El interés industrial por la formabilidad de chapas de aceros de doble fase (DP) se ha incrementado en las últimas décadas, impulsado principalmente por la reciente popularidad de los aceros avanzados de alta resistencia (AHSS) para reducir el peso de partes automotrices. Esto resulta en una fuerte necesidad de determinar la respuesta límite del material frente a solicitaciones típicas de operaciones de conformado y el estudio de los factores que la influencian. La presente Tesis Doctoral aborda el estudio numérico de los factores microestructurales que influyen en el diagrama límite de conformado (FLD) de chapas de acero DP-780. El comportamiento límite del material se modela mediante la técnica de Marciniak-Kuczynski (MK), la cual asume la presencia de una imperfección inicial precursora del proceso de localización; mientras que la descripción constitutiva del material se realiza en el marco de la plasticidad cristalina. El comportamiento anisótropo, la presencia de una distribución preferencial de orientaciones y el efecto de las fases constituyentes – ferrita/martensita – se obtiene mediante una homogeneización autoconsistente de la respuesta viscoplástica a nivel del cristal simple (VPSC). El acople de ambas técnicas (MK-VPSC) permite modelar exitosamente la respuesta límite de las chapas de acero DP-780. Se investiga numéricamente el efecto de parámetros microestructurales típicos de aceros DP, la influencia de la anisotropía y su evolución, así como el efecto del comportamiento del endurecimiento post-estricción en las deformaciones límite. Tanto la fracción en volumen como la plasticidad de la martensita presentan una influencia significativa en la predicción del diagrama FLD, mientras que la evolución de la textura cristalográfica sólo afecta las deformaciones límite bajo solicitaciones biaxiales. El mejor acuerdo con los datos experimentales se encuentra cuando se utiliza una ley de endurecimiento de saturación y cuando la deformación de la martensita es impedida o es retardada hasta el punto de estricción. Un análisis de la actividad de los sistemas de deslizamiento sugiere que, dentro del marco de trabajo del modelo MK-VPSC, la localización ocurre mucho más rápido en la ferrita que en la martensita. Se presenta una extensión del modelo MK-VPSC que permite evitar problemas de convergencia y reducir el costo computacional. Esto se alcanza aplicando directamente las condiciones en velocidad de deformación y tensión, resultantes de las restricciones de equilibrio y compatibilidad, en la banda de inestabilidad del modelo MK. Además, los estados mecánicos dentro y fuera de ésta se resuelven en el marco de referencia de la muestra, evitando rotar las orientaciones cristalográficas y las variables internas a la orientación de la banda para cada incremento, mejorando la eficiencia computacional. Las condiciones de borde generalizadas incorporadas al modelo permiten calcular diagramas FLD basados en trayectorias de carga en deformación (FLDρ) como en tensión (FLDα). / Triggered by the recent popularity of advanced high strength steels (AHSS) for weight-reduction in automotive components, industrial interest in the formability of dual-phase (DP) steel sheets has increased in the last decades. Thus, there is a strong need in the determination of the material’s limit behavior for typical loading conditions in sheet forming operations, as well as the analysis of the influencing factors. This thesis addresses the numerical study of microstructural factors influencing the forming limit diagram (FLD) of DP-780 steel sheets. The material’s limit behavior is modeled by the Marciniak-Kuczynski (MK) model, which assumes an initial imperfection, precursor of the localization process; whereas the material’s constitutive description is performed within the crystal plasticity framework. The anisotropic behavior, the presence of preferred orientation distributions and the effect of the constituent phases – ferrite/martensite – is obtained by a self-consistent homogenization of the single crystal viscoplastic response (VPSC). The coupled techniques (MK-VPSC) can successfully model the limit response of the DP-780 steel sheet. The effect of typical microstructural parameters of DP steels, the influence of anisotropy and its evolution with deformation, as well as the extrapolated post-necking hardening behavior, on the forming limits is numerically investigated. Both the martensitic volume fraction and plasticity have a significant influence on the FLD prediction, while the evolution of crystallographic texture only affects the limit strains under biaxial deformation. The best agreement with experimentation is found when using the saturation hardening law and when the martensite deformation is either not allowed or retarded to occur after the point of necking. An analysis of the slip systems activity suggests that, within the MK-VPSC framework, localization occurs much faster in the ferritic than in the martensitic phase. An extension to the MK-VPSC model is presented in this thesis in order to avoid convergence problems and reduce the computational cost. This is achieved by directly applying the stress and strain-rate boundary conditions, resulting from the equilibrium and compatibility restrictions, at the MK instability band. Moreover, the mechanical states outside and inside the groove are solved in the sample reference frame. This avoids rotating the crystallographic orientations and the internal variables to the current groove orientation for each increment, improving the computational performance. The generalized boundary conditions in the polycrystal model allow calculating either strain ratio (FLDρ) or stress ratio (FLDα) based FLDs.

