FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / A depressÃo à uma doenÃa crÃnica, grave que afeta cerca de 350 milhÃes de pessoas no mundo. O objetivo deste trabalho foi estudar os efeitos antidepressivos do Ãcido lipÃico (ALA) associado a mirtazapina (MIRT) via mecanismos antioxidativos em modelo animal de depressÃo induzido por corticosterona. Camundongos machos adultos receberam 0,3% Tween 80, Corticosterona (CORT 20 mg/kg), MIRT (3 mg/kg), ALA (100 ou 200 mg/kg), sozinhos ou associados por 21 dias. No Ãltimo dia de tratamento os animais foram submetidos aos seguintes testes: campo aberto, labirinto em cruz elevado, suspensÃo de cauda, preferÃncia por sacarose, rota rod e tempo de sono. AlteraÃÃes oxidativas (glutationa reduzida-GSH e peroxidaÃÃo lipÃdica- MDA) e nitrito no cÃrtex prÃ-frontal (CPF), hipocampo (HC) e corpo estriado (CE); e fator neurotrÃfico derivado do cÃrebro (BDNF) no CPF e HC tambÃm foram abordadas. A administraÃÃo crÃnica de CORT desenvolveu alguns comportamentos tipo-depressivos que foram revertidos com MIRT e/ou ALA. A associaÃÃo de ALA e MIRT reverteu o efeito sedativo provocado pela administraÃÃo de MIRT sozinha, assim como a hipersonia causada pela administraÃÃo crÃnica de CORT. A administraÃÃo de CORT, ALA 200 e MIRT associados mostrou um aumento significativos nos nÃveis de GSH no cÃrtex prÃ-frontal (113%), hipocampo (90,27%) e corpo estriado (127%) quando comparado com o grupo tratado com CORT sozinha; efeitos semelhantes foram observados na peroxidaÃÃo lipÃdica e nos nÃveis de nitrito, com reduÃÃo dos nÃveis de MDA e nitrito no hipocampo e corpo estriado dos grupos tratados com a associaÃÃo de CORT, ALA 200 e MIRT quando comparados com o grupo tratado com CORT sozinha, respectivamente. No geral, ALA parece ser uma alternativa para o tratamento da depressÃo quando associado com MIRT, pois aumenta a neuroproteÃÃo e reduz o efeito colateral de sedaÃÃo. / Depression is a chronic, serious illness that affects about 350 million people worldwide. The objective of this work was to study the antidepressant effects of lipoic acid (ALA) associated with mirtazapine (MIRT) via antioxidative mechanisms in animal models of depression induced by corticosterone. Adult male mice received 0.3% Tween 80, corticosterone (Cort 20 mg / kg) MIRT (3 mg / kg), ALA (100 or 200 mg / kg), alone or associated for 21 days. On the last day of treatment the animals were subjected to the following tests: open field, elevated plus maze, tail suspension, preference for sucrose, route rod and sleep time. Oxidative changes (reduced glutathione and GSH-peroxidation lipÃdica- MDA) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (CE); and brain-derived neurotrophic factor (BDNF) in the CPF and HC were also addressed. Chronic administration of CORT developed some kind-depressive behaviors were reversed with MIRT and / or ALA. The association of ALA and MIRT reversed the sedative effect caused by the administration alone MIRT, as hypersomnia caused by the chronic administration of CORT. The administration CORT ALA 200 and associated MIRT showed significant increase in GSH levels in the prefrontal cortex (113%), hippocampus (90.27%) and striatum (127%) compared to the group treated with CORT alone; Similar effects were observed on lipid peroxidation and nitrite levels with reduction of MDA and nitrite levels in the hippocampus and striatum in the groups treated with the combination CORT ALA MIRT 200 and compared with the group treated with CORT alone respectively. Overall, ALA seems to be an alternative for treatment of depression associated with MIRT when, for neuroprotection increases and reduces the side effect of sedation.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [104]-110).

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 53-56).

