Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Abstract ESTABLISHING THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE Antipsychotic medications are used to treat schizophrenia. The present study used the drug discrimination paradigm to measure the subjective effects of the atypical antipsychotic amisulpride and to examine the underlying neuropharmacological mechanisms responsible for the discriminative stimulus property of the drug. Male C57BL/6 mice were trained to discriminate 10 mg/kg (-)S amisulpride from vehicle in a two-lever drug discrimination task. A dose effect curve for (-)S amisulpride yielded an ED50 = 1.77 mg/kg 95% CI [1.28, 2.45 mg/kg]. Substitution testing was conducted for the isomer (+)R amisulpride, racemic (±)SR amisulpride, the atypical antipsychotics clozapine, aripiprazole and the typical antipsychotic haloperidol. There was partial substitution for (+)R amisulpride, and full substitution for (±)SR amisulpride with a significant rightward shift in the dose effect curves. Clozapine, aripiprazole, and haloperidol failed to fully substitute with significant rate suppression at the higher doses. These results demonstrated that (-)S amisulpride has a unique discriminative stimulus that differs from other antipsychotic drugs.

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Cryprosporidium parvum is a coccidian protozoan that colonizes epithelial cells lining respiratory and digestive tracts of animals and humans. Cryptosporidiosis is a well-recognized zoonotic disease infecting primarily neonates and immunocompromised hosts, including human immunodeficiency virus-infected patients. Clinical disease is manifested as a chronic diarrheal illness that is self-limiting in immunocompetent hosts and prolonged and often life-threatening in hosts with compromised immune systems.The lack of a suitable small animal model for screening anti-cryptosporidial drugs and for examining the pathogenicity and immunobiology of chronic cryptosporidiosis was the impetus for this research effort. The objectives of the present study were three-fold: to characterize chronic Cryptosporidium parvum infections in dexamethasone-immunosuppressed mice; evaluate the effects of Cryprosporidium parvum and dexamethasone on B and T lymphocyte proliferation; and determine the effects of the immunomodulator dehydroepiandrosterone on oocyst shedding intensities of mice infected with Cryptosporidium parvum. Adult C57BL/6N mice were immunosuppressed with the synthetic glucocorticoid dexamethasone, then infected with Cryprosporidium parvum (106 oocysts/mouse) investigated for their ability to sustain a four-month chronic infection. Dexamethasone was administered intraperitoneally (125 Jlg/mouse/day) or orally (8 Jlg/ml) in the drinking water ad libitum. Infection chronicity was characterized by evaluating mouse monality, oocyst excretion in the feces, tissue distribution of the parasite, and parasite-induced pathology. A progressive infection with Cryptosporidium parvum occurred in mice immunosuppressed intraperitoneally and orally as long as dexameth sone was administered. Mice receiving dexamethasone given intraperitoneally had a shoner prepatent period and a more consistent, although cyclic, oocyst shedding pattern when compared with mice given dexamethasone orally. Mice given dexamethasone orally exhibited a delayed prepatent period, with a steady increase in oocyst shedding. All mice receiving dexamethasone orally died within three months following oocyst inoculation. Clinical signs included dehydration, icterus, and reduction in spleen and body weights. Clinical signs were more abrupt in mice receiving oral dexamethasone. Parasite colonization involved the entire intestinal tract, including the pyloric ring and Peyer's patches, but was the heaviest in the terminal ileum. Parasites were present in the lungs, gallbladder, and pancreatic ducts. Pathologic abnormalities were isolated to the terminal small intestine and included blunting and fusion of intestinal villi and crypt hyperplasia. Cryptosporidium parvum and dexamethasone administered in vivo reduced B and T lymphocyte responses to the mitogens lipopolysaccharide and concanavalin A. Dehydroepiandrosterone and dehydroepiandrosterone-sulfate resulted in no significant reductions in cryptosporidial activity as determined by oocyst shedding in the feces.

