BP, QUESSEVEUR G, DAVID DJ, GARDIER AM. Effets de l’administration d’une dose unique de escitalopram sur les concentrations extracellulaires de 5-HT et de NA dans le cortex frontal chez la souris WT et KO SERT. 10ème Journées de l'Ecole Doctorale-ED425, Université de Paris Sud 11. 2010, Orsay. NGUYEN TH, GUIARD BP, BACQ A, DAVID D.J.D, DAVID I, QUESSEVEUR G, GAUTRON S, SANCHEZ C, GARDIER AM. Effets de l’administration d’escitalopram sur les concentrations de sérotonine [5-HT]ext et de noradrénamine [NE]ext dans le cortex frontal chez la souris. 11ème Journées de l'Ecole Doctorale-ED425, Université de Paris Sud 11. 2011, Chatenay Malabry. 6 SOMMAIRE DEDICACES 2 REMERCIEMENTS 3 LISTE DES PUBLICATIONS 5 LISTE DES COMMUNICATIONS AFFICHEES 6 SOMMAIRE 7 ABREVIATIONS 10 INDEX DES TABLEAUX 11 INDEX DES FIGURES 12 INTRODUCTION ET OBJECTIFS 13 RAPPELS BIOGRAPHIQUES 18 A. LE SYSTEME SEROTONINERGIQUE ET LES ELEMENTS CLES DE LA REPONSE AUX ISRS 19 1. La sérotonine : synthèse, libération, inactivation, localisation et rôle physiologique 19 2. Les récepteurs de la sérotonine : classification et rôles 21 2.1. Les autorécepteurs 5-HT1A 23 1) Distribution 23 2) Couplage et propriétés électrophysiologiques des récepteurs 5-HT1A 24 3) Expression des récepteurs 5-HT1A chez les patients dépressifs 25 4) Régulation de l’expression du récepteur 5-HT1A 27 5) Dichotomie de réponse aux ISRS des récepteurs 5-HT1A pré- et post-synaptiques 29 6) Les récepteurs 5-HT1A dans les troubles anxio/dépressifs 30 2.2. Les hétérorécepteurs 5-HT2A 32 1) Distribution 32 2) Couplage des récepteurs 5-HT2A 32 3) Polymorphisme du récepteur 5-HT2A (rôle dans la dépression et la réponse aux ISRS) 33 4) Les récepteurs 5-HT2A dans les troubles anxio/dépressifs 34 a) Etudes comportementales 34 b) Rétrocontrôle du système sérotoninergique par les hétérorécepteurs 5-HT2A 35 2.3. Les hétérorécepteurs 5-HT2C 37 1) Variations génétiques du récepteur 5-HT2C 37 2) Distribution 38 3) Couplage des récepteurs 5-HT2C 39 4) Les récepteurs 5-HT2C dans les troubles anxio/dépressif 39 a) Etudes comportementales 39 b) Rétrocontrôle du système sérotoninergique par les hétérorécepteurs 5-HT2C 40 7 3. Le transporteur de la sérotonine 42 3.1. Structure et fonctionnement du transporteur de la sérotonine 42 3.2. Distribution dans le système nerveux central 43 3.3. Pharmacologie du transporteur de la sérotonine 44 3.4. Souris génétiquement modifiées pour le SERT : études de pharmaco-génétiques 45 3.5. Les autres moyens de transport de la sérotonine 46 1) La recapture hétérologue 46 2) La recapture de la 5-HT par les OCT ou les PMAT 47 B. LA DEPRESSION MAJEURE ET TRAITEMENTS 49 1.
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