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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Peptime-mediated interactions in high-resolution 3-dimensional structures

Stein, Amelie 11 June 2010 (has links)
Proteins and protein interactions are involved in virtually all processes of life. Here we study interactions between globular domains and short linear motifs, which form a small interface ideal for transient interactions. Despite the small number of contacts involved, these domain-motif interactions (DMIs) are known to be highly specific in vivo. We have identified hundreds of instances of DMIs in high-resolution 3-dimensional (3D) structures to analyze the molecular basis of their high specificity. Furthermore, we have derived structural parameters to identify DMIs in 3D structures in a more general, motif-independent way. An important class of DMIs are kinase-substrate interactions. By combining the phosphorylation motif with different kinds of contextual information, we could predict substrates of the human kinase Aurora A. Lastly, we have incorporated DMIs into our database of 3D interacting domains (3did) to disseminate our results to the scientific community for future research. Los procesos moleculares subyacentes a la mayoría de funciones biológicas implican la participación directa de una infinidad de proteínas y múltiples interacciones entre ellas. En esta tesis estudiamos un tipo particular de estas interacciones, de carácter transitorio y altamente específicas, dónde un dominio globular en una proteína reconoce un corto péptido lineal en otra (DMIs). En concreto, identificamos múltiples casos de DMIs en estructuras tridimensionales (3D) de alta resolución y analizamos las bases moleculares de su especificidad. Además, derivamos parámetros estructurales globales que nos permiten identificar nuevos casos de DMIs. Así mismo, y como caso práctico, combinamos el motivo de fosforilación propio de la quinasa humana Aurora A con diversas clases de información contextual para predecir y validar 90 nuevos substratos. Por último, incorporamos las caracterizadas DMIs en nuestra base de datos de interacciones en 3D (3did) con el fin de diseminar nuestros resultados entre la comunidad científica.
12

Hormonas tiroideas: efectos de la exposición a compuestos organoclorados y relación con el neurodesarrollo

Álvarez Pedrerol, Mar 19 July 2010 (has links)
Las hormonas tiroideas (HT) son esenciales para el desarrollo normal del cerebro. El desbalance tiroideo en la etapa fetal y postnatal puede producir retraso neuroconductual. La exposición a compuestos organoclorados (OCs) puede alterar los niveles de HT y tirotropina (TSH). El objetivo principal es estudiar el efecto de los OCs en el sistema tiroideo, y la asociación entre las HT y TSH, y el desarrollo neuroconductual y crecimiento en poblaciones sanas. Métodos: A partir de modelos de regresión y modelos GAM se estimó: 1) la relación entre los OCs, y las HT y TSH, y 2) la asociación de las HT, TSH y el consumo de yodo, con el neurodesarrollo y crecimiento, en mujeres embarazadas y niños sanos de diferentes regiones de España. Resultados: La exposición ambiental, tanto prenatal como postnatal, a OCs altera los niveles de HT, especialmente los de triyodotironina. Las concentraciones de tiroxina y TSH se asocian con el neurodesarrollo. El consumo de yodo durante el embarazo se relaciona con el peso al nacer. Conclusiones: La variabilidad en la exposición ambiental a OCs tiene un efecto en los niveles de HT. La variabilidad, dentro de los rangos de referencia, de las concentraciones de tiroxina y TSH tiene un efecto negativo en el neurodesarrollo. / Thyroid hormones (THs) are essential for normal brain development. The thyroid misbalance during prenatal and postnatal period can cause mental retardation. Esposure to organochlorine compounds (OCs) can alter THs and thyrotropin (TSH) levels. The main objective is to study the effect of OCs on thyroid system, as well as the association between TH and TSH, and neurodevelopment and growth in healthy populations. Methods: The association between OCs and THs and TSH, and the association between THs, TSH and iodine consumption, and neurodevelopment and growth was estimated in healthy pregnant women and children from several areas of Spain. Regression and GAM models were used. Results: TH levels (particularly triiodothyronine levels) are affected by prenatal and postnatal exposure to OCs. Thyroxine and TSH concentrations are related to neurodevelopment. Iodine consumption during pregnancy is associated with birthweight. Conclusions: Differences in exposure to OCs have an effect on TH levels. Variations in thyroxine and TSH levels, within reference levels, have a negative effect on neurodevelopment.
13

