Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 5 uppsatser.

Pharmacological magnetic resonance imaging (phMRI) is the use of functional MRI techniques to elucidate the effects that psychotropic drugs have on neural activity within the brain; it is an emerging field of research that holds great potential for the investigation of drugs that act on the central nervous system by revealing the changes in neural activity that mediate observable changes in behavior, cognition, and perception. However, the realization of this potential is hampered by several unanswered questions: Are the MRI measurements reliable surrogates of changing neural activity in the presence of pharmacological agents? Is it relevant to investigate psychiatric phenomena such as reward or anxiolysis in anesthetized, rather than conscious animals? What are the methods that yield reproducible and meaningful results from phMRI experiments, and are they consistent in the investigations of different drugs? The research presented herein addresses many of these questions with the specific aims of 1) Developing pharmacological MRI methodologies that can be used in the conscious animal, 2) Validating these methodologies with the investigation of a non-stimulant, psychoactive compound, and 3) Applying these methodologies to the investigation of typical and atypical antipsychotic drugs, classes of compounds with unknown mechanisms of therapeutic action Building on recent developments in the field of functional MRI research, we developed new techniques that enable the investigator to measure localized changes in metabolism commensurate with changing neural activity. We tested the hypothesis that metabolic changes are a more reliable surrogate of changes in neural activity in response to a cocaine challenge, than changes observed in the blood-oxygen-level-dependent (BOLD) signal alone. We developed a system capable of multi-modal imaging in the conscious rat, and we tested the hypothesis that the conscious brain exhibits a markedly different response to systemic morphine challenge than the anesthetized brain. We identified and elucidated several fundamental limitations of the imaging and analysis protocols used in phMRI investigations, and developed new tools that enable the investigator to avoid common pitfalls. Finally, we applied these phMRI techniques to the investigation of neuroleptic compounds by asking the question: does treatment with typical or atypical antipsychotic drugs modulate the systems in the brain which are direct or indirect (i.e. downstream) substrates for a dopaminergic agonist? The execution of this research has generated several new tools for the neuroscience and drug discovery communities that can be used in neuropsychiatric investigations into the action of psychotropic drugs, while the results of this research provide evidence that supports several answers to the questions that currently limit the utility of phMRI investigations. Specifically, we observed that metabolic change can be measured to resolve discrepancies between anomalous BOLD signal changes and underlying changes in neural activity in the case of systemically administered cocaine. We found clear differences in the response to systemically administered morphine between conscious and anesthetized rats, and observed that only conscious animals exhibit a phMRI response that can be explained by the pharmacodynamics of morphine and corroborated by behavioral observations. We identified fundamental and drug-dependent limitations in the protocols used to perform phMRI investigations, and designed tools and alternate methods to facilitate protocol development. By applying these techniques to the investigation of neuroleptic compounds, we have gained a new perspective of the alterations in dopaminergic signaling induced by treatment with antipsychotic medications, and have found effects in many nuclei outside of the pathways that act as direct substrates for dopamine. A clearer picture of how neuroleptics alter the intercommunication of brain nuclei would be an invaluable resource for the classification of investigational antipsychotic drugs, and would provide the basis for future studies that examine the neuroplastic changes that confer therapeutic efficacy following chronic treatment with antipsychotic medications.

Made available in DSpace on 2015-07-22T20:49:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-27. Added 1 bitstream(s) on 2015-08-11T03:25:33Z : No. of bitstreams: 1 Publico-008.pdf: 1147299 bytes, checksum: c53fe718c40d4278be6155456942dfbe (MD5) / Contexto: a disfunção sexual é frequente entre pacientes com esquizofrenia, sendo relatada como um dos mais incômodos efeitos adversos dos antipsicóticos e esta diretamente relacionada com adesão ao tratamento. Objetivo: a) avaliar a frequência da disfunção sexual em uma amostra de pacientes do espectro da esquizofrenia em tratamento com antipsicóticos; b) investigar 0 efeito dos diferentes antipsicóticos na função sexual; e c) avaliar a acurácia da Escala de Experiência Sexual do Arizona (AS EX) para identificar disfunção sexual. Método: pacientes ambulatoriais com esquizofrenia ou transtorno esquizoafetivo foram entrevistados através de questionários: ASEX e Escala Dickson-Glazer (DGSFi) para avaliação do funcionamento sexual, em uma única entrevista. Resultados: 137 pacientes foram entrevistados. A sensibilidade e especificidade da ASEX em relação a DGSFi foram: 80.8% ( 95% IC= 70.0%-88.5%) e 88.1 % (95% IC=76.5%-94.7%), e a taxa de classificação incorreta foi 9.5%. A curva ROC comparando a pontuação da ASEX e DGSFi revelou valor de 0.93 (IC=0.879¬0.970) com 0 ponto de corte da ASEX encontrando sendo 14/15. A disfunção sexual foi mais alta entre as mulheres (79.2%) do que nos homens (33.3%) (X2=27.41, gl=1, p<0.001). Conclusão: pacientes em tratamento com antipsicóticos mostraram alta frequência de queixas sexuais e ASEX provou ser um instrumento eficaz para identificar disfunção sexual em amostra de pacientes ambulatoriais do espectro da esquizofrenia. Mulheres mostraram frequência mais alta de disfunção, e desejo sexual e habilidade para alcançar orgasmo foram áreas mais afetadas. 