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A depressÃo à uma doenÃa recorrente e incapacitante cujo tratamento està relacionado com modulaÃÃes nos sistemas monoaminÃrgicos em diversas Ãreas cerebrais. A riparina III (ripIII), isolada do fruto verde de Aniba riparia, apresentou, em estudos prÃvios, efeito antidepressivo. Dessa forma, objetivando investigar o potencial antidepressivo da ripIII, foram realizados testes comportamentais como o nado forÃado (TNF), suspensÃo da cauda (TSC), hipotermia induzida por apomorfina e campo aberto. Para avaliar o envolvimento das monoaminas, os animais foram prÃ-tratados com antagonistas especÃficos para receptores 5-HT1A, 5-HT2A/2C e 5-HT3 de serotonina (5-HT), D1 e D2 de dopamina (DA) e a1 e a2 de noradrenalina (NA) no TNF. AlÃm disso, os animais prÃ-tratados com ripIII e submetidos ou nÃo ao TNF tiveram as Ãreas cerebrais hipocampo, corpo estriado e cÃrtex prÃ-frontal retiradas para detecÃÃo dos nÃveis de monoaminas ou para realizaÃÃo dos experimentos de estresse oxidativo, investigando a atividade enzimÃtica da catalase e superÃxido dismutase, quantificando os nÃveis de glutationa reduzida (GSH) e nitrito/nitrato, alÃm do grau de lipoperoxidaÃÃo. A ripIII foi administrada agudamente, por via oral, na dose de 50 mg/kg, em todos os testes. Os resultados mostraram que a ripIII apresentou efeito antidepressivo nos modelos TNF e TSC sugerindo ser especÃfico, uma vez que os animais nÃo apresentaram alteraÃÃes na atividade locomotora no campo aberto. AlÃm disso, no TNF, os antagonistas sulpirida (D2), prazosina (a1), ioimbina (a2), NAN-190 (5-HT1A) e ondansentron (5-HT3) reverteram o tempo de imobilidade da ripIII sugerindo a participaÃÃo desses receptores para o efeito da substÃncia, enquanto nÃo houve alteraÃÃo deste efeito na presenÃa dos antagonistas SCH23390 (D1) e ritanserina (5- HT2A/2C) mostrando o nÃo envolvimento desses receptores no efeito da droga. A ripIII nÃo foi capaz de reverter a hipotermia induzida por apomorfina, que na dose utilizada, induz hipotermia por modular receptores b-adrenÃrgicos, sugerindo que o efeito da ripIII nÃo està relacionado com esses receptores. A ripIII apÃs o TNF, em corpo estriado e cÃrtex prÃfrontal, aumentou os nÃveis de DA, 5-HT e NA, diminuiu os metabÃlitos DOPAC, HVA, 5- HIAA e as taxas metabÃlicas e, no hipocampo, aumentou 5-HT e NA alÃm do metabÃlito 5- HIAA, mas manteve as taxas metabÃlicas. A administraÃÃode ripIII, antes do TNF, reverteu o aumento nos nÃveis de peroxidaÃÃo lipÃdica e nitrito-nitrato, reduziu a atividade da catalase mas aumentou os nÃveis de GSH em hipocampo, corpo estriado e cÃrtex prÃfrontal. Esses parÃmetros nÃo foram alterados nos animais nÃo submetidos ao estresse. Em conclusÃo, o estudo sugere uma aÃÃo moduladora, exercida por ripIII, sobre o funcionamento dos sistemas noradrenÃrgico, dopaminÃrgico e serotonÃrgico, em nÃvel central, como mecanismo para o efeito antidepressivo no TNF, bem como a participaÃÃo de propriedades antioxidantes diretas ou indiretas dessa droga, atravÃs da capacidade de modificar a resposta ao estresse oxidativo neuronal. / Depression is a disabling and recurrent disease whose treatment is related to modulations in monoaminergic systems in several brain areas. Riparin III (ripIII), isolated from unripe fruit of Aniba riparia, has shown previously antidepressant-like effects. Thus, in order to investigate the antidepressant effect of ripIII, behavioral experiments were performed, as the forced swim (FST), tail suspension (TST), apomorphine-induced hypothermia and open field tests. To assess the involvement of monoaminergic system, animals were pretreated with specific antagonists to 5-HT1A-, 5-HT2A/2C-, and 5-HT3-serotonin (5-HT) receptors, to D1- and D2-dopamine (DA) receptors and to 1- and 2-noradrenaline (NA) receptors in FST. Further, animals pretreated with ripIII and submitted or not to the FST had their brain areas such as hippocampus, striatum and prefrontal cortex removed for detection of monoamine levels or to carry out the experiments of oxidative stress, in which, it was investigated enzymatic activities of catalase and superoxide dismutase, measured the levels of reduced glutathione (GSH) and nitrite/nitrate, and lipid peroxidation degree. RipIII was acutely administered orally at a dose of 50 mg/kg in all tests. The results showed that ripIII presented antidepressant effect on the FST and TST suggesting that this effect is specific, since the animals showed no changes in locomotor activity in open field test. In the evaluation of monoaminergic systems, the results showed that the antagonists sulpiride (D2), prazosin (1), yohimbine (2), NAN-190 (5-HT1A) and ondansentron (5-HT3) reversed the immobility time of ripIII on the FST suggesting the involvement of these receptors, while no change of this effect in the presence of the antagonists SCH23390 (D1) and ritanserin (5-HT2A/2C) was observed, suggesting non-participation of these receptors in the drug effect. RipIII was unable to reverse the hypothermia induced by apomorphine that at the dose used, modulates -adrenergic receptors inducing hypothermia, suggesting that the effect of ripIII is not related to these receptors. RipIII, after FST, in the striatum