The role of molecular motor HKLP2 in spindle assembly

Vanneste, David 21 September 2010 (has links)
During cell division, a macromolecular machine is assembled to segregate the two sets of chromosomes carrying the genetic material into the two daughter cells. This machine, the mitotic spindle, is a bipolar array composed of microtubules and proteins that control their dynamics and organization. Kinesins are molecular motors that can apply forces to the microtubules and arrange them in space to assemble a bipolar spindle. Here we characterized the human kinesin Hklp2 as an important player in bipolar spindle assembly and maintenance. Hklp2 is a kinesin that localizes to the spindle microtubules and the chromosomes in mitosis. Its localization to the microtubules depends on TPX2, a crucial factor in microtubule nucleation. Hklp2 localization to the chromosomes necessitates the presence of cell proliferation marker Ki67 whose function is currently unknown. Hklp2 helps the separation of the centrosomes during the establishment of spindle bipolarity and plays a role in the subsequent maintenance of bipolarity during metaphase. This role is probably achieved through a cross-linking of the microtubules. Interestingly, the populations of the kinesin present on the microtubules and the chromosomes have different functions. / Durante la división celular, tiene lugar el ensamblaje de la maquinaria macromolecular encargada de segregar los dos conjuntos de cromosomas en las dos células hijas. Esta maquinaria, el huso mitótico, es una matriz bipolar compuesta de microtúbulos y de proteínas que controlan la dinámica y la organización. Las quinesinas son motores moleculares que pueden ejercer fuerzas sobre los microtúbulos y organizarlos en el espacio para dar lugar al huso bipolar. Este estudio aporta evidencias del papel importante de la quinesina humana Hklp2 en el ensamblaje y en la estabilidad del huso mitótico. Hklp2 es una quinesina que se localiza en los microtúbulos del huso y en los cromosomas durante la mitosis. Su localización en los microtúbulos depende de TPX2, un factor importante en la nucleación de microtúbulos. Para que Hklp2 se localice en los cromosomas, este necesita la presencia del marcador de proliferación Ki67, la función del cual se desconoce actualmente. Hklp2 participa en la separación de los centrosomas durante el establecimiento de la bipolaridad del huso mitótico y posteriormente juega un papel importante en el mantenimiento de esta bipolaridad durante la metafase. Esta función probablemente se consiga haciendo lazos entre los microtúbulos. Las poblaciones de la quinesina presente en los microtúbulos y en los cromosomas tienen funciones diferentes.
14

The role of phosphorylation in the regulation of the chromokinesin Xkid

Ferreira, Vanessa Miriam dos Reis 22 November 2010 (has links)
Xkid is a Xenopus chromokinesin required for metaphase chromosome alignment and for meiosis I to meiosis II transition in oocytes. The aim of this work was to study the regulation of Xkid by phosphorylation using the Xenopus oocyte and egg extract systems. To achieve this, a reliable method to express proteins in egg extract by addition of in vitro transcribed mRNAs was established. Xkid was found to be efficiently phosphorylated in meiosis and mitosis at the cdk1 site. Although phosphoXkid localized efficiently to the mitotic chromosomes, phosphorylation at the cdk1 site had no role in the binding of Xkid to the chromosomes but prevented the protein to localize to the spindle microtubules like the endogenous protein. The dominant negative effect on spindle assembly of a phospho mimicking form of Xkid indicated that phosphorylation plays an important role in the regulation of Xkid function. Several partners for Xkid were identified. / Xkid es una cromoquinesina del sistema de Xenopus, necesaria para el alineamiento de los cromosomas en la placa metafásica y para la transición entre la meiosis I y meiosis II en los oócitos. El objectivo de este trabajo era estudiar la regulación de Xkid por fosforilación en los oócitos y en el extracto de huevos de Xenopus. Para poder cumplirlo se estableció un método para la expresión de proteínas añadiendo al extracto de huevos ARN mensajeros sintetizados in vitro. Los resultados obtenidos sugieren que Xkid es eficientemente fosforilada en el sitio cdk1 durante la meiosis y la mitosis. Aunque la forma de Xkid fosforilada se localiza eficientemente a nivel de los cromosomas mitóticos, esta fosforilación no parece tener ningún papel regulador sobre esta localización. En cambio, parece interferir con la localización de Xkid sobre los microtúbulos mitóticos. El efecto dominante negativo de la forma de Xkid que mimetiza la fosforilación durante la formación del huso mitótico, sugiere además que la fosforilación desempeña un papel importante en la regulación de la función de Xkid. Finalmente, varias proteínas que interaccionan con Xkid han sido identificadas.
15