Made available in DSpace on 2015-12-06T23:46:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2013 / Associação Fundo de Incentivo à Psicofarmacologia (AFIP) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A planta Ocimum gratissimum L. e muito utilizada na medicina popular para tratar condicoes dolorosas. Assim, o presente estudo avaliou a atividade antihipernociceptiva do oleo essencial de Ocimum gratissimum (OEOg) e seus principios ativos isolados (eugenol, trans-cariofileno e mirceno) no modelo de dor neuropatica induzida pela injuria por constricao cronica do nervo ciatico. Para todos os experimentos realizados foram utilizados camundongos machos adultos da linhagem C57BL/6J. Testes preliminares, como triagem farmacologica e rota-rod foram feitos para direcionar a pesquisa e determinar os efeitos adversos das substancias testadas. Poucas alteracoes foram observadas nesses testes. Os animais tratados com trans-cariofileno apresentaram poucos indicios de toxicidade,como alteracoes comportamentais, bioquimicas e histopatologicas. Ja o mirceno, quando administrado na dose de 250 e 500 mg/kg, promoveu aumento das enzimas hepaticas aspartato aminotransferase e alanina aminotransferase, alem de aumento no peso relativo do figado e alteracoes morfologicas hepaticas. Nos testes para averiguar a antinocicepcao aguda e cronica, os camundongos foram tratados por via oral com oleo de milho (grupo controle), 5 mg/kg de morfina (controle positivo dor aguda- ip), 20 mg/kg de pregabalina (controle positivo dor neuropatica u ip), OEOg nas doses de 10, 20 ou 40 mg/kg, eugenol, trans-cariofileno ou mirceno nas doses de 1, 5 ou 10 mg/kg. No teste da placa quente, para avaliar limiar nociceptivo, todos os xenobioticos testados foram eficazes em aumentar significativamente a latencia para os animais lamberem a(s) pata(s), mesmo 4 horas apos a administracao, quando comparados com o grupo controle. No teste da formalina na pata, as substancias utilizadas como tratamento foram efetivas em minimizar a dor dos animais na primeira e segunda fase do teste, mostrando efeito benefico contra a dor neurogenica e inflamatoria. Com relacao aos testes de dor neuropatica, o tratamento com 20 e 40 mg/kg do oleo essencial da planta e as doses 5 e 10 mg/kg dos principios ativos foram capazes de promover antihipernocicepcao, tanto no teste mecanico (von Frey) quanto termico (placa quente). Os experimentos para investigar o possivel mecanismo de acao das drogas testadas indicaram o envolvimento do sistema opioide. Os dados do teste para elucidar o mecanismo de acao do transcariofileno tambem comprovaram a participacao do sistema canabinoide via receptor CB2, uma vez que o efeito foi revertido pelo antagonista CB2 JWH-015. O eugenol apresentou efeito antihipernociceptivo equivalente ao antagonista TRPV1,(SB366791), sugerindo que o efeito antinociceptivo seja tambem devido ao bloqueio de receptores vaniloides. Em sintese, nossos achados corroboram com os relatos da literatura de que o OEOg e seus principios ativos isolados possuem atividade antinociceptiva em modelos de dor aguda e comprovam o efeito antihipernociceptivo nos testes de dor neuropatica. A presenca de atividade biologica da planta justifica ouso popular, o que incentiva a realizacao de outros estudos, principalmente no que diz respeito aos seus constituintes e seus respectivos mecanismos de acao / BV UNIFESP: Teses e dissertações

