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Implication Des Recepteurs 5-Ht2 Dans Trois Modeles Animaux D'anxiete Chez La Souris

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Implication Des Recepteurs 5-Ht2 Dans Trois Modeles Animaux D'anxiete Chez La Souris UNIVERSITE DE NANTES FACULTE DE MEDECINE IMPLICATION DES RECEPTEURS 5-HT2 DANS TROIS MODELES ANIMAUX D’ANXIETE CHEZ LA SOURIS THESE DE DOCTORAT Ecole Doctorale : Chimie-Biologie Discipline : Médecine Spécialité : Neuropsychopharmacologie Présentée et soutenue publiquement par Bríd Áine NIC DHONNCHADHA Le 15 décembre 2003, devant le jury ci-dessous Rapporteurs : Madame Sandra FILE, Professeur de Psychopharmacologie, Université de Londres, Londres, Royaume Uni Madame Catherine BELZUNG, Professeur de Pharmacologie, Université de Tours Examinateurs : Madame Pascale JOLLIET, Professeur de Pharmacologie, Université de Nantes Monsieur Michael SPEDDING, Directeur des Sciences Expérimentale, Servier, Paris Madame Martine HASCOET-LE CLEACH, Docteur en Pharmacologie, Université de Nantes Monsieur Michel BOURIN, Professeur de Pharmacologie, Université de Nantes Directeurs de thèse : Monsieur Michel BOURIN ABREVIATIONS 5-HT : .5-hydroxytryptamine SN : système nerveux SNC : système nerveux central NR : noyaux du raphé NCL : noyau caudal linéaire NRM : noyau du raphé median NRD : noyau du raphé dorsal NRP : noyaux du raphé pallidus NRO : raphé obscurus NRM : raphé magnus SN : substance noire ATV : l'aire tegmentale ventrale NAc : noyau accumbens TpH : tryptophane hydroxylase VMAT2 : transporteur de type 2 vésiculaire de la monoamine SERT : protéine transporteuse de la sérotonine MAO-A : monoamine oxydase-A ARNm : acide ribonucléique c messager i3 : boucle intracellulaire 3 GPCR: G protein-coupled receptor TM : transmembranaires 5,7-DHT : 5,7-dihydroxytryptamine DAergic : dopaminergic DA : dopamine GABA: gamma-aminobutyric acid FPT: Four Plate test L/D: Light/dark test EPM: Elevated Plus Maze ANOVA : ESM : écart standard à la moyenne kg : kilogramme mg : millegramme µl : microlitre min. minute s : second CLHP : chromatographie liquide à haute performance mCPBG : metachlorophenylbiguanide AI Activité intrinsique 2 BUS: buspirone TAG: Trouble D‟Anxiéte Generalisé TP: Trouble de Panique 5-HTTP: 5-hydroxytryptophan IRSS(s): inhibiteur de la recaptage sélectif de la sérotonine(s) AD(s): Antidepresseurs(s) IRSN: inhibiteur mixte de la recaptage de la NA et de la 5-HT HVA: l‟acide homovanillique 5-HIAA: le l‟acide 5-hydroxy-3-indoleactique NA: Noradrenaline PAG: substance grise périaqueductale IS: Test de Interaction Sociale G-S: Test de Geller-Seifter VMAT2 : transporteur vésiculaire de type 2 de la monoamine TpH : tryptophane hydroxylase SERT :protéine transporteuse de la sérotonine MAO A : monoamine oxydase A ARNm : ribonucléique messager CPF : cortex prefrontal AA : d'acide arachidonique PI : phophoinositide MAP-kinase : protéine mitogen kinase BDNF : facteur dérivé neurotrophique cérébral JaK : kinase Janus STAT: signal transducers and activators of transcription PL : Phospholipases Ca++ :Calcium PKC : Proteine kinase C NO : Oxyde nitrique cNOS :NOS constitutive iNOS :NOS inductible AMPc : Adénosine monophosphate cyclique GMPc : Guanine monophosphate cyclique UEEPM : labyrinthe élevé instable ETM : labyrinthe en T élevé EBO : Entrées Bras Ouverts EBF : Entrés Bras Fermés ET : Entrés total TBO : Temps Bras Ouverts TBF : Temps Bras Fermés 3 TT : Temps Total KO: Knouckout SAP: Stretched Attend Posture 4 TABLE DES MATIERES 1 INTRODUCTION ......................................................................................................................................... 9 2. LA SEROTONINE...................................................................................................................................... 12 2.1. HISTORIQUE ....................................................................................................................................... 12 2.2. DISTRIBUTION DE LA SEROTONINE DANS LE SYSTEME NERVEUX ..................................... 13 2.3. LA SYNTHESE SEROTONINERGIQUE............................................................................................ 16 2.4 LES RECEPTEURS SEROTONINERGIQUES ................................................................................... 18 3. DISTRIBUTION DES RÉCEPTEURS 5-HT2 DANS LE SYTEME NERVEUX ................................. 20 3.1 LES RECEPTEURS 5-HT2A ................................................................................................................. 21 3.2 LES RECEPTEURS 5-HT2B ................................................................................................................. 23 3.3 LES RECEPTEURS 5-HT2C ................................................................................................................. 24 3.4 INTERACTIONS ENTRE LES RECEPTEURS 5-HT2 ET LES AUTRES SYSTEMES DE NEUROTRANSMISSION ..... 