The role of NIMA-like kinase Nek9 in mitosis

Schütz, Martin Maximilian 01 July 2011 (has links)
Mitosis is the essential process during which a cell divides into two viable daughter cells. To allow a faithful segregation of the chromosomes into each daughter, the cell forms the bipolar spindle. The NIMA-like kinase family member Nek9 has been previously proposed to play a role in bipolar spindle assembly and in the chromosomal pathway of microtubule assembly. We aimed at gaining a better understanding of Nek9 function by characterizing Xenopus Nek9, xNek9, using the Xenopus egg extract system. We have shown that xNek9 may not act through the kinase cascade xNek9 – xNek6 in meiosis as described for human Nek9 in somatic cells and therefore may have different substrates. Furthermore, we have demonstrated by depletion, increased addition of Flag-hNek9 and a dominant-negative approach that xNek9 is important for bipolar spindle formation. In addition, we have shown that xNek9 depletion causes decreased microtubule density in bipolar spindles and slower RanGTP induced aster formation. We identified xNedd1, the adaptor protein for the γTuRC, as a novel interactor and substrate of xNek9. xNek9 depletion reduces the recruitment of xNedd1 to sperm nuclei induced aster and decreases the number and length of nucleated microtubules. These data suggest that one role of xNek9 in spindle assembly is exerted through xNedd1 regulation. We propose a model for xNek9 – xNedd1 interaction and a putative mechanism for the regulation of xNek9 – xNedd1 explaining how they fulfil their role in bipolar spindle assembly. / La mitosis es el proceso esencial durante el cual una célula se divide en dos células hijas viables. Para permitir una segregación fiable de los cromosomas en cada hija, la célula forma el huso bipolar. Nek9, el miembro de la familia de quinasas NIMA-like ha sido propuesto para desempeñar un papel en el la asamblea del huso bipolar y en la vía cromosómica de ensamblaje de los microtúbulos. Nuestro objetivo era lograr una mejor comprensión de la función Nek9 caracterizando Nek9 de Xenopus, xNek9, utilizando el sistema de extracto de huevos de Xenopus. Hemos demostrado que xNek9 probablemente no actuará a través de la cascada de las quinasas xNek9 - xNek6 en la meiosis como se describe para Nek9 humano en células somáticas y por lo tanto pueden tener diferentes sustratos. Además, hemos demostrado por el agotamiento, la adición incrementada de Flag-hNek9 y un enfoque dominante-negativas que xNek9 es importante para la formación del huso bipolar. Además, hemos demostrado que el agotamiento xNek9 causa una disminución de la densidad de los microtúbulos en los husos bipolares y una formación más lenta de asteres inducidos por RanGTP. Se identificó xNedd1, la proteína adaptadora para el γTuRC, como un interactor y sustrato novedoso de xNek9. El agotamiento de xNek9 reduce la contratación de xNedd1 a los asteres inducidas por núcleos de espermatozoides y disminuye el número y longitud de microtúbulos nucleados. Estos datos sugieren que un papel de xNek9 en el conjunto del huso se husorce a través de la regulación de xNedd1. Proponemos un modelo para la interacción xNek9 – xNedd1 y un supuesto mecanismo para la regulación de xNek9 – xNedd1 explicando cómo cumplen su papel en la ensamblaje del huso bipolar.
16

Sequence-Dependent nucleosome positioning and chromatin remolleing of hormone-responsive genes

