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Paper Del Receptor 5HT1A En El Mecanisme D'acció De Psicofàrmacs

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Paper Del Receptor 5HT1A En El Mecanisme D'acció De Psicofàrmacs Paper del receptor 5HT1A en el mecanisme d’acció de psicofàrmacs Laia Lladó Pelfort ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tesisenxarxa.net) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tesisenred.net) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tesisenxarxa.net) service has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized neither its spreading and availability from a site foreign to the TDX service. Introducing its content in a window or frame foreign to the TDX service is not authorized (framing). This rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. Centro de Investigación Biomédica En Red de Salud Mental Paper del receptor 5HT1A en el mecanisme d’acció de psicofàrmacs Tesi doctoral presentada per Laia Lladó Pelfort Barcelona, juny de 2010 Treball presentat per optar al grau de Doctora per la Universitat de Barcelona, Programa de Doctorat de Neurociències (Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona). Departament de Neuroquímica i Neurofarmacologia Institut d’Investigacions Biomèdiques de Barcelona (IIBB) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Consejo Superior de Investigaciones Científicas (CSIC) Els directors: Dra. Mª Pau Celada Pedrosa Dr. Francesc Artigas Pérez Investigadora IDIBAPS Professor d’Investigació del CSIC Signat: Laia Lladó Pelfort Barcelona, juny 2010 El present treball ha estat finançat amb els següents projectes: - Modulación serotoninérgica de la corteza prefrontal: relevancia en el tratamiento de la depresión y la esquizofrenia. CICYT SAF2007-62378 - Modulación de los circuitos cortico-mesencefálicos por receptores 5-HT1A. Relevancia en la acción terapéutica de los fármacos antipsicóticos. FIS PI060264 - Monoaminergic neurotransmission in prefrontal cortex: Target for augmentation strategies in schizophrenia. SENY Fundació - Effects of F15599 and F13640 on pre- and postsynaptic 5-HT1A receptors in rat brain: in vivo electrophysiological studies. Pierre Fabre Médicament-IDIBAPS - Actividad cortical y alucinaciones. Nuevo modelo experimental para la identificación de dianas terapéuticas en esquizofrenia. FIS PI09/1245 I ha estat realitzat amb el suport econòmic d’una beca predoctoral del programa de la “Junta para la Ampliación de Estudios” (JAE) del Consejo Superior de Investigaciones Científicas (CSIC). A la meva família “Jo no m’assec i deixo que les veus em destrossin. Em defenso el millor que puc. De vegades, els crido tan fort i tan alt que la infermera del meu psiquiàtric ha de posar-me una injecció. Si no puc ignorar-les, intento contestar amb la veu lleugerament més alta que la seva.” Extret del relat d’un malalt d’esquizofrènia Diuen que tots els científics aportem el nostre granet de sorra i que tard o d’hora es veuen els resultats, com passa en un formiguer. Vull donar les gràcies a totes les persones que en aquests anys m’han ajudat a empentar el meu granet de sorra en el formiguer de les malalties mentals. Gràcies pels somriures càlids que cada dia em trobo al laboratori i al passadís, per les calçotades, costellades, asados, sopars i cervesetes vàries, per tots els companys de viatges i excursions, per les aterrades a Montjuïc amb accent argentí, pels cables soldats en bona companyia, per les músiques enganxoses de mitja tarda, per les sessions de jazz a la Ciutadella, els concerts i les festes sense fi, pels wiiiiiis, els grans dies i els atacs de riure, per les xerrades a la terrassa amb cigarros sense cigarro i els cafès sense cafè i pels trens perduts en el millor moment. Perquè no tot en la ciència és ciència. Illustració de portada: Margarita Pelfort Balaguer “El receptacle de l’ànima i del control del moviment voluntari -de fet de les funcions nervioses en general- ha de ser situat al cor. El cervell és un