This thesis consists of four self-contained papers. Essay I (with Linuz Aggeborn): Fluoridation of the drinking water is a public policy whose aim is to improve dental health. Although the evidence is clear that fluoride is good for dental health, concerns have been raised regarding potential negative effects on cognitive development. We study the effects of fluoride exposure through the drinking water in early life on cognitive and non-cognitive ability, education and labor market outcomes in a large-scale setting. We use a rich Swedish register dataset for the cohorts born 1985-1992, together with drinking water fluoride data. To estimate the effects, we exploit intra-municipality variation of fluoride, stemming from an exogenous variation in the bedrock. First, we investigate and confirm the long-established positive relationship between fluoride and dental health. Second, we find precisely estimated zero-effects on cognitive ability, non-cognitive ability and education for fluoride levels below 1.5 mg/l. Third, we find evidence that fluoride improves later labor market outcomes, which indicates that good dental health is a positive factor on the labor market. Essay II: I study the associations between cognitive and non-cognitive abilities and mortality using a population-wide dataset of almost 700,000 Swedish men born between 1950 and 1965. The abilities were measured at the Swedish military enlistment at age 18-20. In addition, I investigate if income and education are good proxies for the abilities. The results suggest that both cognitive and non-cognitive abilities are strongly associated with mortality, but that non-cognitive ability is a stronger predictor. The associations are only partly mediated through income and education. For middle and high income earners and individuals with a college education there are no associations with mortality. However, for low income earners and individuals without a college education, both abilities are strongly associated with mortality. The associations are mainly driven by the bottom of the distributions. Essay III (with Matz Dahlberg, Kevin Mani and Anders Wanhainen): We examine how health information affects individuals' well-being using a regression discontinuity design on data from a screening program for an asymptomatic disease, abdominal aortic aneurysm (AAA). The information provided to the individuals is guided by the measured aorta size and its relation to pre-determined levels. When comparing individuals that receive information that they are healthy with those that receive information that they are in the risk zone for AAA, we find no effects. However, when comparing those that receive information that they have a small AAA, and will be under increased surveillance, with those who receive information that they are in the risk zone, we find a weak positive effect on well-being. This indicates that the positive information about increased surveillance may outweigh the negative information about worse health. Essay IV: I estimate the effect of SSRI antidepressants on the risk of mortality for myocardial infarction (MI) patients using Propensity Score Matching on individual health variables such as pharmaceutical drug prescription, patient history and severity of the MI. The effect of antidepressants on mortality is a heavily debated topic. MI patients have an elevated risk of developing depression, and antidepressants are among the most common treatments for depression and anxiety. However, there are indications that some classes of antidepressants may have drug-induced cardiovascular effects and could be harmful for individuals with heart problems, but there is a lack of large-scale studies using credible identification strategies. My findings indicate no increased risk of two-year mortality for MI patients using SSRI. The results are stable for several specifications and robustness checks.