Zaurín Quer, Roser 16 July 2009 (has links)
Evidències recents han remarcat la importància del paper de l'estructura de la cromatina i el posicionament de nucleosomes en processos cel·lulars bàsics com és la regulació de la transcripció gènica. L'avenç de noves tecnologies en el camp ha permès l'estudi detallat de la disposició de nucleosomes en genomes sencers. Hi ha hagut també molts intents per definir les característiques de la seqüència de l'ADN que podrien arribar a guiar el posicionament dels nucleosomes; sent el conjunt d'aquestes característiques l'anomenat "codi nucleosòmic". En la present tesis doctoral, s'aporten evidències experimentals sobre l'existència d'un grup de nucleosomes molt ben posicionats en el genoma humà. Això ha estat possible mitjançant tècniques com els microarray i la seqüenciació massiva en paral·lel. Aquest treball mostra com aquests nucleosomes, que anomenem "nucleosomes clau", tenen tendència a ocupar regions del genoma amb funcions específiques, la qual cosa indica el seu paper especial. L'ADN els "nucleosomes clau" resulta tenir una alta simetria de curvatura. Aquesta característica inherent a la seqüència fa que sigui possible la predicció in silico de les posicions de nucleosomes d'aquest tipus. En la segona part de la present tesi doctoral, aporto noves evidències experimentals que fan avançar el camp de la organització de la cromatina i la seva dinàmica en el context de la regulació gènica. Les hormones esteroidees indueixen la transcripció dels seus gens diana a través de la unió dels receptors hormonals amb els seu corresponent motiu de reconeixement a l'ADN (HREs), així com el reclutament d'una gran varietat de co- eguladors. El promotor del Virus de Tumor Mamari de Ratolí (MMTV) ha estat un model molt usat per l'estudi dels efectes en l'activació gènica dels receptors hormonals. És conegut que el receptor de progesterona (PR) s'uniex a l'HRE1, accessible, i recluta maquinàries de remodelament de la cromatina que utilitzen l'ATP com a font energètica per expulsar els dimers d'histones H2A/H2B del nucleosoma B del promotor de l'MMTV. Aquí demostro que la màquinaria de remodelament reclutada és específicament BAF. Treballs anteriors van demostrar que la kinasa Msk1 és la responsable de la fosforilació de la serina 10 de la histona H3. En aquesta tesi es demostra que l'acetilació de la Lysina 14 de la histona H3 és essencial per l'activació del promotor, així com per l'anclatge de BAF. Després de l'expulsió dels dimers d'H2A/H2B, la unió d'NF1 al promotor és indispensable per estabilitzar la forma remodelada del nucleosoma. Per l'estudi en més detall de l'activació del promotor de l'MMTV he utilitzat el sistema de minicromosomes, mononucleosomes i tetràmers d'histones H3/H4 reconstituïts en seqüències salvatges i mutants del promotor de l'MMTV. He demostrat que, només quan un fragment de la seqüencia de l'MMTV està reconstituïda en tetràmers, el PR i l'NF1 poden estar units simultàniament a la seva seqüència de reconeixement en el promotor. També aporto evidències on es demostra que la unió d'NF1 al promotor facilita la posterior unió de més mol·lècules de PR als HREs interns (llocs 2 i 3) caracterizant en més detall el sinergisme funcional que existeix entre el PR i l'NF1 en aquestes condicions. / Evidence has been accumulating over the last few years pointing to the importance of chromatin structure and nucleosome positioning in cellular processes such as transcriptional regulation. Recent technological advances in the field have allowed the construction of detailed genome-scale maps of nucleosome positions, and there have been several attempts to define the sequence characteristics that guide the positioning of nucleosomes, the so-called "nucleosome code". In this thesis I give experimental evidence for the existence of a subset of very well-positioned nucleosomes in the human genome based on nucleosome-resolution tilling arrays and on deep sequencing of MNase-digested chromatin using the Solexa-Illumina platform. I show that these nucleosomes, which we have named "key nucleosomes", tend to occupy genomic locations of specific function, indicative of their special role. The DNA of these "key nucleosomes" exhibits a high symmetry of curvature, allowing their precise position on the human genome to be predicted in silico based on the structural attributes of the primary DNA sequence. The second part of this thesis provides new insights into the importance of chromatin organization and dynamics in the context of gene regulation. Steroid hormones induce transcription of their target genes by a complex mechanism requiring binding of the hormone receptors to hormone responsive elements (HREs) and the recruitment of a variety of coregulators. The Mouse Mammary Tumor Virus (MMTV) promoter has long been used as a model for the study of hormone receptormediated gene activation. It is known that progesterone receptor (PR) binds the exposed HRE1 of the MMTV promoter chromatin and recruits chromatin remodellers that catalyse ATP-dependent histone H2A/H2B displacement. I show that the ATP- ependent chromatin remodelling complex BAF, but not PBAF, is recruited after hormone treatment and is necessary for MMTV promoter activation. Along with the previously reported osphorylation of H3S10 by Msk, I show that an early PCAF- ediated acetylation of H3K14 is essential for the activation of the promoter by anchoring the BAF complex. Following transient displacement of H2A/H2B dimers, binding of NF1 is required for stabilizing the remodelled conformation of the MMTVnucleosome. To further study the activation process I have used MMTVminichromosomes, mononucleosomes and H3/H4 tetramer particles reconstituted on wild type MMTV and MMTV promoter fragments with point mutations disrupting binding of PR and NF1. I show that only when MMTV sequences are assembled on H3/H4 tetramer particles can PR bind to all five HREs while allowing NF1 access to its cognate site. Furthermore, I found that binding of NF1 facilitates access of PR to the central HREs 2 and 3, thus contributing to the reciprocal synergism between PR and NF1.
17

