nÃo hà / A depressÃo à um transtorno psiquiÃtrico grave, prevalente, incapacitante que atinge pessoas de todas as classes sÃcio-econÃmicas, etnias e idades. Dados da OMS indicam que os custos com o tratamento deste transtorno representam um prejuÃzo econÃmico considerÃvel para a sociedade. Apesar dos avanÃos no conhecimento da neurobiologia da depressÃo e no mecanismo de aÃÃo dos antidepressivos, a etiologia deste transtorno, ainda, se constitui num desafio longe de ser totalmente esclarecido. Estudos recentes tem sugerido um possÃvel envolvimento do estresse oxidativo na patogÃnese da depressÃo e que substÃncias com potencial antioxidante podem ser utilizadas no tratamento desse transtorno. Baseado neste pressuposto o presente estudo investigou o efeito comportamental e neuroquÃmico do Ãcido alfa-lipÃico (ALA), um antioxidante sozinho ou associado com antidepressivos paroxetina (PXT) e desvenlafaxina (DVS) em modelos animais de depressÃo agudo e crÃnico. Esta tese foi desenvolvida em 2 protocolos experimentais (agudo e crÃnico) que resultaram na elaboraÃÃo de 3 artigos. O primeiro protocolo, que utilizou o modelo agudo, deu origem ao primeiro artigo, cujo objetivo foi investigar os efeitos centrais da administraÃÃo aguda do ALA associado à PXT em vÃrios testes comportamentais. Os animais (camundongos, swiss, machos, 25-30 g) foram tratados com PXT (10 ou 20 mg/kg) ou ALA (100 mg/kg) por via intraperitoneal (i.p.). Nos grupos de associaÃÃo os animais foram prÃ-tratados com ALA (100 mg/kg, i.p.), 30 minutos antes da administraÃÃo de PXT (10 ou 20 mg/kg, i.p.). ApÃs 30 minutos da Ãltima injeÃÃo, os animais foram submetidos aos testes comportamentais de campo aberto (CA), labirinto em cruz elevado (LCE), placa perfurada (PP) e suspensÃo de cauda (SC). Os animais prÃ-tratados com ALA e PXT apresentaram comportamento do tipo-ansiolÃtico, analisado pelo aumento da atividade exploratÃria no teste de CA, LCE e PP e do tipo-antidepressivo verificado pela diminuiÃÃo no tempo de imobilidade no teste de SC, modelos comportamentais muito utilizados para avaliaÃÃo de drogas ansiolÃticas/antidepressivas. O segundo protocolo, que utilizou o modelo crÃnico, resultou no segundo e terceiro artigos. Este protocolo foi proposto para avaliar os efeitos comportamentais (2 artigo) e neuroquÃmicos (3 artigo) da administraÃÃo repetida de ALA sozinho ou associado à DVS, no modelo de depressÃo induzido pela administraÃÃo crÃnica de corticosterona (CORT) em camundongos. Tanto no 2Âe 3 artigos foram utilizados camundongos fÃmeas (25-30 g) que receberam uma injeÃÃo de CORT (20 mg/kg) por via subcutÃnea (s.c.) durante 14 dias. Entre os dias 15 e 21 os animais receberam alÃm da CORT, a DVS (10 ou 20 mg/kg) por via oral (v.o.) ou CORT + DVS (10 ou 20 mg/kg, v.o.) + ALA (100 ou 200 mg/kg, v.o.) durante 7 dias. Outros grupos de animais receberam DVS ou ALA sozinhos nas mesmas doses durante 7 dias. No Ãltimo dia de tratamento, apÃs 1 hora da Ãltima injeÃÃo, os animais foram submetidos aos testes de CA, LCE, SC e nado forÃado (NF). Os animais que receberam injeÃÃo crÃnica de CORT demonstraram um comportamento do tipo-ansioso evidenciado pela diminuiÃÃo dos parÃmetros avaliados nos testes de CA e LCE, e do tipo-depressivo analisado pelo aumento do tempo de imobilidade nos testes de SC e NF. O tratamento com DVS ou ALA foi capaz de reverter o aumento no tempo de imobilidade induzido por CORT. O efeito antidepressivo de DVS foi potencializado na presenÃa de ALA. No terceiro artigo foram verificados os efeitos neuroquÃmicos do ALA sozinho ou associado com DVS atravÃs da determinaÃÃo dos biomarcadores do estresse oxidativo: produtos da peroxidaÃÃo lipÃdica (malondialdeÃdo-MDA), glutationa reduzida (GSH) e atividade da superÃxido dismutase (SOD). CORT aumentou significativamente os nÃveis de MDA (cÃrtex prÃ-frontal, hipocampo e corpo estriado), diminuiu glutationa-GSH (hipocampo) e aumentou a atividade da superÃxido dismutase - SOD (cÃrtex prÃ-frontal e hipocampo) quando comparada com o grupo controle. Nos camundongos tratados com CORT + DVS (10 ou 20 mg/kg) ou CORT + ALA (100 ou 200 mg/kg) os nÃveis de MDA foram diminuÃdos significativamente (cÃrtex prÃ-frontal, hipocampo, mas nÃo no corpo estriado). NÃo houve alteraÃÃo