25 3.4.1 Les récepteurs 5-HT2 et le système dopaminergique (DAergique) ................................................ 25 3.4.2 Les récepteurs 5-HT2 et le système glutamatergique .................................................................... 26 3.4.3 Les récepteurs 5-HT2 et le système GABAergique ........................................................................ 26 4 SIGNAL DE TRANSDUCTION DU RÉCEPTEUR ............................................................................... 28 4.1 LES RECEPTEURS 5-HT2A ................................................................................................................. 29 4.2 LES RECEPTEURS 5-HT2B ................................................................................................................. 30 4.3 LES RECEPTEURS 5-HT2C. ................................................................................................................ 31 5 PHARMACOLOGIE DES RECEPTEURS 5HT2 ................................................................................... 32 5.1 STRUCTURE DU RECEPTEUR COUPLE A UNE PROTEINE G.................................................... 33 5.2 LES RECEPTEURS 5-HT2A ................................................................................................................. 34 5.3 LES RECEPTEURS 5-HT2B ................................................................................................................. 35 5.4 LES RECEPTEURS 5-HT2C ................................................................................................................. 35 5.4.1 Edition de l'ARN du récepteur 5-HT2C .......................................................................................... 36 5.5 ACTIVITE CONSTITUTIVE ............................................................................................................... 37 5.6 CARACTERISATION DES SOUS TYPES DE RECEPTEURS 5-HT2 IN VITRO .............................. 38 5.6.1 Etude de liaison ............................................................................................................................. 39 5.6.2 Etudes de l’hydrolyse des phophoinositides (PI) .......................................................................... 39 5.6.3 Affinité des ligands des récepteurs 5-HT2 ..................................................................................... 40 5.7 CARACTERISATION DES SOUS TYPES DE RECEPTEURS 5-HT2 IN VIVO ................................ 43 5.7.1 Mouvement de torsion de la tête .................................................................................................... 44 5.7.2 Alimentation .................................................................................................................................. 44 5.7.3 Régulation de la température ........................................................................................................ 45 5.7.4 Activite Motrice ............................................................................................................................. 46 5.7.5 Comportement sexuel .................................................................................................................... 47 6 LES MODELES ANIMAUX DE L'ANXIETE ........................................................................................ 48 6.1 LES MODELES D'ANXIETE CHEZ LA SOURIS .............................................................................. 51 6.1.1 Le test du labyrinthe en croix elevé (EPM) ................................................................................... 52 6.1.2 Le test de la double enceinte illuminée (Light/Dark Paradigm, L/D) ........................................... 56 6.1.3 Le test des quatre plaques (Four Plates Test, FPT) ...................................................................... 58 7 SYSTEME SEROTONINERGIQUE ET ANXIETE ............................................................................... 60 7.1 LES RECEPTEURS 5-HT1A ................................................................................................................. 63 7.2 LES RECEPTEURS 5-HT3 ................................................................................................................... 64 8 RECEPTEURS 5-HT2 ET ANXIETE ....................................................................................................... 66 8.1 NEUROANATOMIE DE L'ANXIETE................................................................................................. 67 8.2 LES RECEPTEURS 5-HT2A ................................................................................................................. 70 8.3 LES RECEPTEURS 5-HT2B ................................................................................................................. 73 8.4 LES RECEPTEURS 5-HT2C ................................................................................................................
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