La dépression et l’antidépresseur, phénomènes plus vastes, plus complexes que l’ordre biomédical ne l’entend, répondent à des logiques qui dépassent les seules considérations organiques, corporelles. Certaines recherches montrent d’ailleurs que ces deux entités sont autonomes l'une de l'autre, signifiant que les antidépresseurs sont prescrits pour des raisons indépendantes de la prévalence de problèmes de santé mentale. C’est dans cette optique que, dans ce mémoire, nous examinons les raisons pour lesquelles les individus ont recours aux antidépresseurs suite à une rupture conjugale. C’est à l’aide des récits de huit femmes ayant pris des antidépresseurs suite à une rupture conjugale qu’on a donc investigué les rouages du recours à ces médicaments. À la lumière des résultats, on observe effectivement que la prise d’antidépresseurs semble répondre à une logique qui soit extra–médicale. D’abord par le constat que seules trois d’entres ces huit femmes ont justifié leur prise d’antidépresseurs par la réception d’un diagnostic formel de dépression. Ensuite, par la découverte qu’elle se déploie essentiellement selon une double symbolique au centre duquel prime le lien social. En effet, on a recours aux antidépresseurs suite à une rupture conjugale parce qu’ils sont à la fois l’incarnation d’un lien de confiance avec un être semblable à soi, empathique, le médecin, et le symbole d’un retour à la vie dite ‘normale’ où les manières d’être et d’interagir sont conformes à celles du groupe auquel on s’identifie. On croit que l’importance accordée à la confiance au médecin et à la normalisation quant au recours à l’antidépresseur témoignent du resserrement des liens d’identification propre à l’individualisme contemporain lesquels, en opposition aux grands récits de jadis, sont désormais axés sur une intimité de valeurs et d’objectifs entre semblables. / Depression and antidepressants are far more complex phenomenons than the biomedical order pretends. Some research show that these two entities are independant from one another, meaning that antidepressants are prescribed for reasons independant of mental health problems. In this master’s thesis we examine why individuals have recourse to antidepressants following a relationship break-up; the relationship (marital or not) break-up being a critical situation associated with the prevalence of depression. Eight women who took antidepressants following a relationship break-up were interviewed for this study. The findings show that the recourse to antidepressants appears to respond to a logic that is non-medical. First, by the fact that only three of the eight women interviewed justified their recourse to antidepressants by receiving a diagnosis of depression. Second, by the discovery that these women relied on antidepressants because they are the embodiment of a relationship of trust with someone familiar to themselves, the doctor, and the symbol of a return to a ‘normal’ life.

La dépression est une maladie chronique, récurrente et potentiellement mortelle qui affecte plus de 20 % de la population à travers le monde. Les mécanismes sous-jacents de la dépression demeurent incompris et la pharmacothérapie actuelle, largement basée sur l’hypothèse monoaminergique, fait preuve d’une efficacité sous optimale et d’une latence thérapeutique élevée. Par conséquent, la recherche est amenée à élaborer de nouveaux traitements pharmacologiques. Pour détecter leur action, il est avant tout nécessaire de développer des outils expérimentaux adéquats. Dans cette optique, notre but a été de mesurer l’anhédonie, un symptôme cardinal de la dépression, chez le rat de laboratoire. L’anhédonie a été définie comme une réduction de la récompense et a été mesurée avec le test de consommation de sucrose et la technique d’autostimulation intracérébrale. En vue d’induire l’anhédonie, nous avons effectué une bulbectomie olfactive, une procédure qui entraîne divers changements biochimiques, cellulaires et comportementaux similaires à ceux de l’état dépressif et qui peuvent être renversés par un traitement antidépresseur chronique. Nos résultats montrent que la bulbectomie olfactive produit également l’anhédonie, reflétée par une réduction durable de la consommation de sucrose et par une réduction de l’efficacité de l’amphétamine dans le test d’autostimulation intracérébrale. Ces effets ont été présents jusqu’à trois à quatre semaines suivant la chirurgie. La bulbectomie olfactive a aussi été associée à une augmentation de l’élément de réponse liant l’AMPc dans le striatum, un index moléculaire associé à l’anhédonie. Ces découvertes suggèrent que l’anhédonie peut être produite et étudiée de façon fiable dans le modèle de bulbectomie olfactive et que le circuit de récompense pourrait constituer une cible cohérente pour de nouvelles drogues en vue du traitement de la dépression. / Depression is a chronic, recurrent and potentially deadly disorder that affects over 20 % of the population worldwide. The mechanisms underlying depression are still not understood and current pharmacotherapy, based largely on monoaminergic hypotheses, is plagued by suboptimal efficacy and delayed therapeutic latency. This has lead to a search for novel pharmacological treatments. To achieve this, it is first necessary to develop adequate experimental tools. With this in mind, we aimed to measure anhedonia, a cardinal symptom of depression, in laboratory rats. We defined anhedonia as a reduction in reward, and measured it with the sucrose intake test and in the intracranial self-stimulation paradigm. In order to induce anhedonia, we surgically removed the olfactory bulbs, a procedure that results in a host of behavioral, cellular and biochemical changes that are qualitatively similar to those observed in clinical depression. These changes are long-lasting and reversed by chronic antidepressant treatment, validating olfactory bulbectomy as an animal model of depression. Our results show that olfactory bulbectomy also produces anhedonia, reflected by a stable and long-lasting reduction in sucrose intake as well as a reduction in the rewarding effectiveness of amphetamine in the self-stimulation paradigm. These effects were present even after three to four weeks post-surgery. Olfactory bulbectomy was also associated with increased striatal cAMP response element binding, a molecular index associated with depressive-like behaviour. These findings suggest that anhedonia can be reliably produced and studied within the olfactory bulbectomy model and that reward circuitry may comprise a logical target for novel drugs to treat depression.