significativa nos nÃveis de GSH (cÃrtex prÃ-frontal, hipocampo e corpo estriado), exceto um aumento foi visto nos grupos CORT + ALA (100 mg/kg) (hipocampo e corpo estriado), CORT + DVS 10 mg/kg (corpo estriado) e uma diminuiÃÃo na atividade da SOD em todas as regiÃes cerebrais estudadas quando comparado com o grupo tratado com CORT. Nos grupos CORT + DVS (10 ou 20 mg/kg) + ALA (100 ou 200 mg/kg), a adiÃÃo de ALA, em ambas as doses, diminuiu a peroxidaÃÃo lipÃdica e atividade da SOD e aumentou, de maneira significativa, os nÃveis de GSH nas trÃs regiÃes cerebrais estudadas, com exceÃÃo do grupo CORT + DVS (10 mg/kg) + ALA (200 mg/kg). Nossos resultados contribuem de maneira crescente com as evidÃncias de que antioxidantes tais como ALA poderà ser Ãtil no tratamento das doenÃas relacionadas com o estresse oxidativo, incluindo a depressÃo. / Depression is a serious psychiatric disorder, prevalent and disabling that affects people of all socioeconomic classes and age groups. Despite advances in understanding the neurobiology of depression and the mechanism of action of antidepressants, the etiology of this disorder remains a challenge far from being completely understood. Recent studies have suggested a possible involvement of oxidative stress in the pathogenesis of depression and that substances with antioxidant potential can be used to treat this disorder. Based on this assumption, the present study investigated the behavioral and neurochemical effect of alpha-lipoic acid (ALA) alone or associated with paroxetine (PXT) and desvenlafaxine (DVS) in animal models of acute and chronic depression. This thesis was developed in two experimental protocols (acute and chronic) that resulted in the development of 3 articles. The first protocol, which used the acute model, raised the first article, whose aim was to investigate the central effects of acute administration of ALA associated with PXT in different behavioral tests. The animals (mice, Swiss male, 25-30 g) were treated with PXT (10 or 20 mg/kg) or ALA (100 mg/kg) by intraperitoneal via (i.p.). In associated groups, animals were pretreated with ALA (100 mg/kg, i.p.) 30 minutes before administration of PXT (10 or 20 mg/kg, i.p.). 30 minutes after the last injection, the animals were subjected to behavioral tests of open field test (OFT), elevated plus maze test (EPM), hole board (HB) and tail suspension test (TST). The animals pretreated with ALA and PXT showed anxiolytic-like behavior, analyzed by increased exploratory activity in the OFT, EPM and HB test and an antidepressant-like behavior verified by the decrease in the immobility time in the TST, behavioral models often used to evaluate anxiolytic/antidepressant drugs. The second protocol, which used the chronic model, resulted in the second and third article. This protocol has been proposed to assess the behavioral effects (2nd article) and neurochemical effects (3rd article) of repeated administration of ALA alone or associated with DVS in the model of depression induced by chronic administration of corticosterone (CORT) in mice. Both the 2nd and 3rd article used female mice (25-30 g) which received an injection of CORT (20mg/kg) subcutaneously (s.c.) for 14 days. Between the 15th and 21st day, animals received, in addition to CORT, DVS (10 or 20 mg/kg) by oral route (p.o.) or CORT + DVS (10 or 20 mg/kg, p.o.) + ALA (100 or 200 mg/kg, p.o.) for 7 days. Other groups of animals received DVS or ALA alone at the same doses for 7 days. On the last day of treatment, 1 hour after the last injection, the animals were tested for OFT, EPM, TST and Forced Swimming Test (FST). The animals receiving chronic CORT injection showed an anxiety-like behavior evidenced by the decrease of the parameters evaluated in the OFT and EPM tests and a depressive-like behavior analyzed by increased immobility time in TST and FST. Treatment with ALA or DVS was able to reverse the increase in immobility time induced by CORT. The antidepressant effect of DVS was potentiated in the presence of ALA. In the third article was checked neurochemical effects of ALA alone or associated with DVS through the determination of biomarkers of oxidative stress: lipid peroxidation products (malondialdehyde-MDA), reduced