Submitted by Claudia Rocha (claudia.rocha@udesc.br) on 2018-03-21T13:05:35Z No. of bitstreams: 1 PGCA17MA226.pdf: 928502 bytes, checksum: 1c88be8fef47975d49236c8a6f4ae702 (MD5) / Made available in DSpace on 2018-03-21T13:05:35Z (GMT). No. of bitstreams: 1 PGCA17MA226.pdf: 928502 bytes, checksum: 1c88be8fef47975d49236c8a6f4ae702 (MD5) Previous issue date: 2017-02-24 / Capes / With the aim to investigate methodologies that indicate stress in commercial laying hens, the study was conducted at Poultry Sector of the CAV/UDESC, using 48 HyLine Brown hens, with were 79 wk of age. The hens were housed in appropriate cages and the molt was induced by feed withdrawal for 10 days, five methodologies were investigated (corticosterone plasmatic level - CORT, heterophil:lymphocyte ratio - H/L, catalase - CAT, reduced glutathione - GSH and level of thiobarbituric acid reactive substances - TBARS), in six days of blood samples collect (zero, two, four, six, eight and 10 days of feed withdrawal). The experimental design was completely randomized with eight replicate per day of collection, each hen was considered as an experimental unit. The collections for methods CORT and H/L ratio were obtained at 1600 h and the rest at 0800 h. To determine CORT level and H/L ratio the blood samples were collected from wing vein and jugular vein for other methodologies. In each collection, eight hens were randomly assigned and after procedure they returned to the cages. The Shapiro-Wilk test was applied to verify the normality of the data and the variables presented normal distribution. It was used polynomial regression analysis to determine the moment of maximum stress for each methodology. As all methods provide quantitative results it was possible to use Pearson correlation. Data analysis was done with the SAS (2009). CORT levels, GSH and TBARS there were a quadratic effect in polynomial regression analysis with moment of maximum stress to 4,3; 4,3 and 5,5 days of feed withdrawal, respectively. The hens at day zero had a mean plasma CORT of 1.76 ng/ml with subsequent progressive increase of the hormone until reaches the peak of stress (4.3 days). The H/L ratio had growing linear effect in polynomial regression analysis, with moment of maximum stress to 10 days of forced molted. The enzyme activity of CAT had decreasing linear effect in polynomial regression analysis. For the Pearson correlation coefficients, considering all collection moments, there was not a high correlation between the methods, therefore it is not possible to substitute one method with another. It was concluded that the methodologies of CORT plasmatic levels, H/L ratio, concentration of GSH and activity of the CAT enzyme are indicated to measure stress in commercial laying hens submitted to forced molted induced by feed withdrawal, however, each one has a different moment of maximum stress, making it impossible to use only one method to replace the others / Com o objetivo de avaliar metodologias que indicam estresse em poedeiras comerciais, um experimento foi conduzido no Setor de Avicultura do CAV/UDESC, utilizando 48 poedeiras da linhagem HyLine Brown com 79 semanas de idade. As aves foram alojadas em gaiolas apropriadas e submetidas a um período de muda induzida durante 10 dias de jejum alimentar, avaliando cinco metodologias para indicativo de estresse (concentração de corticosterona plasmática - CORT, relação heterófilo/linfócito - H/L, catalase - CAT, glutationa reduzida - GSH e níveis de substâncias reativas ao ácido tiobarbitúrico - TBARS), em seis dias de coleta de amostras de sangue (zero, dois, quatro, seis, oito e 10 dias do período de jejum alimentar). Adotou-se um delineamento inteiramente casualizado com oito repetições por dia de coleta, sendo cada ave considerada como uma unidade experimental. As coletas para as metodologias CORT e relação H/L iniciaram às 16 h e as demais às 8 h. Para determinar a concentração de CORT e a relação H/L foi coletado sangue da veia ulnar e as demais a veia jugular. Em cada coleta, oito aves foram selecionadas aleatoriamente, e após o procedimento, retornavam às gaiolas. O teste de Shapiro-Wilk foi aplicado para verificar a normalidade dos dados e as variáveis apresentaram distribuição normal. Realizou-se estudo de regressão polinomial para determinar o momento de máximo estresse para cada metodologia. Como todos os métodos fornecem resultados quantitativos foi possível utilizar a correlação de Pearson. Todas as análises estatísticas foram realizadas com o auxílio do pacote estatístico SAS (2009). As metodologias que avaliaram a concentração de CORT, GSH e TBARS apresentaram comportamento quadrático na regressão polinomial com momentos de máximo estresse aos 4,3; 4,3 e 5,5 dias de jejum alimentar, respectivamente. As aves no dia zero apresentaram uma média de CORT plasmática de 1,76 ng/ml, com posterior aumento progressivo do hormônio até atingir o pico de estresse (4,3 dias). A relação H/L apresentou comportamento linear crescente no estudo de regressão polinomial, com momento de máximo estresse aos 10 dias de muda induzida. A atividade da CAT apresentou comportamento linear decrescente na análise de regressão polinomial. Para os coeficientes de correlação de Pearson, considerando todos os momentos de coleta, não houve uma alta correlação entre as metodologias, não sendo possível a substituição de um método pelo outro. Conclui-se que as metodologias da concentração de CORT plasmática, relação H/L, concentração de GSH e atividade da enzima CAT são indicadas para mensurar estresse em poedeiras comerciais submetidas à muda induzida por jejum alimentar, porém, cada uma apresenta um momento diferente de máximo estresse, impossibilitando a utilização de apenas um método em substituição aos demais