Active allothetic avoidance task (AAPA) could be a useful tool to study cognitive deficit of schizofrenia. In this task two different reference frames are created. The subject should distinguish which oriental frame is relevant for navigation and is proper for the solution of the task. This ability is called cognitive coordination. It is proved that the process of cognitive coordination is impaired in schizophrenic individuals, which comes to light in a Stroop test. Schizophrenia-like behavior can be modelled on the rats by a non-competitive NMDA receptor antagonist dizocipline (MK-801). The aim of these thesis was to study the existence of alternative strategies and the influence of different habituation on the performance of rats within AAPA. Furthermore, we have been studying the influence of MK-801 at a dose of 0.15mg / kg on the cognitive coordination in this task. We have found that the rats are able to learn AAPA task after pre-training without distal orientation cues, using relatively efficient alternative strategies. In these alternative strategies the idiothetic navigation is applied. The performance of rats in AAPA task is influenced by different conditions during habituation. We have proved that MK-801 at this dosage has no effect on cognitive performance of the rats in AAPA task, but...

Die vorliegende Arbeit beschäftigt sich mit dem Einfluss der NMDA-Rezeptorantagonisten, Memantin, MK-801, CGS und Ifenprodil auf die hypoxieinduzierte Zellschädigung an kortikalen Zellen der Ratte. Außerdem wurde der Einfluss von subtoxischen Konzentrationen von NMDA sowie von Roscovitin, einem Hemmer Cyclin-abhängiger Kinasen, auf die hypoxiebedingte Zellschädigung untersucht. Ziel dieser Arbeit war es, die neuroprotektive Wirkung dieser Substanzen zu erfassen. Zur Untersuchung der hypoxischen Schädigung wurden zwei 48-Well-Zellkulturplatten mit 15 Tage alten kortikalen Zellen der Ratte verwendet. Eine Kulturplatte wurde für vier Stunden mit HEPES(N-2-Hydroxyethylpiperazine-N’-2-Ethansulfonsäure)-Puffer (ohne Glucose) unter hypoxischen Bedingungen inkubiert. Die zweite Platte, mit glukorisiertem HEPES-Puffer, wurde für vier Stunden unter normoxischen Bedingungen inkubiert. Der HEPES-Puffer wurde nach vier Stunden entfernt, die Kulturplatten mit Dulbecco’s Modified Eagle Medium (DMEM) gewaschen und mit diesem Medium für 24 Stunden unter normoxischen Bedingungen inkubiert. Anschließend wurde das Medium ent¬fernt, durch NMDA, Memantin, Roscovitin, CGS und Ifenprodil ersetzt und die Ansätze für weitere 24 Stunden unter normoxischen Bedingungen inkubiert. Zur Beurteilung der Zellschädigung wurden der Aktivitätsanstieg der Laktat-Dehydrogenase (LDH), die Freisetzung freier Sauerstoffradikale und die Steigerung der Caspase-Aktivität bestimmt. Während die Bestimmung der LDH-Aktivität und die Freisetzung der freien Sauer¬stoff¬radikale nekrotische Veränderungen der Zellen charakterisiert, zeigt eine Zunahme der Caspase-Aktivität apoptotische Vorgänge an. LDH ist ein stabiles zytoplasmatisches Enzym, das in fast allen Körperzellen vorkommt. Beim Absterben der Zelle wird das Enzym durch die Schädigung der Plasmamembran aus der Zelle freigesetzt, so dass es zu einem Anstieg der LDH-Aktivität proportional zur Anzahl der toten Zellen kommt. Diese Aktivität wurde spektrophotometrisch mit einem Mikrotiterplatten-Lesegerät bestimmt. Die Ergebnisse des LDH-Tests zeigen, dass nach der 24-stündigen Behandlung der Zellen mit MK-801 die LDH-Aktivität um 11%, bei Roscovitin um 13%, bei Memantin (5 µM) um 56%, bei Memantin (0,5 µM) um 52% und mit NMDA (5 µM) um 44% signifikant vermindert wurde. Bei einer hypoxiebedingten Schädigung kortikaler Zellen kommt es auch zur Bildung freier Sauer¬stoff¬radikale. 