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-05-31T21:14:12Z No. of bitstreams: 1 Adriana Lima de Oliveira. Microquimerismo fetal em fêmeas de camundongos - CPqGM - Dissertação Mestrado - 2008.pdf: 3543169 bytes, checksum: e3a8306c07bffce080c07532d96950f0 (MD5) / Made available in DSpace on 2012-05-31T21:14:12Z (GMT). No. of bitstreams: 1 Adriana Lima de Oliveira. Microquimerismo fetal em fêmeas de camundongos - CPqGM - Dissertação Mestrado - 2008.pdf: 3543169 bytes, checksum: e3a8306c07bffce080c07532d96950f0 (MD5) Previous issue date: 2008 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / O papel da persistência de células fetais no organismo materno pós-gestação (microquimerismo materno-fetal) é ainda pouco estudado. Para investigar o potencial de reparo tecidual destas células em lesões de coração e músculo esquelético, avaliamos a presença de células fetais nestes órgãos durante a infecção aguda por T. cruzi de fêmeas parturientes que tiveram filhotes GFP+. Fêmeas C57Bl/6 foram infectadas com tripomastigotas da cepa Colombiana de T. cruzi no oitavo dia pós-parto e sacrificadas no 30º dia pós-infecção. A presença de células fetais GFP+ foi avaliada por citometria de fluxo (sete dias pós-parto), por imunofluorescência utilizando anticorpos anti-GFP e por PCR em tempo real usando sondas específicas para o gene GFP de origem fetal. Células fetais GFP+ foram detectadas na circulação de 20% das fêmeas analisadas. Em secções de corações e de músculo esquelético de fêmeas infectadas, detectaram-se células fetais GFP+, algumas das quais expressando miosina, um marcador de células de músculo estriado. No fígado a presença de células GFP+ também foi detectada, porém estas não apresentaram expressão de albumina. Já em secções de coração, músculo esquelético e fígado de fêmeas sadias com fetos fluorescentes não foram encontradas células GFP+. A presença do trasngene gfp de origem fetal, avaliada pela metodologia de PCR em tempo real, é aumentada pela infecção por T. cruzi no coração e músculo esquelético, em comparação com fêmeas parturientes sadias. A presença do transgene gfp de origem fetal é mais elevada no coração do que no músculo esquelético de fêmeas infectadas. Em conclusão, os resultados sugerem que células fetais participam do processo de reparo de lesões do coração e do músculo esquelético, pelo menos no modelo de infecção aguda por T. cruzi. / The role of fetal cells persistence in maternal organism after gestation (fetal-maternal microchimerism) is poorly understood. To investigate the regenerative potential of these cells in heart and muscle lesions, we evaluated the presence of fetal cells in these organs during the acute infection by T. cruzi of parturient female mice which had GFP+ puppies. C57Bl/6 female mice were infected with trypomastigotes of Colombian strain T. cruzi on the 8th day post-partum, and sacrificed on the 30º day post-infection. The presence of GFP+ fetal cells was evaluated by flow cytometry (7 days post-partum) and by immunofluorescence using anti-GFP specific antibodies and by real time PCR using specific probes for GFP gene of fetal origin 30 days post-partum. GFP+ fetal cells were detected in the circulation in 20% of the analyzed females. GFP+ cells were also detected in heart and striated muscle section of T. cruzi-infected mice, some of which expressed myosin, a marker of striated muscle cells. In the liver, GFP+ cells were also found, but none co-expressing albumin. In sections of heart, striated muscle and liver of healthy chimeric females, we did not find GFP+ cells. The presence of gfp transgene of fetal origin, evaluated by real time PCR, was increased by infection with T. cruzi in the heart and skeletal muscle, compared to healthy parturient females. The presence of gfp transgene of fetal origin is higher in the heart than in the striated muscle of infected females. In conclusion, our results suggest that fetal cells participate in the regenerative process in the heart and striated muscle, at least in the model of acute T. cruzi infection.