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.

O objetivo geral da presente tese é testar a hipótese que a pineal faz parte integrante da resposta ao estresse, da mesma forma que está integrada ao processo inflamatório. Dois modelos de estresse, contenção e frio, foram aplicados aos ratos por 30 min ou 2 horas. Os resultados foram: ausência de úlceras gástricas e TNF em nível sérico por ambos os estresses, apenas aumento de corticosterona; somente em duas horas qualquer um dos estresses aumentou significativamente melatonina da pineal; tratamento tanto com metirapona como com mifepristone aboliram indistintamente os efeitos dos estresses; tratamento tanto com talidomida como com fenilefrina não modificaram os efeitos dos estresses. Concluímos que, o estresse moderado agudo, pela ação da corticosterona, promove modulação da pineal na dependência do estado fisiológico da mesma. Confirmamos a existência de uma relação entre as glândulas adrenais e pineal. Afirmamos que a glândula pineal exerce, além de suas clássicas funções cronobióticas, um papel de grande sensor do estado geral ao organismo inteiro. / The objective of this thesis is to test the hypothesis that the pineal is a player on stress response, likewise that it is one player in inflammatory process. Two stress models, restraint and cold, were applied to the rats for 30 min or 2 hous. The results were: absence of gastric ulcers and TNF serum levels in both stresses, just enhancement of corticosterone plasma levels; only in two hours anyone stress increased significantly pineal melatonin; metyrapone or mifepristone treatment abolish indistinctly the effects of the stresses; thalidomide or phenylephrine treatment did not modify the effects of the stresses. We conclude that the acute moderate stress by the corticosterone action promote modulation of pineal on the dependence of the physiological status of itself. We confirm the existence of a network between the adrenal and pineal glands. We affirm that the pineal gland performs, beyond of its chronobiotical classical functions, one role of the great sensor of internal body state to the whole organism.

