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Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains xi, 154 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 118-150).

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Orientador: Cassiana Maria Reganhan Coneglian / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Tecnologia / Made available in DSpace on 2018-08-17T21:32:28Z (GMT). No. of bitstreams: 1 VonWoff_MaryaAnne_M.pdf: 863495 bytes, checksum: 4548e40c4fa7eb23f789ab34f09fa155 (MD5) Previous issue date: 2011 / Resumo: Fármacos para tratamento de distúrbios psíquicos estão entre as substancias ativas mais prescritas no mundo. A ocorrência destes em matrizes ambientais torna-se cada vez mais freqüente. Estudos recentes indicam que o fármaco cloridrato de fluoxetina, um inibidor seletivo da recaptação da serotonina, esta presente em estações de tratamento de efluentes e em águas de superfície. O aumento nas pesquisas ambientais acerca dos fármacos está ligado a sua baixa biodegradabilidade e sua persistência no ambiente. Este trabalho revisa os dados da literatura relacionados à ocorrência ambiental e dados de toxicidade para os organismos não-alvo do medicamento cloridrato de fluoxetina e contribui para a literatura cientifica com testes de toxicidade do fármaco com os organismos-testes Daphnia similis e Pseudokirchneriella subcaptata. Com base em resultados obtidos, realizou-se a estimativa de impacto ambiental para a Estação de Tratamento de Esgotos do rio Piracicamirim. No entanto, não existem padrões estabelecidos para a concentração de fármacos no ambiente, pois não são totalmente conhecidos seus efeitos ecotoxicologicos. Os dados compilados têm o intuito de contribuir para a priorização e determinação da necessidade de estudos que indiquem a ocorrência, destino, transporte, saúde e elucidação dos efeitos causados por fármacos, para a contínua melhoria dos padrões de água no Brasil e no mundo / Abstract: Drugs for treating mental disorders are among the most active substances prescribed in the world. The occurrence of these in environmental matrices is becoming increasingly common. Recent studies indicate that the drug fluoxetine hydrochloride, a selective inhibitor of serotonin, is present in sewage treatment effluents and in surface waters. The large increase in environmental research about the drug is linked to its low biodegradability and its persistence in the environment. This paper reviews the literature related to the occurrence and environmental toxicity data for the non-target organisms of the drug fluoxetine hydrochloride. An increase in contributions from the scientific literature is done on the species Daphnia similis and Pseudokirchneriella subcaptata exposure to fluoxetine hydrochloride. Based on results obtained, we carried out the environmental impact assessment for the Sewage Treatment Station Piracicamirim River. However, there are no established standards for the concentration of pharmaceuticals in the environment because they are not fully known ecotoxicological effects. The data collected are intended to help prioritize and determine the need for studies that indicate the occurrence, destiny, transport, health and elucidation of the effects caused by drugs, for the continuous improvement of standards of water in Brazil and worldwide / Mestrado / Tecnologia e Inovação / Mestre em Tecnologia

Tryptophan is an essential amino acid that is obtained from the diet. Approximately 98 % of ingested tryptophan is metabolized by the enzyme tryptophan 2,3-dioxygenase (TDO). The metabolism of tryptophan by TDO is an important determinant of tryptophan bioavailability to the brain for serotonin (5-HT) biosynthesis, an essential amine in affective disorders such as depression. Studies done on circadian rhythmicity of the enzyme activity have shown that, TDO activity is high during the scoto-phase (dark-phase), which is attributable to the de novo enzyme synthesis that occurs during this phase. 6-Methoxy-2-benzoxazolinontr-(6-MBOA), a structural analogue of melatonin (aMT) was shown to inhibit TDO activity in both the photo-phase (light-phase) and the scoto-phase with greater potency during the light-phase. Further studies were directed at demonstrating the effects of 6-MBOA on the brain tryptophan hydroxylase (TH) activity, which is a rate limiting enzyme in 5-HT biosynthesis and subsequently on 5-HT levels. The findings showed that, 6-MBOA induces TH activity with a concomitant rise in brain 5-HT levels. The blockade of 5-HT re-uptake into the presynaptic neuron leads to an increase in 5-HT available for the stimulatory action of 5-HT receptors. An attempt to establish whether the administration of 6-MBOA would block the binding of 5-HT to receptors on the synaptosomal membrane showed that 6-MBO A only inhibits the binding of 5 -HT at specific concentrations. In view of the positive effects imposed by 6-MBOA on brain 5-HT levels, urinary 5-hydroxyindole acetic acid (5-HIAA) excretion was measured before and after treatment with 6-MBOA. 5-HIAA excretion was found to be significantly increased after 6-MBOA treatment. Extensive research on the biosynthesis of pineal metabolites has been conducted in the past two decades. The pineal metabolites are synthesized from the precursor tryptophan. In order to obtain an overall picture of the effect of6-MBOA on pineal indole metabolism, an organ culture technique was employed. The results obtained showed that although 6-MBOA administration to rats caused a significant increase in aMT production, there was an insignificant increase in NAS production. This is an immediate precursor of aMT. Other pineal indoles were not affected at all by 6-MBOA administration. Furthermore, the production of pineal NAS and aMT showed an inter-individual variation with some animals producing very high, some very low and some produced average levels of these two metabolites in both photo and scoto-phase experiments. A study undertaken to investigate the circadian rhythm in endogenous aMT production using the competitive ELISA technique showed a clear pattern with high levels of aMT produced during the dark-phase and low levels ofaMT produced during the light-phase. Furthermore, the administration of6-MBOA to rats lead to a significant rise in endogenous aMT production.