A unified approach to the emergence of complex communication

Corominas Murtra, Bernat 12 July 2011 (has links)
Aquesta tesi estudia l'emergència de complexitat en sistemes de comunicació naturals, prenent el llenguatge humà com a principal objecte d'estudi. Ens centrem en i) Patrons estadístics de complexitat, ii) Mecanismes generatius i iii) aspectes relacionats amb la teoria de la informació. Primer mostrem un estudi on es quantifica l'emergència de la sintaxi al nivell ontogenètic usant la moderna teoria de xarxes complexes. Posteriorment, es proposa un esquelet matemàtic per a la sintaxi humana amb el propòsit d'identificar les mínimes propietats formals d'un sistema generatiu, essent aquest constructe consistent amb els patrons observats prèviament. Seguidament explorem un patró molt comú en sistemes de comunicació complexes, la llei de Zipf, presentant un argument que explica la seva emergència des de consideracions únicament basades en la teoria de la informació. Finalment, abordem el problema de la referencialitat, proposant una mesura consistent amb la teoria de la informació que evalua el seu grau de conservació en un intercanvi comunicatiu arbitrari. / This dissertation studies the emergence of complexity in natural codes taking human language as the object of study. We focus our analysis in i) Statistical patterns of complexity, ii) Generative mechanisms and iii) Information theoretic aspects of complex communication. We first provide a quantitative identification of the emergence of syntax at the ontogenetic level through modern theory of complex networks. We then propose a mathematical backbone for human syntax with the aim to identify the minimal formal properties for a natural generative system, which is consistent with the previous observed patterns. We follow by studying a well-known statistical pattern of complex communication systems, Zipf's law, for which we propose an information-theoretic argument accounting for its emergence. Finally, the problem of referentiality is studied, proposing an information-theoretic estimator to evaluate its degree of conservation in a given communicative exchange.
18