2’,7’-Dichlorfluorescein Diacetat (2’,7’-H2DCF-DA) wird von den Zellen auf¬ge¬nommen und intrazellulär mit Sauerstoff- und Stickstoffspezies zum Fluoreszenz¬farb-stoff 2’,7’-Dichlorodihydrofluorescein (DCF) deacetyliert. DCF verbleibt dabei in den Zellen, so dass die Messung der Fluoreszenz der Zellen als Maß für intrazelluläre Oxidationsprozesse verwendet werden kann. Die DCF-Fluoreszenz-Änderung wurde mittels eines Fluorimeters gemessen und die daraus resultierenden Daten mit einer im Fluorimeter integrierten Software bearbeitet. Die Ergebnisse zeigen, dass die Freisetzung der freien Sauerstoffradikale, der hypoxiegeschädigten Zellen, signifikant durch Ifenprodil (10 µM) um 119%, Memantin (50 µM) um 88% und NMDA (5 µM) um 134% reduziert wurde. Die hypoxieinduzierte Zellmembranschädigung führt desweiteren zu einem Anstieg der Caspase-Aktivität. Mit Hilfe des Apo-One Homogeneous Caspase-3/7-Assays (Promega) wurde die Aktivität der Caspasen 3 und 7 fluorimetrisch bestimmt. Um die unterschiedliche Zelldichte in den Kulturschalen zu berücksichtigen, wurde eine Proteinbestimmung nach der Bicinchoninsäure-Methode (Smith et al. 1985) durchgeführt. Einen protektiven Effekt auf die Zellschädigung zeigen Memantin und NMDA in Bezug auf die Beeinflussung dieser Caspase-Aktivität. Der hypoxiebedingte Anstieg der Caspase-3-Aktivität konnte nach 24-stündiger Inkubation mit Memantin (5 µM) um 24%, mit Memantin (0,5 µM) um 28% und mit NMDA (5 µM) um 24% vermindert werden. CGS hat in diesen Versuchen keinen protektiven Einfluss auf die hypoxie¬induzierte Zellschädigung. Diese Arbeit zeigt, dass die Applikation niedriger NMDA-Konzentrationen neuroprotektive Effekte auf die Entwicklung der hypoxischen Schädigung von kortikalen Zellen der Ratte hat. Darüber hinaus wird vermutet, dass NMDA sogar einen trophischen Effekt auf das Über-leben der kortikalen Neurone ausübt. Dieser schützende Mechanismus von NMDA scheint denselben, wenn nicht sogar einen größeren protektiven Effekt wie Memantin zu induzieren. Um die Therapiemöglichkeiten der zerebralen Hypoxie durch neuroprotektive Medikamente zu optimieren, wären jedoch weitergehende Untersuchungen besonders als In-vivo-Modelle wünschenswert.

This thesis perpetuates research aimed at deploying a diagnostic expert system for the MK 92 Mod 2 Fire Control System to 28 Oliver Hazard Perry class fast frigates. Referred to as the Maintenance Advisor Expert System (MAES) , this expert system is being jointly developed by the Naval Postgraduate School and Port Hueneme Division, Naval Surface Warfare Center (NSWC PHD). This thesis focuses on the long-term implementation issues related to deploying MAES to the fleet, integrating MAES into the formal training pipeline, and transitioning life cycle Support for MAES to NSWC PHD. MAES long-term implementation issues, which include hardware, software, documentation, and training requirements, are examined within the context of implementation factors and risks historically associated with deploying expert systems. Plans for deploying MAES to the fleet and integrating MAES into the formal training pipeline are provided. As part of the documentation necessary to transition life cycle support of MAES to NSWC, a System Level Description document is also provided

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)- induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe)2, guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe)2 (1 μM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe)2 (5 μM) prevented ROS formation in the hippocampus. GUO (10 and 100 μM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 μM) abolished the pro-oxidant effect of QA. When the non effective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe)2 + GUO and (PhSe)2 + GUO + MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process. / A formação excessiva de espécies reativas de oxigênio (ROS) e alterações na captação de glutamato têm sido associadas como mecanismos chave que contribuem para toxicidade induzida pelo ácido quinolínico (AQ). Assim, nós investigamos se a utilização do disseleneto de difenila (PhSe)2, guanosina (GUO) e MK-801, isoladamente ou em combinação, podem proteger as fatias de regiões cerebrais de ratos da toxicidade induzida por AQ. AQ (1 mM) aumentou a formação de ROS, substâncias reativas ao ácido tiobarbitúrico (TBARS) e diminuiu a viabilidade celular após 2h de exposição. (PhSe)2 (1 μM) protegeu contra esta formação de ROS no córtex e no estriado e além disso preveniu a diminuição da viabilidade celular induzida pelo AQ. (PhSe)2 (5 μM) preveniu a formação de ROS no hipocampo. GUO (10 e 100 μM) bloqueou o aumento na formação de ROS causada pelo AQ e MK-801 (20 e 100 μM) aboliu o efeito pró-oxidante do AQ. Quando as concentrações não-efetivas foram usadas em combinação produziram uma diminuição na formação de ROS, principalmente (PhSe)2 + GUO e (PhSe)2 + GUO + MK-801. Estes resultados demonstram que esta combinação pode ser eficaz para evitar os efeitos tóxicos provocados por concentrações elevadas do AQ. Além disso, os dados obtidos nos ensaios de formação de ROS e viabilidade celular sugerem diferentes vias de atuação na melhora da toxicidade induzida pelo AQ presente no processo neurodegenerativo.