O N-metil- 3-4, metilenodioximetanfetamina (MDMA) ou ecstasy tem sido freqüentemente usado por jovens. Analisamos neste trabalho, dentro de uma perspectiva neuroimune, os efeitos da administração aguda de MDMA em parâmetros comportamentais, neuroendócrinos, hematatológicos e imunes de camundongos Balb/C, usando para esta última finalidade um modelo de asma experimental. O MDMA produziu: 1- aumento diferencial da atividade locomotora nas diferentes zonas do campo aberto; aumento na locomoção total e diminuição da atividade exploratória no hole-board; aumento da porcentagem de entradas e da taxa de permanência nos braços abertos do LCE; aumento no tempo gasto na caixa de saída e diminuição do número de acessos de risco em uma caixa de exposição a um predador; 2- aumento dos níveis séricos de corticoterona; 3- aumento dos níveis de noradrenalina no estriado e córtex frontal, aumento nos níveis de dopamina e de DOPAC no estriado, diminuição dos níveis de DOPAC corticais, aumento de 5-HT e 5-HIAA no estriado, diminuição dos níveis de 5- HIAA e do turnover de serotonina no hipotálamo e diminuição do \"turnover\" de dopamina no estriado e córtex frontal; 4- alteração na migração de leucócitos em camundongos alérgicos com diminuição da porcentagem de linfócitos e monócitos circulantes, diminuição do número de granulócitos no lavado bronco alveolar (LBA), efeitos estes que foram revertidos pelo pré-tratamento com RU-486; 5 redução da expressão de L-selectinas por monócitos e tendência de redução da expressão de L -selectinas por neutrófilos no pulmão; 6- diminuição das produções espontâneas de IL-4, IL-5 e IL-10 e de IL-4 em cultura estimulada com LPS; 7- redução da contração da traquéia isolada de animais alérgicos e 8- redução da desgranulação dos mastócitos em brônquios intrapulmonares. Sugeriu-se que o estresse/ansiedade induzidos pelo MDMA tenham ativado o eixo HHA e/ou do sistema nervoso autonômico simpático dos camundongos, alterando a resposta imune dos mesmos na vigência de um modelo de asma. A inflamação alérgica pulmonar desponta, assim, como importante ferramenta para o entendimento da ação de drogas de abuso em processos neuroimunológicos. / The N-metil- 3-4, metilenodioximetanfetamina (MDMA) or ecstasy is a drug widely used amongst young people. This study was undertaken to analyze, under a neuroimmune perspective, the effects of acute MDMA administration on behavioral, neuroendocrine, hematological and immune parameters on Balb/C mice, using for the latter purpose the allergic lung inflammatory response model. It was observed that MDMA produced in mice: 1- a differential increase on total locomotion in the different open-field zones; an increase on total locomotion and a decrease on exploratory activity in the hole-board; an increase on both percentage of entrances and time spent on plus-maze open arms; an increase on time spent in the starting box and a decrease of risk assessments in a predator exposition box; 2- an increase in corticosterone serum levels; 3- an increase in striatal and frontal cortex noradrenaline levels, an increase in striatal dopamine and DOPAC levels, a decrease in cortical DOPAC levels, an increase in striatal 5-HT and 5-HIAA levels, a decrease in both 5-HIAA levels and 5-HT turnover rates in hypothalamus and a decrease in striatal and cortical dopamine \"turnover\" rates; 4- an alteration on leukocyte migration in allergic mice, i.e., decreased percentage of peripheral blood lymphocytes and monocytes, decreased number of granulocytes on bronchoalveolar lavage fluid ( LBA); these effects were reverted by previous RU-486 treatment; 5- a decrease in L-selectin expression by monocytes and a tendency towards a decrease in L-selectin expression by lung neutrophils; 6- a decrease on expontaneous production of IL-4, IL-5 e IL-10 and IL-4 in LPS-stimulated cultures; 7- a decrease in the contraction of allergic mice isolated trachea; and, 8- a decrease in bronchial mastocytes degranulation. It was suggested that MDMA-induced anxiety/stress symptoms increasing HHA-axis and/or the autonomic nervous system activities this leading to the immune changes observed presently in the allergic lung inflammation model of asthma used. This model, thus, emerges as a useful tool for the understanding of neuroimmune effects of drugs of abuse.

Background Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1–21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animal's lifetime. Methods In Experiment 1, both male and female rats were treated with quinpirole or saline from P1–21 and tested on the place and match-to-place versions of the Morris water task (MWT) from P22–28. In Experiment 2, both male and female rats were administered either acute or chronic injections of quinpirole (1 mg/kg) or saline beginning on P1 until analysis for corticosterone (CORT) on P7, 14, or 21. Results Neonatal quinpirole treatment produced deficits on both versions of the MWT compared with saline control. One day after behavioral testing, brain tissue was harvested, and the hippocampus was analyzed for nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF); NGF was found to be significantly decreased by neonatal quinpirole treatment. Acute or chronic quinpirole treatment on P14 produced a larger increase in CORT than controls and produced larger increases in CORT than control rats on P21. Conclusions These results demonstrate that neonatal quinpirole treatment produces cognitive deficits that could be related to decreases in hippocampal NGF and increases in CORT, resulting in abnormalities in hippocampal development.

No description available.