Submitted by Maurílio Figueiredo (maurilioafigueiredo@yahoo.com.br) on 2013-03-15T20:22:38Z No. of bitstreams: 1 DISSERTAÇÃO_EfeitosAtorvastatinaInfecção.PDF: 5061220 bytes, checksum: d6026ff68f81d581f61b217b666aad56 (MD5) / Approved for entry into archive by Neide Nativa (neide@sisbin.ufop.br) on 2013-03-18T19:49:35Z (GMT) No. of bitstreams: 1 DISSERTAÇÃO_EfeitosAtorvastatinaInfecção.PDF: 5061220 bytes, checksum: d6026ff68f81d581f61b217b666aad56 (MD5) / Made available in DSpace on 2013-03-18T19:49:35Z (GMT). No. of bitstreams: 1 DISSERTAÇÃO_EfeitosAtorvastatinaInfecção.PDF: 5061220 bytes, checksum: d6026ff68f81d581f61b217b666aad56 (MD5) Previous issue date: 2008 / As estatinas, inibidores da b-hidroxi-b-metil-Co A redutase (enzima que catalisa a etapa limitante da síntese de colesterol e isoprenóides), são fármacos de primeira escolha para o tratamento de hipercolesterolemia. Atualmente, estão entre os medicamentos mais prescritos no mundo e seu uso como agentes profiláticos para doenças cardiovasculares tem sido sugerido. A atorvastatina, extremamente difundida, também é capaz de modular a resposta imunológica clinicamente e em modelos experimentais com efeito imunossupressor e antiinflamatório. Diante do potencial de suprimir a resposta pró-inflamatória Th1, nosso trabalho se concentra no estudo do efeito da atorvastatina sobre a infecção experimental por Leishmania major no camundongo C57BL/6, modelo de resistência a esse protozoário sensível à resposta Th1 desenvolvida nesse hospedeiro. De acordo com nossos resultados, o tratamento favoreceu a proliferação do parasito. O controle do horário de administração do fármaco promoveu um crescimento significativo da lesão na pata indicando que o efeito da atorvastatina no camundongo é modulado pelo ciclo circadiano. A atorvastatina não foi capaz de inibir a polarização da resposta imunológica para o tipo 1, pois a produção das citocinas IFN-g e TNF-a e da quimiocina CCL5/RANTES foi aumentada bem como a atividade de NOS II nos animais tratados. Por outro lado, a estatina induziu a ativação de mecanismos regulatórios da resposta imune como as células CD4+CD25high e conseqüente incremento na produção de TGF-b e IL-10 e na atividade de arginase I. Nossos resultados revelam que o tratamento a longo prazo com atorvastatina prejudica o controle da infecção por L. major no camundongo C57BL/6 e sugerem que a disseminação do uso das estatinas deve ser avaliada com cautela especialmente em populações de áreas endêmicas para parasitoses como a leishmaniose. ________________________________________________________________________________________________ / ABSTRACT: Statins are inhibitors of b-hidroxi-b-metil-Co A reductase (the rate limiting enzyme of cholesterol synthesis), so they are the first choice drugs for hipercholesterolemy therapy. Nowadays, statins are some of the most prescribed drugs in the world and their use as prophylactic agents for cardiovascular diseases has been widely suggested. Atorvastatin, an extremely diffused statin, can also modulate immune response when applied clinically or in experimental models and presents immunosuppressor and anti-inflammatory actions. Knowing its potential of suppressing Th1 immune response, this work was focused in the study of the effect of atorvastatin in experimental infection with Leishmania major in C57BL/6 mice, the resistance model against this parasite. In this model, parasite growth is controlled by a Th1 response developed by the host. Our results showed that atorvastatin treatment favored parasite proliferation. When the time of statin administration was controlled, a significant increase in footpad lesion was observed, indicating that the effect of atorvastatin in mice is modulated by the circadian cycle. Atorvastatin did not inhibited the type 1 immune response polarization, since in treated animals increased IFN-g , TNF-a and CCL5/RANTES production and NOS II activity were observed. On the other hand, statin activated regulatory mechanisms of the immune response such as CD4+CD25high cells with an increment in TGF-b and IL-10 production and arginase I activity as consequences. According to our findings, long term treatment with atorvastatin compromises the control of L. major infection in C57BL/6 mice. Our results also suggest that atorvastatin widespread use must be carefully evaluated, especially in populations that live in endemic areas for parasitic diseases such as leishmaniasis.