Finally, the neuroprotective effects of TGP against corticosterone-induced neurotoxicity in rat pheochromocytoma (PC12) cells, an in vitro experimental model of depression were studied. The results showed TGP treatment dose-dependently protected the cells against corticosterone-induced toxicity. The cytoprotection afforded by TGP treatment was shown to be associated with an enhanced antioxidant activity, and increased expressions of neurotrophins including brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3. / Secondly, the antidepressant-like effect of TGP was evaluated by a rat model of depression induced by chronic unpredictable mild stress (CUMS). The results showed that a 5-week CUMS caused depression-like behavior in rats, as indicated by a significant decreases in sucrose consumption (assessed by sucrose preference test) and locomotor activity (assessed by open-field test), and an increase in immobility time (assessed by forced swim test). Intragastric administration of TGP during the five weeks of CUMS procedure significantly suppressed these behavioral changes induced by CUMS. / Taken together, the results confirmed the antidepressant-like effect of TGP. The antidepressive action of TGP may be mediated by the modulation of the hypothalamic-pituitary-adrenal axis function, the inhibition of oxidative stress, and the up-regulation of neurotrophins, thereby leading to the neuroprotective effects. / The antidepressant-like effect of TGP was firstly evaluated by the behavioral despair test, forced swim test and tail suspension test. The results showed that intragastric administration of TGP caused a significant reduction of immobility time in both forced swim and tail suspension tests in mice. TGP treatment also significantly reduced the duration of immobility time in the forced swim test in rats. / The root of Paeonia lactiflora Pall. (Family: Ranunculaceae), commonly known as peony, is a component herb of many traditional formulae for the treatment of depression-like disorders. Previous studies have demonstrated the antidepressive effect of peony extract in mouse models of depression. Total glycosides of peony (TGP) is regarded as the major active ingredients of peony. The present study aims to confirm the antidepressive potential of TGP and evaluate its action mechanisms. / Thirdly, the neuroprotective effects of TGP on CUMS-treated rats and its possible mechanisms were investigated. The results showed that treatment with TGP for 5 weeks produced neuroprotective effects on the hippocampus of CUMS-treated rats. This effect was associated with the attenuation of hypothalamic-pituitary-adrenal axis hyperactivation (characterized by a decreased serum corticosterone level and an increased hippocampal glucocorticoid receptor expression), an inhibition of oxidative stress, and up-regulation of neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3 in the hippocampus. / Mao, Qingqiu. / Adviser: Che Chun-Tao. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 158-186). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Submitted by Rosina Valeria Lanzellotti Mattiussi Teixeira (rosina.teixeira@unisantos.br) on 2015-04-08T18:44:55Z No. of bitstreams: 1 Marcela Potrich Peluffo.pdf: 226215 bytes, checksum: 738e3b8accac2fd4d75e3a41daded914 (MD5) / Made available in DSpace on 2015-04-08T18:44:55Z (GMT). No. of bitstreams: 1 Marcela Potrich Peluffo.pdf: 226215 bytes, checksum: 738e3b8accac2fd4d75e3a41daded914 (MD5) Previous issue date: 2014-03-27 / The World Health Organization estimated depression as the third cause of disability in the ranking of all diseases, responsible for 4.3% loss of healthy life years (DALY). The depressive disorder impairs the ability to function, leading to