and prefrontal cortex, increased levels of DA, 5-HT and NA, decreased DOPAC, HVA, 5-HIAA metabolites and decreased metabolic rates, and in the hippocampus, increased 5-HT and NA and 5-HIAA metabolite, but maintained metabolic rates. The prior administration of ripIII before the forced swimming, reversed the increased levels of lipid peroxidation and nitrite-nitrate, reduced the activity of catalase but increased levels of GSH in hippocampus, striatum and prefrontal cortex. These parameters were not altered in animals not exposed to stress. In conclusion, the study suggests a modulating action exerted by ripIII on the functioning of the noradrenergic, dopaminergic and serotonergic levels in the brain, as a mechanism for the antidepressant effect in the FST, as well as the participation of direct or indirect antioxidant properties of this drug through the ability to modify the neuronal response to oxidative stress

The present experiments investigated the effects of different antidepressant treatments on dopamine (DA) transmission by employing in vivo microdialysis in the nucleus accumbens (NAC) and the striatum of freely moving rats. The treatments were: a) the tricyclic antidepressant desipramine (DMI), b) the novel antidepressant drug bupropion, and c) electrically induced seizures (ECS). The following results were obtained: 1) Neither acute (5 mg/kg), nor chronic (5 mg/kg, b.i.d. X 21) DMI influenced basal interstitial concentrations of DA in the NAC or the striatum. Chronic DMI did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. In contrast, d-amphetamine (1.5 mg/kg, s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC (not in striatum) of the chronic DMI group. d-Amphetamine-induced hypermotility was also enhanced in the chronic DMI group. 2) Bupropion (10, 25 and 100 mg/kg, i.p.) increased extracellular striatal DA concentrations in a dose-, time-, and action potential-dependent manner. Bupropion produced similar responses in the NAC. The in vivo neurochemical effects of bupropion were compared with the effects of other DA uptake inhibitors such as d-amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, and benztropine by direct administration of the drugs to the striatum via the perfusion fluid in increasing concentrations (1 to 1000 μM). The rank order of potency of these drugs as determined by the increases in extracellular DA produced by 10 or 100 μM (following correction for dialysis efficiency of the test compounds in vitro) was: GBR 12909> benztropine> amphetamine= nomifensine= methylphenidate> cocaine> bupropion. Simultaneous in vivo microdialysis in the NAC and striatum was employed to investigate the effects of chronic (10 mg/kg, b.i.d. X 21) bupropion treatment on bupropion (25 mg/kg, i.p.)-induced increases in extracellular DA concentrations. The effect of the challenge bupropion injection was significantly enhanced in the NAC (not in striatum) of the chronic bupropion group. Bupropion-induced hyperlocomotion was also enhanced in the chronic bupropion group. 3) Following a single ECS (150 V, 0.75 sec) interstitial concentrations of DA in the NAC and striatum increased sharply to 130% and 300%, respectively. The ECS-induced DA increase in the striatum was Ca⁺⁺-sensitive, partially TTX-independent, and was not influenced by barbiturate-induced anaesthesia. Seizure activity induced by flurothyl did not influence dialysate DA concentrations from the striatum, but increased dialysate DA from the NAC to 150%. These results suggest that the ECS-induced DA release in the striatum (not in the NAC) is related to the passage of current and not to the seizure activity. A course of ECS (8 treatments, one every second day) did not influence basal extracellular DA concentrations in the striatum or the NAC, while it significantly increased the DA metabolites in the striatum. Chronic ECS did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. d-Amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC of the chronic ECS group. d-Amphetamine-induced hypermotility was also enhanced in the chronic ECS group. These results provide in vivo neurochemical confirmation that chronically administered DMI or ECS do not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI- or chronic ECS-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a potentiation of its effects on interstitial DA concentrations in the NAC. Moreover, these results demonstrate that chronic bupropion-induced behavioral sensitization is accompanied by a selective potentiation of its effects on interstitial DA concentrations in the NAC. Taken together, the present data provide direct neurochemical evidence that these antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. / Medicine, Faculty of / Graduate

http://dx.doi.org/10.1016/j.jad.2015.03.021 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19618号 / 医博第4125号 / 新制||医||1015(附属図書館) / 32654 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 清水 章, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19963号 / 医博第4153号 / 新制||医||1017(附属図書館) / 33059 / 京都大学大学院医学研究科医学専攻 / (主査)教授 村井 俊哉, 教授 森田 智視, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser + 1 appendix.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 5 uppsatser.