0 uso de antipsicóticos, principal mente 0 uso de combinações, foi associado com piora do funcionamento sexual.. / Background: sexual dysfunction is frequent in patients with schizophrenia, it is reported as one of the most distressing antipsychotic’s adverse effects and it is directly related to treatment compliance. Objective: a) to assess the frequency of sexual dysfunction in a sample of outpatients with schizophrenia and schizoaffective disorder under antipsychotic therapy; b) to investigate the effect of different antipsychotics on sexual function; and c) to evaluate the accuracy of the Arizona Sexual Experience Scale (ASEX) to identify sexual dysfunction. Method: Outpatients with schizophrenia or schizoaffective disorder were asked to fulfill both the ASEX and the Dickson Glazer Scale for the Assessment of Sexual Functioning Inventory (DGSFi) at a single interview. Results: 137 patients were interwied. The sensitivity and specificity of the ASEX in relation to DGSFi were: 80.8%, (95% CI= 70.0%-88.5%) and 88.1% (95% CI= 76.5%-94.7%), and the misclassification rate was 9.5%. The ROC curve comparing the ASEX and the DGSFi scores revealed a value of 0.93 (CI= 0.879-0.970), with the optimum cut-off point of ASEX being 14/15. Sexual dysfunction measured was higher in females (79.2%) than in males (33.3%) (2 = 27.41, d.f.=1, p<0.001). Discussion: Patients under antipsychotic treatment showed a high level of sexual complaints, and the ASEX proved to be an accurate instrument to identify sexual dysfunction in an outpatient sample of patients with schizophrenia spectrum. Females showed a higher frequency of sexual dysfunctions and sexual drive and ability to reach orgasm were the most affected areas. The use of antipsychotics, especially the combinations, was more likely to impair sexual functioning. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2014-12-17T15:37:13Z (GMT). No. of bitstreams: 1 RaquelSM_DISSERT.pdf: 1210364 bytes, checksum: 4fa725d4ec9ab3f0348c1172d9b3ef02 (MD5) Previous issue date: 2012-04-27 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Toxoplasma gondii is a protozoan parasite that induces behavioral changes in rodents. The aim of this study was to evaluate the effect of infection by T. gondii during the chronic phase in working memory and impulsivity in rodents as well as the effect of antipsychotics to reverse any behavioral changes resulting from infection. Female Wistar rats (n = 40) were infected with 25 cysts of the strain ME-49 T. gondii after 4 months the animals were subjected to behavioral tests: tolerance to delay gratification, in which the animal must choose between two rewards, a smaller and more immediate, but delayed and the test of spontaneous alternation, in which the animal must use spatial cues to remember previously visited arms. Antipsychotic drugs were intraperitoneally administered during the testing of the behavioral experiments, the antipsychotic is haloperidol (1.5 mg / kg) administered 60 min before the start of the session and the antipsychotic clozapine (2.5 mg / kg) 30 min before. Animals infected with the parasite did not show operating deficits of memory, and motor impairment did not develop, however motor impairment was observed only in animals treated with haloperidol. It was found that administration of clozapine and haloperidol increased the percentage of alternation in infected and control groups in task switching espont?nea.N?o no distinction between control animals and infected the test of tolerance to delay gratification in relation to the percentage of choices greatest reward, during the pre-training and training, in which there is a delay of 15 s to access the great reward, however it was observed that infected animals prefer the greatest reward, when there is a delay of 30 s when compared to control group. The administration of clozapine possible that infected animals chose the greatest reward in the delay of 30 seconds during the test. These data suggest that infected mice do not exhibit deficits in working memory and that clozapine has therapeutic efficacy in improving cognitive performance of mice infected / O Toxoplasma gondii ? um protozo?rio parasito que induz altera??es comportamentais em roedores. O objetivo do presente estudo foi avaliar o efeito da infec??o pelo T.gondii durante a fase cr?nica na mem?ria operacional e na impulsividade de roedores, bem como o efeito de antipsic?ticos em reverter as eventuais altera??es comportamentais decorrentes da infec??o. Ratos wistar f?meas (n=40) foram infectadas com 25 cistos da cepa ME-49 do T. gondii, ap?s 4 meses os animais foram submetidos aos testes comportamentais: toler?ncia ao retardo de gratifica??o, na qual o animal deve escolher entre duas recompensas, uma menor imediata e uma maior, mas com retardo e o teste de altern?ncia espont?nea, na qual o animal deve utilizar pistas espaciais para recordar bra?os previamente visitados. Os antipsicoticos foram administrados via intraperitoneal durante a fase teste dos experimentos comportamentais, sendo o antipsic?tico haloperidol (1,5 mg/kg) administrado 60 min antes do inicio das sess?es e o antipsic?tico clozapina (2,5 mg/kg) 30 min antes. Os animais infectados com o parasito n?o apresentaram d?ficits de memoria operacional, e n?o desenvolveram preju?zo motor, no entanto foi observado preju?zo motor apenas nos animais tratados com haloperidol. Foi verificado que a administra??o de clozapina e haloperidol aumentou a porcentagem de alterna??o em grupos controle e infectado na tarefa de altern?ncia espont?nea.N?o existe distin??o entre animais do grupo controle e infectado no teste de toler?ncia ao retardo de gratifica??o em rela??o a porcentagem de escolhas pela maior recompensa, durante as fases de pr?-treinamento e treinamento, no qual existe um retardo de 15 s para o acesso da grande recompensa, no entanto foi verificado que animais infectados preferem a maior recompensa, quando existe um retardo de 30 s quando comparado ao grupo controle. A administra??o da clozapina possibilitou que os animais infectados escolhessem a maior recompensa, no retardo de 30s na fase teste. Estes dados sugerem que ratos infectados n?o apresentam d?ficits de mem?ria operacional e que a clozapina apresenta efic?cia terap?utica em melhorar o desempenho cognitivo de ratos infectados