glutathione (GSH) and activity of superoxide dismutase (SOD). CORT significantly increased MDA levels (prefrontal cortex, hippocampus and striatum), reduced glutathione - GSH (hippocampus) and increased the activity of superoxide dismutase - SOD (prefrontal cortex and hippocampus) compared to the control group. In mice treated with CORT + DVS (10 or 20mg/kg) or ALA + CORT (100 or 200 mg/kg) MDA levels were significantly decreased (prefrontal cortex, hippocampus, but not in the striatum). There was no significant change in the levels of GSH (prefrontal cortex, hippocampus and striatum), but an increase was seen in the groups CORT + ALA (100 mg/kg) (hippocampus and striatum), CORT + DVS10 mg/kg (striatum ) and a decrease in SOD activity in all brain regions investigated compared with the group treated with CORT. In groups CORT + DVS (10 or 20 mg/kg) + ALA (100 or 200 mg/kg), the addition of ALA, at both doses, reduced lipid peroxidation and SOD activity and increased significantly the levels of GSH in the three brain regions studied, except for the group DVS + CORT (10 mg/kg) + ALA (200 mg/kg). Our results contribute to the increasing evidence that antioxidants such as ALA may be useful in the treatment of diseases related to oxidative stress, including depression.

Plusieurs études ont montré que les maladies cardiovasculaires constituent un risque majeur de développement du trouble dépressif chez l’homme. Plus précisément, à la suite d’un infarctus du myocarde, 15 à 30 % des patients développent une dépression majeure dans les 6 à 8 mois suivant l’évènement cardiaque. Dans un modèle d’infarctus du myocarde chez le rat, développé dans notre laboratoire, nous avons noté la présence de comportements compatibles avec une dépression, deux semaines après l’infarctus. Nous avons également détecté des cellules apoptotiques dans le système limbique dès les premières minutes de reperfusion, nombre qui atteint son apogée à 3 jours de reperfusion. Nous avions émis l’hypothèse que l’apoptose que l’on observe dans le système limbique serait reliée à la réponse inflammatoire induite par l’infarctus du myocarde. Les comportements reliés à de la dépression ont été prévenus par l’administration d’un inhibiteur de la synthèse des cytokines pro-inflammatoires, la pentoxifylline, le célécoxib, un inhibiteur de la cyclooxygenase-2, par des probiotiques ainsi que par différents antidépresseurs. Les résultats des deux premières études de cette thèse montrent que la desvenlafaxine, un Inhibiteur de la recapture de la sérotonine et noradrénaline (IRSN) prévient les comportements dépressifs tout en diminuant l’apoptose à 3 jours post-infarctus dans le système limbique. Les comportements similaires à ceux d’une dépression que présentent les rats deux semaines après l’évènement cardiaque sont encore présents à 4 mois post-infarctus, si aucun traitement n’est entrepris. De plus, ces animaux développent des troubles d’apprentissage que la desvenlafaxine peut prévenir, et ceci même si le traitement n’est présent que pendant les 2 premières semaines post-infarctus. Dans la troisième étude de cette thèse, nous avons voulu savoir si le nerf vague était impliqué dans les effets bénéfiques de deux probiotiques sur l’apoptose dans le système limbique après un infarctus du myocarde. Nos résultats ont démontré que les probiotiques réduisent l’apoptose dans le système limbique après un infarctus du myocarde, mais que cet effet est perdu en présence d’une vagotomie. Les résultats obtenus démontrent que l’infarctus du myocarde induit une mort par apoptose dans le système limbique de même que des comportements dépressifs et des problèmes d’apprentissage à long terme. Ces problèmes peuvent être diminués par un traitement à la desvenlafaxine, et ceci même si le traitement n’est présent que pour les deux premières semaines post-infarctus. Finalement, nous avons observé que les probiotiques avaient des effets bénéfiques sur l’apoptose dans le système limbique par un mécanisme impliquant le nerf vague. En conclusion, plusieurs interventions différentes sont efficaces pour limiter les conséquences de l’infarctus du myocarde sur le système limbique et un traitement court est efficace pour prévenir les problèmes à plus long terme. / Several studies have highlighted that disruption of the cardiovascular functions is a major risk of developing depressive disorder in humans. 