Cushing's syndrome and glucocorticoid therapy lead to central obesity, insulin resistance, and symptoms of altered energy regulation similar to those observed in the metabolic syndrome. We hypothesized that excess glucocorticoids alter energy sensing/signaling in skeletal muscle through mediation of the LKB1/AMPK signaling pathway. To test this hypothesis, three 100 mg pellets of corticosterone were implanted subcutaneously in each of nine rats for two weeks. Responses were compared with sham operated controls fed ad libitum or food restricted to produce the body weights similar to the treatment group rats. After the treatment period, animals were anesthetized and the right gastrocnemius-plantaris and soleus were removed for analysis. After tibial nerve stimulation for 5 min, the left gastrocnemius-plantaris and soleus were also removed. We assessed AMPK activity and subunit expression, as well as several metabolic indicators including ATP, creatine phosphate, creatine, glycogen, and malonyl-CoA levels in rested and stimulated gastrocnemius-plantaris and soleus muscles. We found that high levels of glucocorticoids decreased AMPKγ3 subunit expression in the gastrocnemius-plantaris. We also observed reduced AMPKα2 activity in the stimulated gastrocnemius-plantaris, but not the soleus; and that this decreased activity corresponded to a significant reduction in phosphorylated TBC1D1, a protein involved in signaling GLUT-4 translocation. Finally, in the gastrocnemius-plantaris, we also noted an increase in glycogen stores in the hypercorticosteronemic rats. Our data suggest that altered energy sensing/signaling associated with high levels of glucocorticoids may be due in part to inhibition of AMPKα2 activity and the high energy state produced by increased glycogen stores. We also conclude that high levels of glucocorticoids decrease the levels of AMPKγ3 and diminish insulin/contraction signaling through phosphorylated TBC1D1.

Despite the lack of robust clinical response, treatment strategies for cancer-induced depression (CID) are currently limited to those developed for non-cancer-related depression. The work presented in this dissertation conceptualizes CID as a pathophysiologically distinct form of depression. To investigate CID at the most basic level, we first developed a preclinical model that was validated by comparison to an established model of stress-induced depressive-like behaviours. The positive control model was developed by chronically treating female BALB/c mice with oral corticosterone (CORT). The CID model was developed using subcutaneous inoculation with 4T1 mammary carcinoma cells. Anhedonia, behavioural despair, and dendritic atrophy in the medial prefrontal cortex (mPFC) were observed in both models. Similar to many human cancer cell lines, 4T1 cells were shown to secrete significant amounts of glutamate, which was markedly attenuated using the system xc- inhibitor sulfasalazine (SSZ). In CID mice, oral treatment with SSZ was at least as effective as fluoxetine, a popular clinical antidepressant, at preventing depressive-like behaviours. This effect was primarily attributable to intact SSZ, rather than its anti-inflammatory metabolite. RNA-sequencing was performed on hippocampal samples from CID and CORT animals. Analysis of differential expressed genes (DEGs) revealed significant overlap between the two models. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and biological process gene ontologies (GO:BP) terms related to ion homeostasis and neuronal communication were enriched for both models. CID was associated with additional DEGs that were not identified in the CORT model. These DEGs were enriched in KEGG pathways and GO:BP terms related to neuronal development, intracellular signalling cascade, learning, and memory. These studies suggest that CID may involve a distinct aetiology, and that glutamate secretion by cancer cells presents a viable target for antidepressant treatment. The development of mechanism-based therapeutics for CID will dramatically improve the quality of life for cancer patients. / Thesis / Doctor of Philosophy (PhD) / Cancer patients are at a high risk of developing depression. In addition to the psychological stress caused by a cancer diagnosis, there is evidence that cancer causes depression through biological pathways. To investigate these pathways, a mouse model of cancer-induced depression (CID) was developed. This model showed comparable behavioural and structural brain deficits to those observed in a stress model of depression. Cancer cells secrete elevated levels of glutamate, a signalling molecule that is involved in depression. In CID mice, inhibiting glutamate release had an antidepressant effect similar to that of fluoxetine, a standard clinical antidepressant. A genetic analysis on brain samples from the CID model revealed significant overlap with the stress model of depression. CID mice had additional changes relevant to learning, memory, and brain cell development that were not detected in the stress model. A better understanding of CID will lead to better treatment strategies developed specifically for cancer patients.

No description available.

No description available.