Background: Although suicide seasonality has been well-documented, surprisingly little is known about its underlying mechanisms. Methods: In this thesis, data from three Swedish registers (Cause of Death Register, National Patient Register, Prescribed Drugs Register) and data from the Swedish Meteorological and Hydrological Institute were used. In Study I, the amplitude of suicide seasonality was estimated in completed suicides in 1992-2003 in individuals with different antidepressant medications or without antidepressants. In Study II, monthly suicide and sunshine data from 1992-2003 were used to examine the association between suicide and sunshine in groups with and without antidepressants. In Study III, the relationship between season of initiation of antidepressant treatment and the risk of suicidal behavior was explored in patients with a new treatment episode with antidepressant medication. In Study IV, the complex association between sunshine, temperature and suicidal behavior was investigated in patients with a new treatment episode with an antidepressant in two exposure windows (1-4 and 5-8 weeks) before the event. Findings: Study I: Higher suicide seasonality was found in individuals treated with selective serotonin reuptake inhibitors (SSRIs) compared with those given a different antidepressant treatment or those without any antidepressant treatment. Study II: In individuals treated with SSRIs, there was a positive association between sunshine and suicide, with the association stronger in men treated with SSRIs compared with men treated with other antidepressants. An effect modification by age was observed. Study III: The elderly (65+) had a higher risk of suicide when initiating antidepressant treatment in summer and a higher risk of suicide attempt when starting antidepressant therapy in spring and summer. Younger patients (0-24) demonstrated a higher risk of suicide attempt when treatment was initiated in autumn. Study IV: In the elderly (65+), a harmful association was observed between the risk of suicide attempt and the average daily temperature during the four weeks before the suicide attempt, as well as with average daily sunshine during both exposure windows (1-4 and 5-8 weeks) before the suicide attempt. Significance: Our results provide epidemiological support for the role of the serotonergic system in seasonality of suicide in which both medication and climate may be involved.

No description available.

Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) often prescribed for the treatment of anxiety and depression. Many of its effects are thought to be mediated by the dentate gyrus, but the mechanism by which some patients respond to treatment and some do not remains poorly understood. In this study we have characterized a previously-unknown component of the behavioral response to fluoxetine in the dentate gyrus, using a combination of genomic, behavioral, and imaging techniques. We have found that different components of the opioid system are involved in the treatment efficacy of fluoxetine in the dentate gyrus. Specifically, we have identified a population of anatomically and transcriptionally distinct mature granule cells that are defined by their high levels of proenkephalin expression after fluoxetine treatment. Furthermore, we have shown that the delta opioid receptor is partly mediating some of the behavioral effects of fluoxetine in a neurogenesis-independent manner. These results open an interesting new avenue for research into the involvement of the opioid system in the behavioral response to SSRIs.

Major depression is a complex disease involving genetic and environmental factors. Previous studies suggest that functional genetic polymorphisms that alter the serotonin (5-HT) system in combination with psychosocial stress can synergistically increase the strength of these associations. In addition, depression is associated with several neurological disorders involving neuronal injury, including stroke (i.e. post-stroke depression, PSD). Both forms of depression are treated with 5-HT-selective antidepressants like fluoxetine, but remission rates do not exceed 50%. Evidence showed that alterations affecting the 5-HT system, directly or indirectly, lead to anxiety or depression phenotypes and may elucidate determinants of response to antidepressants. To better understand common and unique alterations in both genetic- and injury-related depression, I have generated and investigated two novel mouse models that exemplify a serotonin-related genetic risk (Flx-Freud-1 mice) and an injury model (ischemic lesion), to identify similarities and differences in their behavioral phenotypes, and in response to fluoxetine treatment. In the Flx-Freud-1 mouse model, 5-HT neuron-specific adult knockout of Freud-1, a key repressor of the 5-HT1A receptor gene, led to overexpression of 5-HT1A autoreceptors thought to negatively regulate the 5-HT system. These mice showed increased 5-HT1A autoreceptor responses, reduced 5-HT levels and a robust anxiety and depression phenotype that was resistant to chronic fluoxetine treatment. These behaviors were dependent on increased 5-HT1A autoreceptors since they were not seen in mice lacking 5-HT1A autoreceptors in adult Freud-1 knockout background. Instead an opposite anti-depressed phenotype emerged, suggesting that Freud-1 might have additional functions in 5-HT cells. In the PSD model, the vasoconstrictor endothelin-1 was injected to induce transient ischemia in the left medial prefrontal cortex, iv part of the circuitry thought to be damaged in PSD in humans. This stroke resulted in a persistent anxiety, depression and cognitive impairment. Chronic fluoxetine treatment alone or combined with voluntary exercise was effective to reverse the behavioral and cognitive phenotypes in this PSD mouse model.The results of genetic and SSRI treated stroke models show that changes in 5-HT system contribute to widespread dysregulation of the neuronal circuitry implicated in depression, anxiety. Genetic alteration of the 5-HT system conferred fluoxetine-resistance, while cortical stroke which indirectly altered the 5-HT system remained responsive to fluoxetine. Following unilateral stroke, there was increased activity of the contralateral hemisphere, including the prefrontal cortex and limbic areas involved in anxiety and depression, and activation of the 5-HT system. Effective treatment with chronic fluoxetine alone or combined with exercise significantly reduced and balanced the contralesional neuronal activation in affected regions that correlated with improvements in phenotypes. In conclusion, this work implicates genetic changes that directly alter the 5-HT system in resistance to chronic fluoxetine treatment. Therefore, the Flx-Freud-1-induced 5-HT1A autoreceptor overexpression mouse model may provide a useful pre-clinical model of antidepressant resistance. In contrast, in the PSD model, in which expression of 5-HT1A autoreceptors remained intact, chronic fluoxetine treatment reversed depression and anxiety phenotypes. This model may provide insight into changes in neuronal activity that allows antidepressants to mediate behavioral and cognitive improvement.