Glutamatergic receptors are targets for many L-glutamate structure analogues, which cause neurotoxicity. This study investigated the actions of two dicarboxylic compounds, the first had cyclic framework and rigid structure, and the other had an acyclic framework and flexible structure, on the glutamatergic neurotransmission, oxidative damage and behavior in mice. The first compound evaluated was D,L-cis-2,3-pyrrolidine dicarboxylate (D,L-cis-2,3-PDC), a new glutamate analogue. D,L-cis-2,3-PDC reduced sodium-independent [3H]-L-glutamate binding by 50% in lysed membrane preparations and had no effect on sodium-dependent glutamate binding. Intracerebroventricular administration (ICV) of D,L-cis-2,3-PDC (7.5 - 25 nmol/ 5μl) induced dose-dependent tonic-clonic convulsions. The co-administration of MK-801 (7 nmol/ 2.5 μl; ICV), a noncompetitive NMDA receptor antagonist, with D,L-cis-2,3-PDC (16.5 nmol/ 2.5 μl; ICV) fully protected the animals against D,L-cis-2,3-PDC-induced convulsions, while the co-administration of DNQX (10 nmol/ 2.5 μl; ICV), a AMPA and KA receptors antagonist, increased the latency to convulsion and did not alter the percentage of animals that had convulsions. These results suggest that D,L-cis-2,3-PDC-induced effects are mediated predominantly by NMDA receptors activation. The second compound studied was succinate, the accumulating substrate in succinate dehydrogenase (SDH) deficiencies and SDH inhibitor intoxication. Adult male mice received an ICV injection of succinate (0.7, 1.0 and 1.7 μmol/ 5 μl) or 0.9% NaCl (5 μl) and had their exploratory behavior assessed in an open field for 10 min. Succinate (0.7 and 1.0 μmol/ 5 μl) decreased locomotor activity behavior and increased thiobarbituric acid reactive substances (TBARS) and protein carbonylation in the forebrain. Conversely, 1.7 μmol of succinate did not alter locomotor activity or oxidative damage parameters. The involvement of NMDA receptors in the succinate-induced increase of total protein carbonylation content and exploratory behavior inhibition was assessed by co-administrating MK-801 (7 nmol/ 2.5 μl, ICV) with succinate (1 μmol/ 2.5 μl, ICV). The co-administration of MK-801 protected against succinate-induced increase of total protein carbonylation and decrease of locomotor activity. These results suggest the involvement of NMDA receptors in these effects of succinate, which may of particular relevance for succinate-accumulating conditions, such as SDH inhibitors intoxication and inherited SDH deficiencies. / Os receptores glutamatérgicos são alvos da ação de muitas neurotoxinas análogas ao L-glutamato. Neste estudo foram investigadas as ações de dois compostos dicarboxílicos, um de cadeia cíclica e estrutura rígida e o outro de cadeia acíclica e estrutura flexível, sobre a neurotransmissão glutamatérgica, dano oxidativo e comportamento em roedores. No primeiro trabalho foi investigado se o D,L-cis-2,3-dicarboxilato de pirrolidina (D,L-cis-2,3-PDC) altera a ligação de [3H]-L-glutamato em membranas plasmáticas de córtex de ratos adultos e se os receptores N-metil-D-aspartato (NMDA) estão envolvidos nas convulsões induzidas por este composto. O D,L-cis-2,3-PDC reduziu a ligação de [3H]-L-glutamato Na+-independente em 50% nas preparações de membranas rompidas e não apresentou efeito sobre a ligação de [3H]-L-glutamato Na+-dependente. A administração intracerebroventricular (ICV) de D,L-cis-2,3-PDC (7,5; 25 nmol/ 5 μl) induziu convulsões generalizadas do tipo tônico-clônica nos camundongos, de uma maneira dose-dependente. A co-administração de MK-801 (7 nmol/ 2,5 μl; ICV), um antagonista não-competitivo dos receptores NMDA, com D,L-cis-2,3-PDC (16,5 nmol/ 2,5 μl; ICV), protegeu totalmente os animais das convulsões induzidas por D,L-cis-2,3-PDC, enquanto que a co-administração de DNQX (10 nmol/ 2,5 μl; ICV), um antagonista dos receptores