15-30% of the general population develops major depression within 6 to 8 months after a myocardial infarction. To better understand the underlying mechanisms and identify therapeutic pathways, we use a rat model of post-myocardial infarction developed in our laboratory. We have observed in these animals an increased apoptosis in the limbic system, which starts in the first minutes following reperfusion and peaks 3 days post-reperfusion. As a result, a depression-like phenotype and learning impairments appear 2 weeks after the myocardial infarction, which will persist up to 4 months after the infarct. We hypothesize that the observed apoptosis and the resulting depressive-like behavior are mediated by the inflammatory response induced after myocardial infarction. Indeed, depression-like behavior is prevented by the administration of an inhibitor of the pro-inflammatory cytokines, (pentoxifillyne, celecoxib), as well as by probiotics. In this thesis, we show that desvenlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI) prevents death by apoptosis in the limbic system. Desvenlafaxine also helps to improve the depressive-like behavior in these rats as well as the learning impairments, even if the treatment is administered during the first 2 weeks post-reperfusion. Finally, we have discovered that vagotomy prevents the probiotics effect over the apoptosis appearing after myocardial infarction, highlighting the importance of the vagus nerve in the beneficial effects of probiotics. In conclusion, several interventions are effective in limiting the consequences of myocardial infarction on the limbic system and also key to prevent the apparition of secondary psychological disorders.

La dépression majeure et les douleurs chroniques sont deux problématiques distinctes, mais liées par une comorbidité élevée et un effet néfaste sur la qualité de vie des individus atteints. Ce mémoire est consacré aux liens qui les unissent et présente deux études. L’étude 1 évalue l’impact de la déplétion aiguë du tryptophane sur les mécanismes endogènes de freinage de la douleur chez des participants sains. L’étude 2 évalue l’intégrité des mécanismes endogènes de freinage de la douleur chez des patients souffrant de dépression majeure (DM) avant et après un traitement aux antidépresseurs à double action (Duloxétine ou Desvenlafaxine). Les données des patients de l’étude 2 sont aussi comparées à celles d’un groupe de sujets sains pour mieux comprendre l’effet de la DM sur les mécanismes endogènes de freinage de la douleur. L’étude 1 montre que la déplétion aiguë du tryptophane bloque les mécanismes endogènes de freinage de la douleur. L’étude 2 montre que les patients souffrant de DM ont une capacité de freinage de la douleur intacte, qui est réduite par l’administration de médicaments. En conclusion, les mécanismes de freinage de la douleur semblent affectés par la déplétion aiguë du tryptophane. Les participants en DM ont une capacité d’inhibition de la douleur préservée par rapport aux sujets sains et affectée suite à la prise du médicament. Ces résultats permettent d’envisager un écart théorique entre la DM et les douleurs chroniques. / While major depression and chronic pain are distinct set of issues, they share high comorbidity rates and are both detrimental to those who suffer, affecting their quality of life. Based on two studies, this master’s thesis centers on the relationships between these issues. A first study (1) evaluates the effect of acute tryptophan depletion on endogenic mechanisms of pain reduction. A second study (2) assesses the endogenic mechanisms of pain reduction of patients who suffer from major depressive disorders (MDD) before and after the intake of a dual action antidepressant (Duxoletine or Desvenlafaxine). In conclusion, study 1 shows that the acute tryptophan depletion inhibits the endogenic mechanisms of pain reduction. Study 2 shows that patients who suffer from MDD have intact pain reduction mechanisms that are reduced by the intake of medication. The results suggest a theoretical gap between notions of MDD and chronic pain.