deficiency in the production of more than 50% of patients. The treatment may be pharmacotherapy, psychotherapy, and in some cases eletroconvulsive therapy. This study examined the prevalence of the use of antidepression medications in the city of São Paulo, Brazil and is part of a large study Pos traumatic stress disorder on the São Paulo city: prevalence, commordity and associated factors. This is a one phase cross-sectional survey carried out in São Paulo, Brazil. A multistage probability to size sampling scheme was performed in order to select the participants (3000). The measurements included psychiatric diagnoses (CIDI 2.1), and psychoactive medications. The interviews were carried between June/2007 February/2008. The statistical analyses will be weight-adjusted in order to take account of the design effects. The frequency of use of psychoactive medications in individuals with depressive disorder 13%, 12,8% make use of antidepressant medication and 8% benzodiazepines, so with a large number of concurrent use of two medications. Among those who are using antidepressants, 63% use selective serotonin reuptake inhibitors, 34% use a tricyclic antidepressant and the other 3% make use of selective inhibitors of noradrenaline reuptake and various antidepressants. Was associated with the use of antidepressant medications females (2,7; IC 95% 1,5 ¿ 4,9), age over 30 years, being widowed or divorced or separate without living with the partner, with schooling above 13 years. It was concluded that there is a great way to go in our country in relation to mental health policies. Advances such as ensuring access to medicines and qualified professionals have already occurred, but show still insufficient. / A Organização Mundial da Saúde estima a depressão como a terceira causa de incapacidade no ranking de todas as doenças, responsável por 4,3% de perda de anos de vida saudáveis (DALY). O transtorno depressivo prejudica a capacidade laboral de mais de 50% dos pacientes. Os tratamentos podem ser farmacoterapia, psicoterapia e, em alguns casos, o tratamento eletroconvulsivante. O objetivo deste estudo foi avaliar o uso de medicamentos antidepressivos em indivíduos com diagnóstico de transtorno depressivo na população da cidade de São Paulo, Brasil. Um estudo de corte transversal foi realizado com amostra probabilística, em multiestágios, da população da cidade de São Paulo, Brasil. Foram entrevistados 2536 indivíduos. As medidas incluíram diagnósticos psiquiátricos (CIDI 2.1) e o uso de medicamentos psicoativos, incluindo antidepressivos. As entrevistas foram realizadas entre Junho/2007 e Fevereiro/2008. As estimativas foram ajustadas para o efeito do desenho por meio da análise de amostras complexas. A prevalência de uso de medicação psicoativa em indivíduos com transtorno depressivo foi de 13%, 12,8% utilizando de medicação antidepressiva e 8% benzodiazepínicos, portanto com número grande de uso concomitante das duas medicações. Entre aqueles que fazem o uso de antidepressivos, 63% usam inibidores seletivos da recaptação de serotonina, 34% usam antidepressivo tricíclico e os outros 3% fazem o uso de inibidores seletivos da recaptação de noradrenalina e antidepressivos variados. O uso de medicamentos antidepressivos esteve associado ao sexo feminino (2,2; IC 95% 1,0 ¿ 5,0), idade acima de 30 anos (2,7; IC 95% 1,1 ¿ 6,5), ser viúvo ou divorciado ou separado não morando junto com o parceiro (2,0; IC 95% 1,0 ¿ 4,2), com escolaridade acima de 13 anos (3,1; IC 95% 1,2 ¿ 7,9). Foi concluído que há um grande caminho a ser percorrido em nosso país em relação às políticas de saúde mental. Avanços como a garantia de acesso aos medicamentos e profissionais qualificados já ocorreram, mas se mostram ainda insuficientes.