AMPA e KA, aumentou a latência das convulsões, mas não alterou a percentagem de animais que tiveram convulsões. Estes resultados sugerem que os efeitos induzidos por D,L-cis-2,3-PDC são mediados principalmente pela ativação dos receptores NMDA. No segundo estudo, foi investigado se o sucinato, substrato que se acumula nas deficiências da enzima sucinato desidrogenase (SDH) e nas intoxicações por inibidores da SDH, causa lipoperoxidação e carbonilação protéica, e se os receptores NMDA estão envolvidos no dano oxidativo induzido por sucinato. Camundongos machos adultos receberam uma injeção ICV de sucinato (0,7; 1,0; 1,7 μmol/ 5 μl) ou 0,9 % de NaCl (5 μl) e seu comportamento foi analisado em um campo aberto por 10 minutos. Sucinato (0,7; 1,0 μmol/ 5 μl) diminuiu a atividade locomotora e aumentou as substâncias que reagem ao ácido tiobarbitúrico (TBARS) e carbonilação protéica no cérebro. Por outro lado, 1,7 μmol de sucinato não alterou a atividade locomotora ou os parâmetros de dano oxidativo. O envolvimento dos receptores NMDA no aumento induzido por sucinato do conteúdo de carbonilação protéica e da inibição do comportamento exploratório foi avaliado pela co-administração de MK-801 (7nmol/ 2,5 μl, ICV) com sucinato (1 μmol/ 2,5 μl, ICV). A co-administração de MK801 protegeu contra o aumento induzido por sucinato da carbonilação protéica e na diminuição da atividade locomotora. Esses resultados sugerem o envolvimento dos receptores NMDA nesses efeitos do sucinato, os quais são de grande relevância nas condições em que acumula sucinato, tais como as intoxicações com inibidores da SDH e deficiências dessa enzima causadas por erros inatos do metabolismo.

La mégacaryopoïèse représente le processus de différenciation des cellules souches hématopoïétiques (CSH) en mégacaryocytes (MK). Ce processus précède la thrombopoïèse qui aboutira à la formation des plaquettes sanguines. Ces processus complexes ont lieu 1) au sein de la structure tridimensionnelle (3D) de la moelle osseuse, 2) dans les vaisseaux sinusoïdes de la moelle et 3) dans la circulation sanguine. Le but général de ce travail a été de comprendre le mécanisme de chaque étape. Le premier objectif a été d’étudier les effets d’une structure poreuse 3D mimant celle de la moelle osseuse, sur la différenciation mégacaryocytaire et la production plaquettaire in vitro. Cette étude a permis de démontrer que la synergie entre l’organisation spatiale et les signaux du microenvironnement améliore la production en MK et en plaquettes. Par la suite, nous avons souhaité caractériser in vitro et in vivo les plaquettes produites en conditions de flux. Nous avons notamment mis en évidence la capacité des plaquettes produites in vitro dans un système de microfluidique, à s’incorporer et à participer à la formation d’un thrombus in vitro et in vivo contrairement aux plaquettes obtenues en statique. Ces travaux prouvent donc l’intérêt d’une part, de mimer le microenvironnement de la moelle osseuse et d’autre part, de reproduire les forces de cisaillement du sang afin d’améliorer et d’augmenter la production de plaquettes in vitro pour de futures applications en thérapeutique. / Megakaryopoiesis is a process allowing hematopoietic stem cell (HSC) to proliferate and differentiate into megakaryocytes (MK). It is followed by thrombopoiesis allowing blood platelet production. These processes occur 1) in the bone marrow three-dimensional (3D) structure, 2) in the bone marrow sinusoid vessels and 3) in the blood flow. Our general aim was to decipher the mechanism associated to each process. The first objective was to study the effects of porous 3D structure on MK differentiation and platelet production. This study demonstrated that the synergy between spatial organization and biological cues improved MK and platelet production. We also characterized platelets produced from mature MK in flow conditions, with respect to their in vitro and in vivo properties. We highlighted the capacity of flow-derived platelets to incorporate in a thrombus in vitro and in vivo, compared to static-derived platelets. These works represent some new developments for mimicking the bone marrow structure and to reproduce blood shear forces in order to improve and increase in vitro platelet production for therapeutic use.