Ecology of the marine copepod genus Oithona

Zamora Terol, Sara 29 September 2013 (has links)
Copepods have a crucial role in the pelagic marine ecosystem, for their participation in the nutrient cycling and carbon export in biogeochemical cycles, and their role as link organisms between primary producers and higher trophic levels. Historically, marine zooplankton studies have focused on large organism (> 1mm), due to the use of relatively large mesh sizes in plankton nets, which has resulted in an underestimation of the importance of small copepods such as the genus Oithona. The study of small copepods, and especiall of Oithona, has raised special interest in recent years due to its great abundance and ubiquitous presence in both coastal and oceanic regions, and with a distribution that extends from polar to tropical . Besides their numerical dominance, Oithona also makes up a significant fraction of the biomass of copepods in certain regions. Their described low metabolic rates, coupled with an ambush feeding behavior and low mortality, are considered the clue of their success and of their capacity to maintain active populations throughout the year. Although new insights on the ecology of Oithona have been acquired in the past decade, knowledge on their vital rates is still very scarce. The lack of studies on the ecophysiology of Oithona contrasts with the large amount of studies conducted on calanoid copepods on aspects related to feeding, growth, and egg production. The main objective of this thesis was to contribute to a better knowledge and understanding of some biological and ecological aspects of the genus Oithona. For that purpose, we carried out laboratory experiments with cultured specimens, and experimental lab and fieldwork with natural populations in polar and tropical regions. In the laboratory we studied the effect of food concentration on ingestion and fecundity rates of Oithona davisae. The results obtained indicate that Oithona davisae is able to feed at very low food concentrations, which indicates its ability to exploit oligotrophic environments. Oithona capacity to reproduce continuously throughout the year, even in environments or periods of low food availability, was confirmed by the relatively high fertility rates observed in laboratory experiments at low food concentrations. The trophic role of Oithona, their natural diet and ingestion rates were studied in different pelagic ecosystems; as well as the fecudity of adult females in these ecosystems, and their relationship with environmental factors. We also investigated some aspects of the population ecology Oithona in polar regions (abundance, vertical distribution and migration patterns). The results of the in situ investigations were carried out in order to compare life strategies between Oithona species of contrasting habitats. In polar environments, winter reproductive activity of the adult females was observed, which highlights the importance of small copepods in high-latitude environments, especially when large calanoid are not present in the productive zone of the water column. Moreover, the strategy of Oithona life in polar area is different from that of large calanoid, and it benefits from its independence from the spring blooms of phytoplankton to maintain active populations throughout the year. The ability of Oithona to successfully survive when unfavourable conditions are present in the water could explain the success of this genus of copepods in marine environments around the world.
19

Pharmacogenomic study of oppioid addicts in methadone treatment / Francina Fonseca Casals

Fonseca Casals, Francina 17 November 2010 (has links)
Although the well established efficacy of methadone maintenance treatment (MMT) in the opioid dependence disorder, there is a group of patients that are poor responders. The study of the influence of methadone pharmacodynamics and pharmacokinetics in dose requirements and program outcome remains still controversial. The aim of this dissertation is to study the pharmacodynamic and pharmacokinetic factors involved in the methadone maintenance treatment efficacy. The study recruited opioid dependence patients (DSM-IV criteria) from a MMT community program. Patients were clinically assessed and blood samples were obtained in order to evaluate methadone plasma concentrations of (R,S)-, (R) and (S)- methadone. Allelic variants of genes encoding the following proteins were assessed: BDNF, OPRM1, MYOCD, mGluR6, mGluR8, CRY1, NR4A2, 1q31.2 (rs965972), 2q21.2 (rs1867898), CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19 and P-glycoprotein. Responders and non-responders were defined by means of illicit opioid consumption detected in random urinalyses. Differences in response status were found depending on different single nucleotide polymorphisms (SNPs of genes encoding for BDNF, MYOCD and GRM6. The CYP2D6 metabolizing phenotype was associated with response to MMT, and also with methadone dosage requirement and methadone plasma concentrations. / Els programes de manteniment amb metadona (PMM) han demostrat eficàcia en el tractament del trastorn per dependència d'opiacis malgrat la persistència de pacients amb mala resposta al tractament. L'estudi dels factors farmacodinàmics i farmacocinètics implicats en la resposta terapèutica ofereix resultats controvertits. L'objectiu de la tesi doctoral que es presenta és estudiar els factors farmacodinàmics i farmacocinètics de la metadona que poden estar implicats en l'eficàcia del tractament. S'han inclòs pacients ambulatoris diagnosticats de trastorn per dependència d'opiacis (segons criteris DSM-IV) en PMM. Els pacients s'han avaluat a nivell clínic i s'han obtingut mostres de sang per a l'estudi de les concentracions plasmàtiques de (R,S)-, (R) i (S)- metadona. S'han estudiat també les variants al·lèliques dels gens que codifiquen per: BDNF, OPRM1, MYOCD, mGluR6, mGluR8, CRY1, NR4A2, 1q31.2 (rs965972), 2q21.2 (rs1867898), CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19 i P-glicoproteïna. La mostra s'ha dividit en responedors i no responedors en funció del nombre de controls d'orina positius per a heroïna en analítiques realitzades de forma aleatòria. Es van detectar diferències en resposta al tractament segons les variants dels gens codificants per a BDNF, MYOCD i GRM6. També es va detectar una associació entre el fenotip de CYP2D6, la resposta al tractament, la dosi requerida de metadona i les concentracions plasmàtiques.
20