òrgan de menor importància, potser necessari per refredar la sang.” Aristòtil (384-322 a.C.) Citat a Nussbaum (1978) Aristotle’s De Motu Animalium. Princeton University Press, Princeton, NJ “El foll”, 1904 Pablo Ruiz Picasso (1881-1973) Aquarella sobre paper Índex Abreviacions 5 Introducció general 11 L’escorça prefrontal 13 Definició 13 Funció 14 Subdivisions funcionals 14 Primats Rata Connectivitat 16 Connectivitat amb el tàlem Connectivitat cortico-cortical Connectivitat subcortical Arquitectura 17 Tipus de neurones corticals 17 Neurones piramidals Interneurones GABAèrgiques Altres tipus neuronals Relació entre diferents tipus de neurones corticals Unitat funcional 22 Activitat cortical 23 Interacció recíproca entre l’EPF i els sistemes moduladors ascendents 25 Sistemes moduladors ascendents 25 Sistema serotoninèrgic Connectivitat entre sistemes moduladors i l’EPF 29 Interacció entre sistemes moduladors i l’EPF 30 Modulació de la fisiologia cortical Modulació de les funcions corticals 1 El receptor 5-HT1A 33 Descobriment, clonatge i descripció del gen 33 Distribució anatòmica del receptor al sistema nerviós 33 La proteïna: El receptor 5-HT1A com a GPCR 34 Mecanismes de transducció de senyals Desensibilització del receptor Oligomerització Funció 36 Relació del receptor 5-HT1A amb les funcions cognitives Esquizofrènia 41 Introducció 41 Simptomatologia i diagnosi 41 Etiologia, fisiopatologia i hipòtesis 42 Tractament 44 El receptor 5-HT1A en la fisiopatologia i el tractament de l’esquizofrènia 46 Estudis en animals Estudis en humans Depressió 47 Introducció 47 Simptomatologia i diagnosi 47 Deteriorament cognitiu en depressió Etiologia, fisiopatologia i hipòtesis 48 Tractament 49 El receptor 5-HT1A en la fisiopatologia i el tractament de la depressió 50 Variants del gen del receptor 5-HT1A Quantificació del receptor en pacients depressius El receptor 5-HT1A i la hipòtesi relacionada amb l’estrès El receptor 5-HT1A i la hipòtesi neurotròfica El receptor 5-HT1A i el tractament monoaminèrgic Dolor 55 Introducció 55 2 El receptor 5HT1A en el processament i el tractament del dolor 56 Hipòtesi de treball i objectius 61 Materials i mètodes 65 Materials 65 Animals Fàrmacs Registres electrofisiològics in vivo en rata anestesiada 66 Preparació dels animals Preparació dels elèctrodes Sistemes Identificació de les neurones Farmacologia Histologia Anàlisi de dades Microdiàlisi intracerebral in vivo en rata anestesiada 78 Preparació de les sondes de microdiàlisi Preparació dels animals Obtenció de mostres Histologia Anàlisi de mostres Anàlisi estadístic 80 Resultats 85 Treball 1 87 L’agonista 5-HT1A 8-OH-DPAT provoca excitacions de les neurones piramidals d’EPFm a través de l’acció preferent sobre les interneurones GABAèrgiques Treball 2 131 L’F15599, un nou agonista del receptor 5-HT1A, amb acció preferencial sobre els heteroreceptors postsinàptics in vivo Treball 3 145 Efectes in vivo del nou agonista 5-HT1A F13640 sobre autoreceptors i heteroreceptors 5-HT1A de rata Treball 4 181 Efecte de diferents agonistes 5-HT1A sobre les oscil·lacions de baixa freqüència de l’EPFm de rata 3 Treball 5 209 Caracterització del DU 125530, un antagonista 5-HT1A amb possible aplicació en la potenciació de tractaments antidepressius Discussió general 247 Selectivitat regional 247 Senyalització dirigida per agonista 249 Excitacions produïdes per agonistes d’un receptor inhibitori 251 Les interneurones GABAèrgiques podrien tenir un paper clau en la desinhibició de les neurones piramidals d’EPF 253 Control de la via dopaminèrgica mesocortical i esquizofrènia 255 Interneurones GABAèrgiques i esquizofrènia 258 Millora del tractament antidepressiu 260 Ús d’agonistes 5-HT1A pel tractament del dolor 262 Activitat oscil·latòria 263 Conclusions 267 Bibliografia 271 4 Abreviacions 5-HIAA 5-hydroxy-indolacetic acid 5-HT Serotonina; 5-hidroxi-triptamina 5CSRTT 5 choice serial reaction time task 8-OH-DPAT 8-hidroxi-N,N-dipropil-2-aminotetralina
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