Non-competitive antagonists of NMDA receptors can induce psychomimetic effects - they can cause schizophrenia-like behavior in healthy volunteers. MK-801 is such an agent. It is often used to model schizophrenia-like behavior in experimental animals. On the other hand, non-competitive antagonists of NMDA receptors show antidepressant effects both in patients suffering from depression and in animal models. Currently, cognitive deficit is considered to be a crucial symptom of the schizophrenia. Cognitive coordination is a process distinguishing irrelevant and relevant stimuli. A disruption of this process could play a pivotal role in cognitive deficit in schizophrenia. Active Allothetic Place Avoidance task (AAPA) could be a useful tool to study this phenomenon. In this task an animal has to distinguish between two spatial (reference) frames, whereas one of them is irrelevant and the other is relevant. The aims of my diploma thesis were: to study 1) behavioral strategies of laboratory rats in AAPA task and 2) effect of MK-801 on behavioral strategies and cognitive efficiency of rats in this task. The rats demonstrated two different strategies in the AAPA task. The first strategy was an active avoidance of an aversive sector; the second one was "freezing" with minimal active movement on the arena. Application...

Primary polydipsia, excessive drinking without known medical cause, continues to occur with a significant prevalence in psychiatric populations. While the etiology of polydipsia remains unknown, the fact that it is significantly associated with a diagnosis of schizophrenia has led some to postulate that the two may share common neurological pathophysiologies. Animal models of schizophrenia-like symptoms have focused on modeling the core behavioral and neurochemical features of the illness, like cognitive deficits and enhanced dopamine transmission. Here, we used three well-established models, including repeated amphetamine treatment, subchronic MK-801 (an N-methyl-D-aspartate [NMDA]-receptor antagonist), and post-weaning social isolation. We also examined a “double-hit” model, combining NMDA-receptor antagonism and social isolation. We paired these models to test the hypothesis that drinking will be enhanced in a paradigm of excessive drinking in the rat. In rodents, non-physiologic drinking can be induced by intermittent presentation of food (e.g., one sugar-pellet a minute) in the presence of a drinking spout to a hungry animal, termed schedule-induced polydipsia (SIP). Animals pretreated with pharmacological or non-pharmacological models of schizophrenia-like symptoms showed significantly increased SIP, The “double hit” model did not further increase drinking above that of either social isolation or MK-801 treatment alone. A moderate amount of spontaneous polydipsia in the homecage of MK-801-treated rats was also observed and resulted in one death secondary to excessive drinking, a phenomenon also found in inpatients with schizophrenia. Following repeated treatment with AMPH, there was some evidence that over time, animals learned to drink increased amounts independently of the scheduled food presentation. This evidence suggests that the excessive drinking behavior observed in polydipsia associated with schizophrenia may have a learned component. In summary, animal models of schizophrenia-like symptoms augmented SIP behavior, showing that polydipsia associated with schizophrenia may be modeled in rodents. As each model has been shown to modify dopamine transmission to some degree, the evidence suggests augmented SIP may reflect changes in dopamine transmission and dopamine may be the common link between polydipsia and schizophrenia. Further research is necessary to fully elucidate the mechanisms underlying SIP, polydipsia and schizophrenia. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-10-31 17:43:18.34

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