Neurobiological mechanisms involved in MDMA-Seeking behaviour and relapse

Orejarena, Maria Juliana 06 September 2010 (has links)
(+) 3,4-metilendioximetanfetamina (MDMA), popularmente conocida como "éxtasis", es una droga susceptible de producir adicción en algunos individuos. Actualmente es consumida principalmente por adolescentes y jóvenes. Los particulares efectos psicoactivos inducidos por la MDMA, permiten distinguirlo de manera clara de otros psicoestimulantes o compuestos alucinógenos. Esta droga actúa principalmente activando el sistema dopaminérgico y serotonérgico en los circuitos neurales de placer. Sin embargo, los mecanismos neurobiológicos implicados en las propiedades adictivas de esta droga no han sido aún esclarecidos. El trabajo presentado en esta Tesis Doctoral ha puesto de manifiesto algunos aspectos claves de estos procesos que eran desconocidos hasta el momento. Hemos encontrado que el receptor de serotonina 5-HT 2A participa de forma critica en las propiedades reforzantes de la MDMA, contrario a lo observado en el caso de otros psicoestimulantes. Además, el bloqueo farmacológico de este receptor puede prevenir la reinstauración de la búsqueda de la MDMA, desencadenada por un estímulo o clave previamente asociado a su consumo. Estos efectos pueden ser debidos al bloqueo del control excitatorio que normalmente ejercen estos receptores sobre los niveles de dopamina en estructuras mesolímbicas, como ha sido revelado en nuestros estudios de microdiálisis. Hemos demostrado también que la MDMA puede actuar como clave interoceptiva y desencadenar la recaída a la búsqueda y consumo de cocaína. Adicionalmente, nuestros estudios han mostrado que tanto la activación del sistema dopaminérgico mesolímbico, como los cambios en la expresión génica en diferentes ´areas cerebrales que ocurren tras la administración de la MDMA, dependen de si el sujeto participa de manera activa en el consumo de esta droga, o si por el contrario la recibe de forma pasiva. En conclusión, este trabajo resalta la importancia de los procesos de aprendizaje y memoria sobre las propiedades reforzantes/recompensantes de la MDMA. Además, nuestras investigaciones aportan nuevas evidencias en relación a la participación del sistema serotonérgico en la búsqueda y recaída al consumo de esta droga. / (+) 3,4-methylenedioxymethamphetamine (MDMA), commonly known as "ecstasy", is currently a highly consumed drug with liability to produce addiction in some individuals. MDMA induces unique psychoactive effects that clearly distinguish it from hallucinogenic or psychostimulant drugs. MDMA mainly enhances the activity of both the serotonergic and the dopaminergic system in the esolimbic brain reward pathways. However, the neurobiological mechanisms underlying its possible addictive properties are still not fully understood. In the present work, we have contributed to this subject by establishing that the serotonin 5-HT2A receptor, in contrast to what has been observed for other drugs of abuse, is critical for MDMA-induced reinforcement. Moreover, the pharmacological blockade of this receptor can prevent cue-induced relapse. This effect is possibly mediated by its excitatory control over basal and MDMA-induced increase in midbrain dopamine, as supported by our microdialysis data. Furthermore, we have also shown that MDMA can act as an interoceptive cue to induce relapse to cocaine-seeking behaviour. Additionally, we demonstrated differential changes at the level of the dopaminergic brain reward pathway and gene expression changes in different brain areas, following self-administeredMDMAin comparison to passive administration. These results underpin the impact of a learning component in the rewarding/reinforcing properties of MDMA, and provide new evidence for the serotonergic involvement in MDMA-seeking behavior and relapse.

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