The hippocampus, a brain region that is part of the limbic system in the medial temporal lobe, is critical to episodic memory, or the memory of autobiographical events. The hippocampus plays an important role in the consolidation of information from short-term memory into more permanent long-term memory and spatial memory which enables navigation. Hippocampal damage in humans has been linked to memory loss, such as in Alzheimer’s disease and other dementias, as well as in amnesia such as in the case of patient H.M. The role of the hippocampus has been well characterized in humans but is less understood in rodents due to contradictory findings. While rodents have served well as model organisms in developing our understanding of the cognitive map that is critical for spatial navigation, there has been substantial contention over the degree to which the rodent hippocampus supports non-spatial memory, specifically the memory for items or objects previously encountered. The overall objective of this research is to gain a better understanding of how neuronal circuits involving the hippocampus and perirhinal cortex function to support object memory in the brain. Chemogenetic technologies such as DREADDs (designer receptor exclusively activated by designer drugs) have proven to be effective tools in remote manipulation of neuronal activity. First, a series of behavioral tasks was used to validate the effects of DREADD inactivation in the CA1 region of dorsal hippocampus in C57BL/6J male mice. DREADD inhibition resulted in significant impairment in the spontaneous object recognition (SOR) task and of spatial memory in the Morris water maze. In conjunction, mice were implanted with bilateral perirhinal cortex guide cannulae to allow for temporary muscimol inactivation during distinct time points in the SOR task to further investigate the nature of its relationship with the hippocampus. The results reveal an unexpected role for the perirhinal cortex in the retrieval of strong object memory. Finally, Arc mRNA expression was quantified in CA1 of dorsal hippocampus and perirhinal cortex following both weak and strong object memory formation. The results indicate that the perirhinal cortex and hippocampus have distinct, yet complementary roles in object recognition memory and that distinction is gated by memory strength. Understanding the neural mechanisms supporting the weak-strong object memory distinction in mice is an important step not only in validating mice as a suitable model system to study episodic memory in humans, but also in developing treatments and understanding the underlying causes of diseases affecting long-term memory such as Alzheimer’s disease. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

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Developmental 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure can permanently alter immune system ontogeny, resulting in the dysregulation of a number of vital immune pathways. We hypothesized that developmental exposure to TCDD may also impair the establishment of self-tolerance, resulting in an increased risk of autoimmunity. For example, we observed that a single prenatal TCDD exposure given to non-autoimmune-prone high affinity aryl hydrocarbon receptor (AhR) C57BL/6 mice resulted in an immune complex-mediated autoimmune disease during the adult stage. Further using a similar TCDD exposure protocol, autoimmune-prone low affinity AhR SNF1 mice exhibited acceleration and exacerbation of lupus-like nephritis in adulthood. Examination of these mice showed that perinatal TCDD exposure adversely affected both primary immune organs of the adaptive immune system. In the thymic compartment, prenatal TCDD affected thymocyte cellularity, differentiation and maturation as well as central tolerance as indicated by high levels of autoreactive Vβ TCR T cells in the periphery. Prenatal TCDD also altered bone marrow B lymphopoiesis and B cell maturation and differentiation in the spleen. Functionally, these B cell changes resulted in high serum autoantibodies titers to dsDNA, ssDNA and cardiolipin suggesting a loss in central B cell tolerance. The functional assessment of T cells, via cytokine production showed that prenatal TCDD mice altered Th1/Th2 levels. As a result, significant changes were detected in the kidney characterized by increased immune complex deposition in the glomeruli, lymphocytic infiltration and general pathologic changes. This would suggest that multiple immune pathways are affected by prenatal TCDD and work either independently or synergistically to display immune-mediated disease during aging. Importantly, this study has also shown that the sex of an individual appears to influence both the type of immune pathways affected by TCDD as well as the progression and severity of the autoimmunity. In summary, these studies clearly demonstrate that postnatal immune system impairment due to prenatal TCDD exposure is not limited to immunosuppression but also can include inappropriate immune activation manifested as a hypersensitivity that can lead to the onset of autoimmune disease. / Ph. D.