In humans and other organisms, monoaminergic systems are crucial in neuronal function and behavior. The monoamine transporters (MATs), which can be found on the presynaptic plasma membrane of neurons in the central nervous system (CNS), are crucial in the regulation of neurotransmitter concentration in the synaptic cleft. As the duration and concentration of neurotransmitters in the cleft affect further downstream signaling responses, these proteins are important targets for both understanding neuronal physiology and compounds of interest. Multiple theories exist proponing the contribution of MATs to a variety of mental and neurological disorders, including depression. This theory establishes that depression is caused by imbalances in monoamine neurotransmitters. Compounds such as Fluoxetine (FLX) are classified as selective serotonin reuptake inhibitors (SSRIs), these drugs selectively block the reuptake of neurotransmitters at the serotonin transporter (SERT). Since differences in MAT selectivity of inhibitory compounds are influential to selecting efficacious antidepressant treatments, we utilized a unique fluorescent analysis technique to explore three therapeutic compounds of interest (in-vitro) which contain structural similarity to FLX. Our results confirm the selectivity of FLX at SERT, and classify the novel compounds studied into different potential categories of reuptake inhibitors. We hope these compounds will be studied further to elucidate their potentially therapeutic roles and mitigation of undesired side effects seen in other medications.

University of Macau / Institute of Chinese Medical Sciences

Depression and post-traumatic stress disorder are common psychiatric comorbidities related to stress. These conditions are frequently treated with antidepressants such as selective serotonin reuptake inhibitors (SSRI’s). However, there are individual differences in susceptibility to stress-induced psychopathologies and response to antidepressants. Therefore, there is a need to identify biologic factors that predict vulnerability to stress and response to treatment. Furthermore, few studies have examined the neural correlates of antidepressant treatment response in a stress-susceptible animal model. This dissertation had three specific aims: 1) to characterize behavioral predictors of stress vulnerability by studying three dimensions of temperament (reward dependence, novelty-specific activity and harm avoidance) before stress exposure using a stress-susceptible rat strain, 2) to identify the neural network effects of response and non-response to SSRI treatment using a stress-susceptible animal model, and 3) to determine the neurophysiologic correlates of helplessness susceptibility. This was examined via measurement of regional brain metabolic capacity and functional connectivity within relevant neural circuits, and measurements of corticosterone and heart rate. These effects were studied in rats that underwent inescapable shock exposure followed by escape testing. Holtzman rats showed greater predisposition to helpless behavior following inescapable shock compared to Sprague Dawley and Long-Evans strains. Also, increased activity in a novel environment and low heart rate appeared to be markers of helplessness susceptibility in Holtzman rats. Limbic-cortical network effects were identified that distinguished between responders and non-responders to antidepressant treatment in the Holtzman strain. Finally, hypermetabolism of the lateral habenula and a less interactive prefrontal-limbic cortex were identified in subjects with higher susceptibility towards helplessness within the Holtzman strain. Similar findings have been reported with other depression animal models and human neuroimaging studies. These findings support that the helpless dimension of mood disorders can be accurately modeled with the Holtzman rat strain and confirm that the lateral habenula and prefrontal cortex are key regions mediating the helpless phenotype and response to SSRI treatment. / text

No description available.

In this thesis, rodent models of chronic pain were used to explore analgesic mechanisms that may potentially be engaged in spinal and peripheral compartments by systemically-administered amitriptyline, a tricyclic antidepressant. The first project (Chapter 2) identified the roles of spinal adenosine A1 and serotonin 5-HT7 receptors, as well as of peripheral adenosine A1 receptors, in the acute antinociceptive effects of amitriptyline in mice. The second project (Chapter 3) examined the potential utility of amitriptyline as a preventive analgesic against persistent post-surgical pain, and involved perioperative administration of amitriptyline after peripheral nerve injury in rats. Changes in post-injury behavioural outcomes, as well as spinal noradrenergic sprouting, were assessed. Overall, spinal serotonergic pathways linked to adenosine A1 receptors, as well as peripheral adenosine A1 receptors, appear to be important in antinociception by amitriptyline. Preventive analgesia by this drug does not appear to result from anatomical changes in spinal noradrenergic pathways.